Topic list final physio 2019

6.2. Hemostasis and the role of trombocytes.

Hemostasis ​refers to the arrest of bleeding after injury, involving a large variety of pro and anticoagulants that allow repair while also avoiding thrombosis and bleeding disorders. This system is a complicated balance of positive and negative feedback mechanisms using a variety of clotting factors/enzymes, platelets, fibrin and anticoagulant proteins, WBCs and RBCs to form a plug. Three mechanisms act to stem the flow of blood: vasoconstriction, platelet aggregation, and blood coagulation. Hemostasis is divded into primary and secondary hemostasis: PRIMARY HEMASTASIS: refers to the immediate vasoconstriction, the platelet activation and then the blood coagulation that occurs minutes after that SECONDARY HEMASTASIS:is the later formation of the fibrin mesh network that stabilizes the clot. At some point this is followed by fibrinolysis as the fibrin network is degraded. Hemostasis steps: VASOCONSTRICTION: 1)Upon injury of the blood vessel wall, there is an immediate contractile response called vasoconstriction​ that is evoked first due to endothelin release and neurogenic reflex, then by locally released vasoconstrictor substances (thromboxane A2, serotonin, adrenaline, extracellular K+ ions). However, the main purpose of vasoconstriction is to give time for the more effective hemostatic processes to take place. PLATELET ACTIVATION: 2)The next phase consists of platelet adhesion, activation, and aggregation.​ Within seconds of an injury, platelets begin to adhere to the injured area, and this initial adherence activates the platelets. Activated platelets release ADP a​ nd thromboxane A2,​ which cause additional platelets to adhere. The platelets aggregate to form the thrombus/plug, which will block the small blood vessels of the injury. Platelets are prevented from aggregating along a normal vessel by the action of NO​ and prostacyclin,​ which are released from uninjured endothelial cells, and this also keeps the thrombus from getting too big. 3) Platelets ​(also called thrombocytes, derivatives of megakaryocytes) are the main actor in primary hemostasis. The major functions of platelets are (1) adhesion and aggregation with each other (2) formation of a phospholipid surface for blood coagulation factors, and (3) secretion of granules with biologicallyactive molecules. They are small and sphericallyshaped with glycoproteins​ and glycoprotein receptors,​ a dense tubule cytoskeleton (that acts as a mobile calcium storage), dense granules​ (containing ADP, serotonin, and polyphosphates to activate platelets), α granules​ (produced by the liver but stored in platelets, contain clotting factors), and actin/myosin​ for later contraction to reduce the size of the clot. Platelets first adhere to the injured space via glycoproteincollagen binding with glycoprotein GP VI and GP IaIIa. This interaction initiates a tyrosine phosphorylation cascade (IP3 calcium release) that initiates nearby platelet activation. Endothelial cells also release the von Willebrand factor (vWF)​ that allows another platelet glycoprotein to bind to the injury area and is also used as part of the coagulation cascade. There is a weak connection between platelets and collagen via GP VI and GP Ia/IIa to surface integrins, and a stronger connection via GP IbIXV and vWF (know that the connection is made stronger when vWF is involved, and not just the glycoproteins). REGULATION OF PLATELET ACTIVATION: Platelet activation is increased by TXA2​ production (from arachidonic acid via ​ phospholipase A2/ cyclooxygenase pathway, inhibited by aspirin) and thrombin​ binding the thrombin receptor (which cleaves a peptide → conformational change → activation). Serotonin and epinephrine​ also activate platelets. When platelets are "activated," this means that there is a calcium release​ that allows the thrombocyte cytoskeleton rearrangement, shape change, and secretion of clotting factors. The shape change of platelets is associated with a disassembly and reassembled cytoskeleton to make the thrombocyte larger and bind better to other platelets. This increases platelet aggregation. Another important change in activated platelets is the change to make their cell surface contain more negative charges. This occurs by flipping phosphatidylserines​ to the surface, which leads to plug formation and aids in the formation of the coagulation factors. Coagulation cascade is covered in the next topic. Note that if the cut in the blood vessel is very small, the cut may be sealed by a platelet plug and not a blood clot.

2.1. Impulse generation and conduction in the heart. Mechanism of pacemaker potential. Control of pacemaker activity and impulse conduction.

IMPULSE GENERATION: The heart consists of contractile cells and conducting cells. The conducting cells are primarily responsible for impulse generation and pacemaker activity of the heart found in the SA node of the right atrium, just lateral to the inlet of the SVC. They do not generate much force, just rapidly spreading potential. FREQUENCY OF CONDUCTING CELLS: -SA : 70-80/min -AV: 40-60/min -purkinje fibers : 20-40/min IMPULSE CONDUCTION: -Conduction of cardiac AP's takes place via local currents of depolarizing regions of cells to regions which remain at Em (Na+ inward current in ventricular myocytes, and Ca2+ in SA/AV nodes) -The current then spreads from cell to cell through gap junctions between the intercalated discs of the myocytes. -There are 2 factors which affect the conduction velocity: --> size of the inward current: the higher the inward current, the faster the conduction -->resistance: -low R due to the gap junctions leads to fast conduction and the large diameter conduct faster CONDUCTION VELOCITY OF CONDUCTING CELLS: -SA node: <0,01m/s -Atrial myocytes: 1-1,2 m/s -AV node: 0,02-0,05 m/s -bundle of his: 1,2-2,0 m/s -purkinje fibers (large diameter): 2-4m/s -ventricular myocytes: 0,3-1,0m/s --> Nodal cells (AV, SA) conduct more slowly due to their SLOW RESPONSE AP'S (will get back to it) --> The fastest conducting fibers are purkinje as their diameter is about 70-80mikro m --> the SLOWEST conduction velocity takes place in the AV node in order to delay ventricular contraction and allow time for ADEQUATE VENTRICULAR FILLING DURING DIASTOLE. -----> The transmission between sa and av, takes about 100ms due to: -electrical insulation - fibrous skeleton of heart -small diameter of the conducting fibers - the AV bundle must cross the fibrous tissue with it's PENETRATING FIBERS which have very thin fibers, thus low conduction velocity SO, ROUTE OF CONDUCTION GOES AS FOLLOWS: SA --> AV --> bundle of his -->taware branches -->purkinje fibers -->ventricular myocytes -The normal sinus rhythm is the pattern and timing of electrical activation of the heart. To have a NORMAL SINUS RHYTHM: --> AP's must originate from SA node --> impulses must occur at a regular rate of 60-100 impulses/min --> and the activation of the myocardium must occur in the correct sequence with the right timing NERVOUS CONTROL OF IMPULSE CONDUCTION: -CALLED DROMOTROPIC EFFECT (speed/velocity) -positive dromotropic effect: SY mediated! increase in ca2+ current which is resp for the upstroke of AP in AV and SA -Negative dromotropic effect: PSY mediated, decrease ca2+ current and increased K+ current. Mainly done via the LEFT VAGUS NERVE innervation of av node. MECHANISM OF PACEMAKER POTENTIAL: -The Ap's in SA and AV nodal cells are "SLOW RESPONSE" ap's, whereas the contractile cells and other parts of the conduction system produce "FAST RESPONSE" ap's! 1)If channels open at -50mV causing a funny current = influx of Na+ via HCN channels (hyperpolarization-activated cyclic nucelotide-gated cation channel), which slowly depolarizes the cell --> THIS IS THE PACEMAKER POTENTIAL/ PRE-POTENTIAL! 2) At -40mV, initial depolarization begins as T-type voltage gated Ca2+ channels open allowing ca2+ influx 3)at -25mV, L-type VD ca2+ channels open (t-type inactivate at this point) causing further depolarization 4) Repolarization begins as several types of VD K+ channels open to let K+ out CONTROL OF PACEMAKER ACTIVITY: -The pace of the pacemaker activity is controlled by SY and PSY -They change: --> MINIMUM DIASTOLIC POTENTIAL (most neg Em value) --> SLOPE OF PREPOTENTIAL (rate of depol via the funny current DRAW GRAPHS!: SYMPATHETIC CONTROL: -will have a positive chronotropic effect -NE --> Beta1 rec --> Gs --> ^cAMP which binds to the HCN If channels to increase their activity and the slope of the prepot. PARASYMPATHETIC CONTROL: -negative chronotropic effect via the RIGHT VAGUS (SA IS IN THE RIGHT ATRIUM) -negative dromotropic effect VIA LEFT VAGUS --> AV NODE) -Ach--> M2 receptor --> Gi --> decr cAMP and Gibeta,gamma --> decreaed funny current due to the cAMP and increased GIRK (inwardly rectifying K+ channels responsible for hyperpol. They lengthen the time for pacemaker potentials to reach the treshold) DRAW GRAPH: -Both Sy and PSY affect the heart at the same time and balance each other's activities, HOWEVER, the PSY effect is stronger --> blocking beta1 receptors aka SY effect by PROPRANOLOL only decreases HR by 10bpn -->blocking M2 receptors with atropine increases HR with about 50bpm LATENT PACEMAKERS: In case of SA node failure, other conducting tissues of the heart can take over and initiate pacemaker potentials, because THEY ALSO CONTAIN HCN CHANNELS (!), so the area with the highest number of these channels (after SA ofc) takes over first. --> When the SA NODE IS FUNCTIONAL, there is an OVERDRIVE SUPRESSION, which supresses these latent pacemakers from spontaneously firing. This is taken away when the SA node fails

3.1. Lung volumes. Dead space in the breathing apparatus. Alveolar ventilation. Mechanical properties of the airways, chest wall and lung. Pressure-volume relationship in the respiratory system, surface tension in the alveolus and compliance of the chest wall.

(Draw the graph!) STATIC LUNG VOLUMES: are measured using a spirometer, and include -TIDAL VOLUME= 500ml the normal inspiration and expiration. Air fills alveoli and airways -INSPIRATORY RESERVE VOLUME = 3000mL, is the maximal inspiration someone can breath in above the tidal volume -EXPIRATORY RESERVE VOLUME= 1200mL, is the max exhalation besides the tidal volume -RESIDUAL VOLUME = 1200mL is any gas left in the lungs after the expiratory reserve volume and it cannot be exhaled fully, nor can it be measured using a spirometry LUNG CAPACITIES: -INSPIRATORY CAPACITY: tidal V + Ins reserve V = 3500mL -FUNCTIONAL RESIDUAL CAPACITY (FRC)= 2400mL is measured using the helium dilution and body plethysmography because residual volume cannot be measured with spirometry. This is medically important since, for instance, in emphysema, FRC is increased, because the lungs are more compliant and the equilibrium between the inward recoil of the lungs and outward recoil of the chest wall is disturbed. -VITAL CAPACITY= 4700mL, the max air that can be inhaled and exhaled -TOTAL LUNG CAPACITY = all of the lung volumes = 5900mL DEAD SPACES IN THE LUNGS: relate to the parts that do NOT PARTICIPATE in the gas exchange. There is an anatomical and a physiological dead space! --> ANATOMICAL DEAD SPACE: is the V of the conducting airway including the nose, mouth, trachea, bronchi and bronchioles. The space is about 150ml, se when you take in a tidal breath of 500ml, 150ml of the air does not reach the avleoli for gas exchange. --> PHYSIOLOGICAL DEAD SPACE: is the total volume of air that does not participate in gas exchange, thus is the anatomical dead space + functional dead space of the alveoli. Functional dead space is the space of the ventilated alveoli that do not participate in gas exchnage. This can be due to the lack of pulmonary capillary blood perfusion to the alveoli. In a normal, healthy person, there is very little functional dead space, so this is generally a pathalogical thing. THE BREATHING APPARATUS: The flow of air, like any fluid, moves from a region of higher to a region of lower pressure. The flow of air into the lungs requires a pressure gradient between the atmosphere = 760mmHg (outside) and alveolar pressure (transpmonqry p) inside. This is created by the contraction of the inspiratory muscles. When they contract the chest wall increases in volume and the alveolar pressure decreases to a subatmospheric pressure so that air will flow into lungs. THE MECHANICAL PROPERTIES OF THE APPARATUS: -Muscles of inspiration: diaphragm via the phrenic nerve (during exercise: ext intercostal muscles, scalenes) -Muscles of expiration: is a passive process, but during exercise the internal intercostal abd abdominal muscles are important for compressing the thorax The mechanical properties of the lung is embodied in it's elasticity and compliance (which can be further reflected in the pressure-volume relationship of the lung). This can be a method of recognizing pathological diseases of the lung such as emphysema and fibrosis. The lungs have a pariteal pleura (connected to the chest wall) and a visceral pleura (connected to the lungs), which are separated from each other via a thin layer of pleural fluid. The intrapleural pressure is negative, meaning that it is lower than the atmospheric pressure as explained previously in the air flow movement of the lungs. This aids the elasticity (returning to it's original shape) of the lung and helps keep the alveoli open, and thus allow gas exchange to occur. The transmural pressure is just the difference of p between the inside of the lung and the intrapleural p. TRANSMURAL P= alveolar pressure - intrapleural pressure. It is about -2 - -4mmHg and is important as it overcomes the lung's tendency to retract as the chest wall is increasing. So the transmural pressure is the force that keeps the lungs open. If air comes into the pleural cavity, pneumothorax occurs where the intrapleural pressure and the atmosphere equalize and thus the lungs collapse. Another aiding factor in keeping the lung open is the surfactant, which is a lipid layer produced by the type II pneumocytes. Surfactant lowers the surface tension of the lungs and increases compliance (as alveoli themselves have a tendency to retract due to elastic fibers and as it is energetically favorable to have a minimal surface area) thus making it easier to inspire. Surfactant (with the aid of transmural pressure) also keeps alveoli slightly open, keeping them from collapsing. We need the resistance that the liquid, lipid, surfactant provides since a gas's complience is higher for exhalation than inhalation, which would cause hysteresis. The surface tension of the surfactant molecules are stronger at the beginning of inhalation, thus aiding gas exchange by lowering the complience of inhalation. (There is a graph I need to draw!) There should be a balance between the compliance and elasticity of the lung but in the disease emphysema, the compliance of the lung is increased as the wall is too soft and thus inhaling isn't a problem, however exhaling all the air present in the lungs is a problem as the elasticity of the lungs are decreased and thus the start volume of inspiration is elevated which is not good. In fibrosis, compliance is decreased and the elasticity of the lung is increased. So breathing in and expanding lung volume is problematic due to the stiffness of the lung walls, while expiration isn't a problem ALVEOLAR VENTILATION: Alveolar ventilation is the exchange of gas between the alveoli and the external environment. It is the process in which O2 is brought into the body from the outside. There is a alveolar ventilation equation which shows the relationship between the alveolar ventilation and the alveolar or arteriolar pCO2. It is critical to understand that the rate of CO2 production in the body can be taken as a CONSTANT (assuming that you are not doing any physical work), so therefore an increase in alveolar ventilation causes a decrease in the alveolar/arterial pCO2. Alveolar and arterial pCO2 can be used interchangeably to write either alveolar or arterial pCO2 because alveolar CO2 partial pressure is equilibrated with the arterial CO2 pp, unless there is additional functional dead space. (Look at the pic and draw the equation + the graph)å

5.5. Degradation and absorption of nutrients. Absorption of water, potassium and sodium. Absorption of iron and vitamin B12.

Digestion is the chemical breakdown of ingested foods into absorbable molecules. Absorption is the movement of nutrients, water and electrolytes from the lumen of the intestine into the blood. There are two possible paths for absorption: the cellular path where the substance must cross the apical membrane, and the paracellular path in which substances move across the tight junctions between intestinal epithelial cells. The structure of the intestinal mucosa is ideally suited for absorption of large quantities of nutrients. Structures such as the fold of Kerckring the villi and the microvilli increase the sotal surface area by 600-folds! Degradation of carbobohydrates: Only monosaccharides are absorbed by the intestinal epithelial cells. These include glucose, galactose and fructose. (Draw picture to aid explanation) alpha-amylase (salivary), pancreatic amylase digest starch into alpha-dextrins, maltose and maltotriose. These disaccharides are further digested into glucose by alpha-dextrinase, maltase, sucrase. Trehalose, lactose and sucrose is digested by trahalase, lactase and sucrase. Absorption of carbohydrates (must be able to draw this): Glucose and galactose is absorbed by mechanisms using Na+-dependent cotransport. Glucose and galactose are absorbed by secondary active transport, using the Na+-glucose cotransporter (SGLT1) against an electrochemical gradient. The energy for this step is created by the Na+/K?-ATPase in the BL memb. Fructose is absorbed using facilitated transport (GLUT5). Essential aa's: Phe Val Thr Tryptophan Isoleucine Met His Ala Leu Lys Digestion of proteins occur in the stomach and small intestine. By the action of pepsin in the stomach (which is activated from it's pro form, pepsinogen by HCL in the stomach), pancreatic and brush-border proteases. The endopeptidases (pepsin, trypsin, chymotrypsin, elastase) hydrolyze the interior peptide bonds of proteins. The exopeptidases (carboxypeptidase A and B) hydrolyze one aa at a time form the C-terminal end of the proteins. The first step in the intestinal protein degradation is the activation of trypsin from trypsinogen by the brush-border enzyme enterokinase. A small amount of trypsin is produced, which catalyzes the conversion of all the other enzymes as well. FINALLY, THE PANCREATIC PROTEASES DIGEST THEMSELVES AND EACH OTHER. ABSORPTION OF PROTEINS: IMP: carbs are absorbable ONLY in their monosaccharide form, while proteins are absorable in larger units, both dipeptides and tripeptides. L-aa's are absorbed like the monosaccharides with Na+-aa cotransported energized by the Na+ gradient. However, most ingested protein is absorbed in the dipeptide and tripeptide forms, in which they are taken up by H+-peptide cotransporter, which is driven by an H+-gradient created by the Na+-H+ exchanger, and then they are further digested into aa's by cytosolic peptidases inside the cell. These exit the cell and enter the blood by fascilitated diffusion. Absorption of lipids (fyll gjerne inn mer detaljer en annen gang): Lipids are digested to monoglycerides, FFA's, cholesterol and lysolecithin by pancreatic enzymes. The products of the lipid digestion is solubilized in micelles with bile acids since lipids are hydrophobic. At the apical membrane of the intestinal cells, the lipids are released from the micelles and diffuse into the cells. When they are inside, they are packaged (SER (adds the lipid droplets)-->golgi<--RER(gives the apoproteins) into chylomicrons and transferred into lymph vessels by exocytosis. Absorption of iron: total: 4g daily loss: 0,1g Iron is absorbed across the apical membrane as free iron or as heme iron. The free iron has to be in the ferrous state (Fe2+) to go through the transported DMT-1 on the apical membrane. Inside the intestinal cells, heme iron is digested by lysosomal enzymes, releasing free iron, fe2+. The free iron absorption is dependant on pH as ferric (Fe3+) salts ARE NOT soluble at pH7, whilst Fe2+ ARE! The free iron enters the duodenal apical membrane driven by the H+-gradient maintained by Na+/H+. Heme also enters. Heme is oxygenated, Fe3+ is reduced to Fe2+ and leaves the cell through ferroportin (can only transport fe2+). Fe2+ is then oxidized into fe3+ and binds transferring to be transported in the blood. Absorption of VitB12: The water-soluble vitamins include vit C, B1, B2, B6 and B12 which is a fairly easy process in which they are absorbed via an Na+-dependent cotransport in the small intestine. However, with vitB12 (cobalamin) it is a bit more complicated as it requires intrinsic factor from the stomach. Vit B12 is bound to proteins in food and the the acidic pH in the stomach releases it from the diatery proteins. VitB12 then binds to haptocorrin, which causes the parietal cells to release intrinsic factor. Due to the alkaline pancreatic juice, haptocorrin is degraded and released from vitB12. Now IF and VitB12 binds and forms a complex that can be absorbed by the ileum via receptor mediated phagocytosis. Absorption of water, K+ and Na+: The colon has a standing osmotic gradient for absorption of water. This is created by the Na+ pumps in the apical membrane of the intestinal cells which pump Na+ into the cell (reabsorbing it), creating a hypotonic fluid inside the lumen of the colon. Water follows the Na+ through paracellular absorption via the tight junctions. K+ is secreted in the colon via the Na+/K+-channels which are upregulated by aldosterone. This explains how having diarrhea causes an increased K+ secretion and hypokalemia by increased loss of K+ in the feces.

6.7. The human blood group systems. Blood transfusion procedures. The anaphylactic reaction

A BLOOD GROUP is a classification based on the presence or absence of heriditary ANTIGEN'S on THE SURFACE OF RBC'S. There are MORE than 300 different known RBC surface antigens, but most of them are weak ag's which have little significance in blood transfusion!!! The two systems which actually have importance in medicine is the: -ABO --> the ag's are actually several different sugars which are synthetized by a series of glycosyl transferase enzymes. The blood type depends on which of these ag's they have present on their RBC's and thus, also WHICH OF THE ENZYMES ACTIVITIES THE PERSON EXPRESSES -Rh --> this system consists of around 50 defined ag's BUT the c, e, d, C, E and D ag's are the most important (really, only the D antigen is the important one that we check for +/-) blood grouping systems as their AG's actually induce very strong immune responses! ABO SYSTEM, THE ANTIGENS: H-ANTIGEN: -absolutely ALL individuals express this enzyme FUCOSYLTRANSFERASE which results in an ag containing a terminal FUCOSE molecule on the RBC surface. - If this is the only ag present, then the individual has blood type 0! A-ANTIGEN: -if an individual expresses an additional enzyme, other than the fucosyltransferase called the N-ACETYLGALACTOSAMINE TRANSFERASE, then the H-antigen will have a N-ACETYLGALACTOSAMINE bound to it, which creates the A antigen! -Presence of the A antigen results in blood type A! B-ANTIGEN: -If an individual expresses the activity of the enzyme GALACTOSYLTRANSFERASE, then the H-antigen will have additional GALACTOSE bound to it, producing the B antigen - Presence of the B antigen results in blood type B BLOOD TYPE AB: -is formed when both the enzymes for the ag A and ag B is coexpressed! INHERITANCE OF THE ABO BLOOD TYPES: -Involves the co-dominance of A and B alleles and recessive O allele. Aka, we have 4 phenotypes and 6 different genotypes (AA, BB, AB, OO, AO, BO). -It is important to state that the abo alleles are not evenly distributed throughout the population and the frequency actually vary among the different races also! FREQUENCY OF THE BLOOD TYPES: O+ and A+ most common and the AB groups are least common!!! O+: 37% O-: 8% A+ : 33% A- :7% B+ : 9% B- : 2% AB+ :3% AB- : 1% IMPORTANCE OF ABO TYPING IN BLOOD TRANSFUSIONS: -Results from the fact that individuals who do not express an ag will produce ab's (IgM type ab's which doesn't cross the placenta!!!) towards it as we get exposed to the ag's through bacteria, plants and food. -The infusion of the wrong blood type will result in binding of the non-self ag's by these ab's and subsequent complement activation, phagocytosis and intravascular hemolysis of the RBC's!!! (THERE IS A TABLE. SO JUST REMEMBER THAT IF YOU HAVE THE AG, THEN YOU DO NOT EXPRESS ANTI-ANTIBODIES TOWARDS IT. This means that the O blood type will not have any ag's and thus anti-A ab's and anti-B ab's and can't get blood from any other people than people with the same blood type. People with blood type AB, does have a lot of ag's and thus, they do not have anti- antibodies and can get blood from everyone!) RH BLOOD GROUP: -as said before, it is the D antigen that is most important when it comes to the rh blood grouping. The D antigen is a protein that acts as a GAS CHANNEL for NH3 or Co2 -It is inherited dominantly -Rh negative people do not express the D ag -Anti-D is an antibody of the IgG type, meaning that is can cross the placental barier. This means that when Rh NEGATIVE mothers carries their Rh+ fetus, they are exposed to the antigen for the first time and produces antibodies against it. HENCE, if the mother gets pregnant again with another Rh+ child, the anti-D ag's will produce an immune response to the D-antigen and cause RBC lysis, which will eventually harm the fetus!!!! This can be prevented by: -preventing mixing of the maternal and the fetal blood by c-section -or by injecting preventative anti-D antibodies into the mother before delivery which neuttralize the D-ag from the child's blood and prevents it being recognized by the maternal immune system! BLOOD TRANSFUSION PROCEDURES: When doing a blood transfusion, both the donor blood and reciient blood should be tested for ab's against each other in what is called a TWO-SIDED TEST (on the lab exam). What we check for is agglutination (ab-ag complexes that clump together). It is important to state that something called COLD-AGGLUTINATION can occur because an ag called: cold-agglutinin can bind to the ab's if the temperature becomes lower, so it is important to do this experiment with prewarmed blood (body temp). If the wrong blood is given somehow, then antihistamines should be given to prevent anaphylactic shock. If the response is serve and life-threatening, then CORTICOSTEROIDS should be given to inhibit the immune response and EPI could also be given! THE ANAPHYLACTIC REACTION: Release of chemical mediators stored in mast cells promotes the allergic reactions known as IMMEDIATE HYPERSENSITIVITY REACTIONS, because they occur within a few minutes after penetration by an antigen of an individual previously sensitized to the same or a very similar ag. The steps in an anaphylactic reaction are the following: 1) First exposure to the allergen (example is bee venom), results in production of IgE ab's by plasma cells. 2) The IgE's then bind to mast cells which are mostly find in the dermis, respiratory tract and GI (some people have a theory that they bind to basophils and convert them to active mast cells later) 3)When a second exposure comes to the allergen, and the allergen binds to the Ige's on the mast cells, it triggers the release of the mast cell granules containing: histamine, leukotrines, ECF-A and heparin (the degranulation of the mast cells results from activation of the complement system and the C5a and C3a does this) 4)Histamine causes contraction of smooth muscle (bronchioles for ex) and dilates + increases blood vessel permeability (hence the red face, dramatically lowering the BP and hard breathing)

3.2. Gas exchange in the respiratory system. The pulmonary circulation. Ventilation-perfusion relationship

GAS LAWS: -BOYLE'S LAW: If volume of a container increases, then the gas pressure increases. So if lung volume decreases then alveolar gas pressure increases, hence air flows out of lungs -> expiration. -DALTON'S LAW: In a gas mixture the pressure exerted by each individual gas in a space is indep of the pressure of other gases in the same mixture. The partial pressure of o2 is 159mmHg because o2 is 21% of the total atmospheric gas volume. So 21% of 760mmHg is 159mmHg -HENRY'S LAW: The partial pressure of gas in the liquid phase is equal to the pp of gas in ha phase. O2 in alveoli is same as arterial o2 pp --> in blood, there are 3 forms of gases: -FREE -BOUND: like o2, CO2 and CO which is bound to hbg -CHEMICALLY MODIFIED: only nitrogen gas is never modified or bound. Chemically modified gases is for ex when CO2 is changed to bicarbonate GAS EXCHANGE: Mixed venous blood comes through the right side of the heart, branches into pulmonary capillaries and the partial pressure differences between the alveoli (o2:100mmHg, CO2: 40mmHg, H20: 47mmHg) and the capillary (O2: 40mmHg, CO2: 46mmHg, H20: 47mmHg) are the driving force of the gas exchange, -The PHYSIOLOGICAL SHUNT is a small fraction of blood that bypasses the alveoli and is not arterialized, therefore leading to a slightly lower pO2 (95mmHg) due to the bronchial arteries and the coronary venous blood flow, which both go directly into the left ventricle rather than going through the pulmonary circulation DIFFUSION VS PERFUSION LIMITED GAS FLOW: -->DIFFUSION LIMITED GAS FLOW: means the total amoun tof gas transported across the alveolar barrier is limited by the ability of the gas to diffuse fast enough --> PERFUSION LIMITED GAS FLOW: the amount of gas transported across the barries is limited to the blood flow (perfusion). In these cases the only way to increase the blood flow is to increase the blood flow. -----> O2 diffusion in the lungs is usually perfusion limited! -Normal pulmonary blood gets oxygenated in 0,25s, but the blood stays in the capillary for 0,75 seconds. Meaning that blood IS SATURATED LONG BEFORE IT LEAVES THE CAPILLARY! This is perfusion-limited gas flow! (At high altitudes, the driving force for gas exchange changes as the atmospheric levels of O2 and CO2 changes, thus the complete saturation happens more slowly) PULMONARY CRICULATION: The pulmonary blood flow equals the blood of the right heart. -However, the pulmonary blood flow has a much lower pressure and resistance. -When there is a decrease in O2, contrary to the reaction of the systemic circulation, the pulmonary capillaries will vasoconstrict since the blood might need to be redirected to a better ventilating alveoli, or they all constrict to slow down the blood flow of pulmonary capillaries so that the low O2 levels have time to saturate, allowing the ideal ventilation/perfusion ratio. ---> NOTE THAT IF THERE IS CHRONIC HYPOXIA THEN PULMONARY VASOCONSTRICTION CAN CAUSE PULMONARY HYPERTENSION, that the right ventricle is not equipt to deal with. This causes HYPERTROPHY/enlargement of the right ventricle as it has to pump against a higher resistance now! EFFECTS OF GRAVITY ON PULMONARY BLOOD FLOW: -Blood flow and ventilation is lower at the top of the lung compared to the bottom of the lung. Due to: -gravity, when standing causes more of the blood to flow to the bottom of the lung due to the difference in hydrostatic pressure -The alveolar pressure is higher at the top of the lung, since the lung is pulled down a bit when standing, so the volume increases at the top part, causing a more neg alveolar pressure (-10mmHg =top, vs -2mmHg = bottom), the alveoli are more open due to this and thus, there is better alveoli at the top part of the lung. VENTILATION/PERFUSION RELATIONSHIP: -the ratio should be around 0,8 on average, meaning that alveolar ventilation (l/min) is 80% of the pulmonary blood flow: 8L o2 for 10L blood) -Due to the low blood flow at the top of the lung, the ratio is actually quite high here, and since there isn't that much blood to perfuse, the Po2 levels are high, and pCO2 is low since it isn't that much blood and thus time to carry out the exchange! (low/low = high). HUSK, Q= LOW, V=LOW, Q/V=HIGH, pO2=HIGH, pC02= low!!! If there is a defect or inefficiency in the V/Q ratio, either ventilation or perfusion tries to balance it back. EMBOLISM: high ratio, since the blood perfusion is limited EXERCISE: low ratio, because both perfusion and ventilation increases

6.4. The physiological role and function of phagocytes.

INNATE SYSTEM: Phagocytes are a key component of the INNATE immune system​. This system is the way the body defends itself from pathogens without requiring any adaptive response. It includes: ● Physical barriers, such as skin and the mucosa of the gastrointestinal tract ● Circulating effector proteins, such as the complement system and antimicrobial peptides ● Cytokines such as TNFα and IL1 ● Innate immune cells, that being the phagocytes​ and natural killer cells The innate immune system is responsible for the initial, immediate response to infection by pathogens. The cells and responses involved are relatively nonspecific and recognize common patterns that are typical of many viruses, bacteria, worms, or fungi. If the innate immune response is not strong enough to fight off an infection, the adaptive immune system​ takes effect and produces specific antibodies that can target these pathogens. PHAGOCYTES: Phagocytes include: -Neutrophils 60-72% --> mostly associated with bacterial infections. -Eosinophils 2-4% --> Their granules are MAJOR BASIC PROTEIN (MBP), which produce ROS's. Are mostly effective against multicellular parasites, such as worms and larvae -Basophils 0,5-1%--> They synthetize lipid mediators such as leukotrienes and produce cytokines. They also, like mast cells, release histamine to induce inflammation and heparin to prevent blood clotting. They are responsible for inflammatory reactions during the immune response as well as allergic reactions -Monocytes 3-8% --> Called monocytes when in the circulation and then they differentiate into macrophages and dendritic cells (important link between the innate and adaptive systems as they activate the Th cells) when they migrate into tissues. They produce TNFalpha to activate neutrophils and monocytes. Important in viral infections -dendritic cells --> APC's to T helper cells to activate them -(NK's are technically not phagocytes as they are similar to lymphocytes and differentiate from the lymphoid cell lineage, BUT they do have similar functions to phagocytes and are also part of the innate immune system) ^They all originate in the bone marrow from the myeloid cell lineage similarly like RBC's and platelets. LEUKOCYTE MIGRATION: Migration is initiated by endothelial cells and increased migration is initiated by cytokines. WBC's migrate to their destination in 4 stages: -ROLLING: in the blood vessels across the endothelial cells. This first occurs due to a "danger" signal via selectins, where carbohydrates are the ligands -ADHESION: to the endothelial wall. This is mediated by integrins and one important ligand is the ITAM peptide -DIAPEDESIS/TRANSENDOTHELIAL MIGRATION/EXTRAVASATION: The leukocytes squeezes between the endothelial cells and moves to the interstitial space. Mediated by integrins also -MIGRATION: to the destination that needs it via chemotaxis. Chemokines (CC, CXC) and chemoattractants (small microbial-derived peptides) mediate this. G-coupled transmembrane proteins are also involved in this process HOW DOES THE PHAGOCYTES OF THE INNATE SYSTEM FUNCTION: So, the innate system recognizes special molecular patterns present on microorganisms, but not the body's own cells called PAMPs (pathogen-associated Moelcular patterns) -Examples of PAMP's: --> LPS (liposaccharide) and plagella er present on bacteria -->dsRNA are present on viruses -->beta-glucans present on the cell wall, which is indicative of fungi The cells of the innate system can recognize these PAMP's using their special receptors called PRRs (pattern-recognition receptors). Some important PPR's: -Toll-like receptors: are special as they recognize both viruses and bacteria using different parts of their structure. The i.c = recognizes viral components The e.c= recognizes the bacterial components --> In response to recognizing non-self structures, the TLR's produce and upregulate adhesion molecules on the cell surface. -Mannose receptor -Scavenger receptor -I.C Nod like receptor PHAGOCYTOSIS: is the uptake of microbes by phagocytes, which involve the direct attachment of phagocytes to microbes via their PRR's to initiate the process. The wanted result, is for the cell to opsonize the microbe. Opsonization is the coating of pathogens and foreign particles with ab's and compliment proteins so that a phagocyte can eat them. --Phagocytes can bind to a microorganism without ab's or complement fragments, HOWEVER THE DEGREE OF BINDING IS FAIRLY LOW. --The phagocyte will bind slightly better if the pathogen is coated in Ig's --It will bind even better if it is coated in only C3b proteins --The best binding of a phagocyte to a microbe is when the microbe is coated WITH BOTH AB'S AND c3b. After binding to the microbe, the phagocyte will envelop the microbe and ingest it. Then, lysosomes come and destroy the microbe with enzymes and ROS (reactive oxygen species) via oxidative bursts. Additionally, degranulation of the granulocytes occurs, in which antimicrobial molecules are released from the granules of the granular phagocytes. --> NK and mast cells can also go through this!!!

2.9. Local control of circulation. Myogenic, humoral control mechanisms. Functional and reactive hyperemia.

LOCAL CONTROL MECHANISMS: -AUTOREGULATION: "Bayliss effect" - the maintenance of constant blood flow to an organ despite changing arterial pressure. This controlling of flow is only applicable when arterial pressure is neither too high nor too low (THERE IS A GRAPH). Many organs show their own autoreg curves, such as kidney's, brain, heart and skeletal muscle. The mechanism of autoregulation is achieved by dilating or constricting the smooth muscle of the small arteries and arterioles which have MYOGENIC TONE. MYOGENIC CONTROL: The myogenic tone/hypothesis states that when the vascular smooth muscle is stretched, it contracts. Thus, if arterial pressure is suddenly increased, the vascular wall and thus the smooth muscle in the vessels are stretched, which activate mechanosensitive cation channels to depolarize and activate L-type ca2+ channels to increase the i.c ca2+ levels leading to smooth muscle contraction. This can be explained by Laplace's law: TENSION = PRESSURE * RADIUS, so if pressure goes up, reducing the radius can maintain a constant vascular wall tension LOCAL CONTROL: Two substances doesn't have ANY SY INNERVATION, and is only regulated by local control: -precapillary sphincters -smooth muscle of arterioles and metaarterioles These have to be regulated by local metabolites, causing vasodilation. These include: -decreased pO2 -increased pCO2 -increased lactate levels -decreased pH -increased adenosine levels -increased extracellular K+ levels FUNCTIONAL HYPEREMIA: Illustrates the concept that blood flow to an organ is proportional to its metabolic activity. If the "cell function" increases, then the metabolism increases --> metabolites incr --> vasodil --> more blood supplied to cell to supply nutrients REACTIVE HYPEREMIA: Is an increase in blood flow in response to or reacting to a prior period of decreased blood flow. For example, reactive hyperemia, is the increase in the blood flow to an organ that occurs following a period of arterial occlusion. During the occlusion, the O2 debt is accumulated. The increase in blood flow that follows the occlusion is proportional to the length of the time that flow was occluded to compensate for the loss. When the flow was blocked, metabolites were building up, causing vasodilation and thus the flow is increased when restored. However, the increased flow fastly washes away the metabolites and restores normal flow (There is a graph) ENDOTHELIUM-MEDIATED : When the local metabolite conc increase, the resistance decreases as vasodilation response is occuring --> increasing local flow --> this causes SHEAR STRESS --> which activates the endothelial cells via a receptor which causes the endothel cells to produce NO (from O2 and arg). NO --> incr cGMP --> cGMP-dep protein kinase activation which inhibits smooth muscle activation --> VASODIL. Prostaglandin I2 (prostacyclin) also causes vasodil from endothelial cells, via a similar pathway, however, now gs-coupled --> PKA HUMORAL CONTROL: Vasoconstrictors: -Endothelin -Angiotensin II --> via AT1 receptors (gq-coupled) Vasodilators: -Histamine -serotonin

7.8. Female sexual endocrinology

OVARIES: Cortex: contain ALL the oocytes and are responsible for steroid hormone synthesis Medulla: is a mixture of cell types Hilum: blood vessels and lymph passes through here --> the functional unit of the ovaries is a single functional follicle! --> the female sex hormones are mainly bound to sex hormone binding globulin (SHBG) in the circulation to protect from the metabolism and the enzyme aromotase is necessary for it's synthesis. OOGENESIS: Unlike male gametogenesis, ovaries produce 1000000 primordial follicles PRIOR to birth, and puberty doesn't result in production of more primoridal follicles, only their maturation. By the time puberty starts, there are only 400 000/300 000 follicles left. -ovulation marks the completion of meiosis I and the formation of a polar body -fertilization marks the completion of meiosis II which forms the ovum and a 2nd polar body. I HAVE A DRAWING THAT EXPLAINS IT ATTACHES TO THE TOPIC! HORMONAL SYNTHESIS AND SECRETION: -The THECA INTERNA CELLS (contain LH receptors which increase the cholesterol desmolase activity) to synthetize progesterone from pregnenolone and they synthetize androstenedione. -Androstenedione then diffuses to the GRANULOSA CELLS (which has FSH receptors) which contain the enzyme 17BETA-HYDROXYLASE DH + AROMATASE . to convert testosterone into 17beta-estradiol <-- this step is increased by FSH. MENSTRUAL CYCLE: (MUST DRAW) -The variability of the menstrual cycle depends on the variability of duration of the follicular phase, the LUTEAL PHASE IS CONSTANT: -FOLLICULAR PHASE: Is dominated by 17beta-estradiol which increases and causes proliferation of the endometrium, which has a negative feedback on LH and FSH -The primoridal follicle develops into a graafian follicle OVULATION: -14 days before menses -ovulation follows a burst of estradiol which has a positive feedback on FSH and LH --> causing a surge which causes the ovulation and increased cervical mucous quantity and quality. THE LUTEAL PHASE (CONSTANT): -this is when the corpus luteum develops and secretes estradiol + progesterone and prepares the endometrium to receive a fertilized ovum REGULATION OF THE MENSTRUAL CYCLE: -It depends on where in the menstrual cycle the female is. --> follicular stage, estradiol will have an inhibitory effect on the anterior pituitary --> during ovulation, estradiol will gave a positive effect on the ant pit --> during the lutheal stage, progesterone will have a negative effect on the ant pit! (^DRAW) ESTROGEN ACTIONS: -increase uterine myometrial contractibility, motility -increases libido -decreases Rank L to favor bone formation -increases prolactin secretion from the anterior pituitary, but inhibits lactation of the mammary gland -decreases LDL PROGESTERONE ACTIONS: --> aids fertilization -acts as a chemoattractant of sperm -promotes sperm capacitation -helps development of the breast

7.4. Insulin secretion and the regulation of the secretion. The effects of insulin on the intermedier metabolism. Diabetes mellitus.

PRODUCTION: Insulin is the hormone most associated with the "well-fed" state and it is secreted by the beta cells of the pancreas from the islets of langerhans. These islets contain both: -alpha cells --> glucagon -beta --> insulin -delta --> somatostatin And what is special about their structure is that the cells interact with each other in 3 ways: --Via gap junctions, through ionic currents (alpha and beta cells) --via the blood flow which firstly flows from the centre of the islet, where the beta cells are located and thus hit these first, before hitting the delta and alpha cells as well. It is important to note that the cells are bathed in VENOUS blood which is important since they are regulating the blood suger levels --via their innervation - adrenergic, cholinergic and peptinergic neurons allow a change in the the bevaiour of the cells. SYNTHESIS: Insulin is a peptide hormone which consists of 1 alpha chain, 1 beta chain and a connecting peptide with disulfide bridges. -It is firstly made in the nucleus as a strand of mRNA which is made into the preproinsulin that has all of the mentioned segments + A SIGNALLING PEPTIDE!). It is then sent to the ER, where the signalling peptide is cleaved off, creating proinsulin which is folded (disulfide bridges fold) in the ER and sent to the GOLGI, where the connecting chain (peptide C) is cleaved off, creating MATURE INSULIN. BOTH INSULIN AND PEPTIDE C is stores in secretory granules --> the function of beta cells is sometimes tested by determining the peptide C presence in urine. SECRETION: Normally, 30-40 units of insulin is secreted per day. There are several factors for isnulin secretion, but the most important one is increased blood glucose levels. 1)Glucose in the blood is taken up by the beta cells of the pancreas through the GLUT 2 transports to move glucose into the cell (GLUT 2 has low affinity for glucose and thus, only works when the glucose conc is high, like after a meal) 2) Glucose, then, gets phosphorylated to make it stay inside the cell by glucokinase (also low affinity) 3)Glucose --> glycolysis --> produce ATP 4) The generated ATP closes the ATP-SENSITIVE INWARDLY-RECTIFYING K+ CHANNELS. When these channels are open, the cell i s HYPERPOLARIZED and thus hard to stimulate. When they are closed, it leads to depol of the cell membrane, leading it closer to 0mV 5) This depol opens the voltage-dependant Ca2+ channels and intracellullar ca2+ levels increase 6) Leading to exocytosis of insulin from the secretory granules to the circulation REGULATION OF SECRETION: -STIMULATORS: Ach--> M rec --> Gq-coupled proteins which stimulates phospholipase C mediate increased i.c ca2+ levels and thus exocytosis of insulin --> Increased levels of FFA's and aa's can be used to produce ATP which again, closes the K+ channels and increases secretion of insulin -->Sulfonylurea drugs: are used in type 2 DM since they stimulate insulin release from beta cells since they close the ATP-dep K+ channels (by binding to the SUR regions) -INHIBITORS: -->hypoglycemia -->somatostatin -->leptin -->epi/NE --> alpha2 receptors --> FFA's ACTIONS: -Insulin acts when the peptide molecule binds to the INSULIN RECEPTOR on the target cell membrane. The receptor has two alpha (e.c) and beta subunits (i.c and has tyrosine-kianse activity) and it spans the cell membrane. When insulin binds to the alpha subunit, it causes a conf change in the receptor which causes autophosphorylation of the beta units. Once phosphorylated, the tyrosine kinase activity acts to phosph several othe proteins which acitvates/inactivtaes various metabolic pathways. The receptor is then endocytosed and degraded or recycled. Insulin dowgnregulates it's own receptor by decreasing synthesis rate and causing increased degradation, which partially explains the mechanism of DM type II insulin desensitivity. The actions of insulin are strongly ANABOLIC, and facilitates the storage of metabolic fuel and inhibits their release. Many of it's effects are the opposite effects of cortisol and/or glucagon. 1)DECREASE BLOOD GLUCOSE (AVOIDS FORMATION OF GLUCOSE) --> Increased glucose transport into the cell via the insulin-dependent GLUT4 transporter which are responsible for taking up large amounts of glucose after a meal to prevent hyperglycemia > GLUT4 can be found mostly in adipose and skeletal muscle, but also alpha cells, CT and lymph. > GLUT 2 can be found in the non-insulin regulated glucose uptake organs such as the liver, pancreas beta and kidney's --> Insulin increases glycogen formation and inhibits glycogenolysis --> Inhibits gluconeogenesis 2) DECREASES BLOOD FFA'S AND INCREASE TAG SYNTH AND STORAGE (WEIGHT GAIN): --> insulin decreases the mobilization and oxidation of FFA's while also increasing the storage of FFA's in adipose 3) DECREASES THE AA CONC: --> increases the uptake in cells and protein synthesis, while it inhibits protein lysis 4) PROMOTES K+ UPTAKE (to increase activity of the Na+/K+ pump to increase E expenditure) 5)Increases phophodiesterase enzyme activity which increases cAMP levels 6) Appetite is decreased by increasing leptin levels, however leptin inhibits the secretion of insulin so this is a form of negative feedback 7) glycolysis is increased 8)glucagon secretion from alpha cells is inhibited by insulin DIAEBTES MELLITUS TYPE I, JUVINILE DIABETES, INSULIN-DEPENDENT DM: -Is an autoimmune process in which the beta cells deteriorates which results in insufficciency/absence of insulin. It was completely lethal until insulin supplemention became possible -The typical symptoms include: --> being very skinny, because the signal for the insulin-dependent GLUT4 receptors aren't there, so hyperglycemia occurs. The adipocytes also never gets the signal from insulin to stop lipolysis, so the blood FFA's increase, these FFA's can go into ketogenesis (since the body is in starvation mode without insulin) and produce ketone bodies which leads to ketoacidosis and can eventually lead to coma. --> Being very thirsty and having sweet tasting pee is not uncommon, which happens because, during hypeorglycemia, the kidney isn't able to reabsorb all the glucose and thus, some of it is excreted in the urine. This also drives water and electrolyte loss (osmotic diuresis), which is what is causing the excessive thirst. DM2, NON-INSULIN DEPENDANT, INSULIN RESISTANCE: -Associated with lifestyle and the damaging effect it has on the ability of the pancreatic beta cells to secrete and produce insulin. --> There is a strong correlation between DM type II and central obesity, lack of exercise, atherosclerosis, hypertension and coronary heart disease -A person with type II DM needs double the amount of insulin to maintain normal blood glucose levels, since the response of insulin is impaired and the resistance from the effective tissues is high. - As a result of overwork, beta cells become exhausted and insulin secretion gradually decreases. --> TNF, Leptin (remember the negative feedback route, people with high fat content, produce more leptin, which aids insulin resistance since leptin inhibits insulin secretion), resistin TREATMENT OF DM TYPE II: -Diet: goal is to decrease the lipid content of the body -exercise: this aids GLUT4 expression, and will reduce the blood sugar levels -Sulfonylurease: increase insuklin secretion by closing the ATP-dep K+ channels -Pharmacological induction of adiponectin (reduces insulin resistance) GLUCOSE TOLERANCE TEST: The glucose tolerance test starts out by the patient fasting and then ingesting a large amount of glucose, which is then tested every 30 minutes for 2 hrs. NORMAL VALUE OF FASTING BLOOD GLUCOSE SHOULD BE AROUND 5mM. Is it between 6.1-7mM, then this is considered pre-diabetic. After ingesting the glucose, the nromal levels should be a bit higher, however, they shouldn't be higher than 11,1mM which is considered pre-diabetic. (There is a graph to draw) -->Also, if blood glucose levels are high over a long period of time, then Hbg will become glycated and this is a typical sign of DM I patients. --> As stated, peptide C can be used to determine the secretion of insulin from beta cells.

8.3. Physiology of pain sensation.

Pain receptors are called nociceptors since they detect "noxious" stimuli that may indicate damage taking place. Types of pain: -nociceptive: the calssic, typical concept of pain, results from noxious stimuli -neuropathic: pain is caused by a problem with the pathway, such as damage to the sensory nerve fibers -central: the central pathway of the pain sensory mechanism is affected for ex thalamic pain Propagation of pain: Pain is felt in two different stages since it is caried by both slow and fast fibers. -Firstly, a delta fibers are used to propogate the sharp, quick pain. These are myelinated. The fibers arise from the I-V lemina of the dorsal horn -Secondly, the unmyelinated C fibers carry the dull, burning pain. These fibers originate from the substantia gelatinosa of the dorsal horn. The nociceptive pathways include: -the spinothalamic tract (topic 8.2), crosses in the anterior white commissure -the spinoreticular tract (from spinal chord to reticular formation. Responsible for alertness. Pain generally makes a person feel more alert. -the spinomesencephalic tract (goes to the midbrain, more specifically, the periaqueductal grey matter. The midbrain is the starting point of a descending pathway which goes down and regulates transmission of pain to the spinal cord). Changes in pain sensitivity: HYPERALGESIA= heightened sensitivity to pain. It involves a lower treshold to pain. There are 3 types of hyperalgesia: -PRIMARY HYPERALGESIA: damaged cells release mediators that cause increased sensitivity to pain. The mediators are: --K+ (if it leaks out of cells it is a sign of damage and causes local hyperkalemia. This increased e.c K+ causes depol of nociceptive n endings) --H+, area becomes more acidic which the n endings respond to via the Transient receptor (TRPV) channels) --Bradykinin: produce a calcium signal causing hyperalgesia --prostaglandins: they are derivatives of arachidonic acid that is converted by COX enzymes. Aspirin inhibits these, which is how aspirin reduces pain. -SECONDARY HYPERALGASIA: near to the damaged cells there is hyperalgesia, although the region itself is not damaged. Mediators include: --substance P which causes vasodil --CGRP - calcitonin gene related peptide that causes vasodilation --Bradykinin - vasodil and sensitization of neurons (PART OF BOTH 1ST AND 2ND HYPERAGLASIA) --histamine- vasodil and hypersensitive n endings -CENRTAL HYPERALGESIA: the pain sensation stimulates the local network area in the substantita gelatinosa, causing an increase in excitability of neurons connected to the area near the injury. This causes a partial activation of non-injured n endings Other examples of changes sensitivity to pain is: -Allodynia which refers to experiencing a pain sensation after a normal, non-nociceptive stimulus as when touching burned skin. It hurts, but the touch itself isn't damaging. -Referred pain: there is a pain sensation in areas that are not the same as where the nociceptive stimulus is. Example is the classical myocardial infarction where the pain isn't in the heart, but the chest and left arm. This is due to the segmental organization of the system overlapping so the heart viscera and left arm skin occupy the same region of the dorsal horn and the excitability of the neurons spread. Regulation of pain sensation: CENTRAL: ex: a soldier may not feel pain in battle due to excessive cortical stimuli/stress PERIPHERAL: 3 types: -Gate control theory: explains how excessive pain stimulus causes the person to touch that area which leads to an analgesic effect and reduced activation of the pain sensation. (There is a picture I should draw) -Diffuse noxious inhibitory controls (DNIC) - means that certain noxious stimuli can cause diffuse analgesia. This is the basis of acupuncture. -Descending analgesic pathways: The activity of the descending analgesic pathways is to inhibit the spinothalamic tract neurons!!!! The components include the raphe nucleus (serotonin production) of the medulla and the periaqueductal gray matter of the midbrain. The ascending nociceptive axons release excitatory transmitters like Glu and subP, while opiates usually inhibit the activity of these nociceptive pathways by inhibiting both the presyn and the postsyn afferent neuron terminals. PRESYN TERMINAL: there is an opiate receptor on the axon terminal that activiates Gi G proteins, which inhibits the calcium channel needed for depol. POSTSYN TERMINAL: also stim Gi G proteins, but here it opens K+ channels to hyperpolarize the cell. So it counteracts the stimulatory effect of glu or subP Opiates perform disinhibition. This means that they inhib an inhibition, thus activating the descending pathway. (SKJØNNER IKKE) Endogenous opiates are all peptides: -enkephalin (two types: methionine-enkephalin and leucine-enkephalin) are produced by pre-proenkephalin -beta-endorhin: derived from POMC (pre-pro-opiomelanocortin The opiate receptors (all of them are Gi coupled aka they decrease cAMP and hyperpolarizes the cell via the opening of K+ channels): - They are divided into three groups: mu, delta and kappa. THE MU RECEPTOR IS THE TARGET OF MORHPIN.

4.1. Circulation of the kidney. Glomerular-filtration

RENAL FUNCTIONS: -produce and excrete urine and other substances -eliminate metabolites and waste products -maintain the water/salt balance -acid/base balance -hormone production --> Renin is produced in the kidney which aids in producing ATII --> erythropoetin, EPO (important in erythropoesis) --> calcitriol (vit D, since the kidney expresses 1-alpha hydroxylase which is the rate limiting step in this reaction) RENAL CIRCULATION: (Renal a--> segm a --> interlobar a --> arcuate --< interlobular a --> aff arteriole --> glomerular capillaries --> efferent arteriole --> peritubular capillaries (for the cortical nephrons) --> vasa recta (for the juxtamedullary nephrons --> venules --> interlob --> arcuate --> interlob --> renal v) -Kidney weighs about 300-400g -the majority of it's blood flow is for glomerular filtration, NOT the metabolic processes occuring in the kidney cells themselves. -RENAL BLOOD FLOW: 1200-1300ml/min (20-25% of CO) -RENAL PLASMA FLOW: 600-700ml/min (1/2 of blood flow) -GBR: 120ml/min -Filtration fraction (FF) =GFR/RPF = 20% normally PRESSURE CHANGES THROUGHOUT RENAL VASCULATURE: (DRAW GRAPH) -Due to increased resistance in arterioles, the pressure drops massively. This helps to protect glomerular capillaries from excessively increased blood pressure, that prevents increased blood flow and increased GFR NEPHRONS: Nephrons is the functional unit of the kidneys They can be either CORTICAL or JUXTAMEDULLARY: -CORTICAL NEPHRONS: --> 90% of all neprhons --> located in the outer cortex --> efferent arterioles gives the PERITUBULRA CAPILLARIES which supllies these nephrons -->loop of henle extends into the outer medulla --> their desc+asc limbs of lopp of henle is equal -JUXTAMEDULLARY NEPHRONS: -->10% of all neurons --> close to the border between the cortex and the medulla --> efferent arterioles gives the VASA RECTA to supply these nephrons --> loop of henle extends deeper into the medulla --> desc part of the loop of henle is longer! REGULATION OF THE RENAL CIRCULATION: There are 4 very important reasons why we need to regulate the renal blood flow! 1) To protect glomerular capillaries from excessively high BP --> done so by autoregulation in the afferent arteriole in case of elevated systemic BP (it can autoregulate this between Bp values 80-180mmHg) 2)Balance blood supply for INDIVIDUAL NEPHRONS, as each nephron needs to be in balance with the surrounding nephrons. --> Done by the TUBULOGLOMERULAR FEEDBACK: --> IMPORTANT: It balances the blood supply for individual nephrons!!! There are approx 1 million nephrons in each kidney and the TG feedback is there to make sure that each individual nephron is in homeostasis with the others. Very important!!! Increased glomerular filtration of NaCl, detected by macula densa cells via Na+/K+/2Cl- transporter. Na+ pumped out via Na+/K+-ATPase, and adenosine formed and sent out to bind to A1 receptor on afferent arteriole's SM via paracrine signaling. Ca2+ signal induced in SM cells cause VASOCONSTRICTION (regulates glomerular filtration) 3)Conserve Na+ in the case of deficiency: --> The macula densa cells sense if there is low NaCl levels and signals to the juxtamedullary cells / granular cells) to produce renin --> Juxtamedullary cell is part of the SLOW-ACTING BARORECEPTOR SYSTEM! They release renin to the blood which converts angiotensiongen to AT1 (in the lungs), and then ACE converts AT1 --> AT2 in the kidney. Angiotensin II constricts the efferent arteriole and stimulates ALDOSTERONE secretion thus increasing Na+ reabsorption and the GFR 4)Redistribute blood flow to vital organs in case of severe BP drop --> similar to the above described mechanism --> slow-acting barorecptors remember! GLOMERULAR FILTRATION: THE GLOMERULAR STARLING FORCES: -Glomerular/capillary hydrostatic: aff: 53mmHg, eff: 51mmHg -Capillary oncotic: aff: -26mmHg, eff: -33mmHg (this decreases further due to the increased concentration of unfiltered proteins in the efferent a) -Bowman's hydrostatic: aff: -12mmHg, eff: -12mmHg -Bowman's oncotic : aff + eff : 0mmHg as NO proteins should pass -->NET ULTRAFILTRATION PRESSURE: aff: 15mmhg, eff: 6mmHg (this value DIRECTLY affects the rate of glomerular filtration!!!) -The GFR and FF are higher than in normal capillary filtration rates because: --The glomerular capillary pressure is x2 the systemic cap pressure - and because the FILTRATION COEFF determined by the permeability and filtration surface area is 1++x higher in glom cap than systemic cap! The glomerular filtration barrier consists of: 1)FENESTRATED CAPILLARIES, which are perm to water, small solutes and some proteins, but their negative charged surface glycoproteins repel large anionicproteins 2)BASEMENT MEMBRANE --> type IV collagen + laminin, negative charged which also repel anions 3)PODOCYTE PROCESSES: they surround the glomerular capillaries, but they do have FILTRATION SLITS (20-30mikrom) GENERAL GLOMERULAR FILTRATION RULE: The larger or more neg charged the molecule is, the less likely it is to pass the filtration barrier. --> RENAL CLEARANCE: means the volume of plasma per unit time from which all of a given substance has been removed by the kidney's and excreted in the urine (Cx) -Albumin is not filtered due to it's size and negativity -Glucose: is filtered, but should be COMPLETELY REAB, however, the glucose reabsorption transporters can be saturated when the blood glucose levels are too high and the increased glucose in the urine can be a diagnostic tool for DM -PAH (para-aminohippurate), is filtered and completely SECRETED, aka it is completely cleared and completely excreted in the urine. THUS, !!! RPF =C,PAH !!! (we can also calc RBH using: RBF = C,PAH/ (1-Ht) (as hematocrit is what seperates the blood from the plasma) -Inulin, is filtered and not reabsorbed. !!!! C,inulin = GFR !!!!! -Creatinine: filtered, but NOT reabsorbed! Creatinine is a byproduct of skeletal muscle metabolism! !!! C,creatinine = GFR!!!! (There is a graph to draw, but basically, IF GFR DROPS, THEN CREATININE LEVELS INCREASES TO MAKE UP FOR IT!) GOMERULAR FILTRATION REGULATION: -TO DECREASE GFR: --> when our blood pressure is too low, SY neurons are activated via NE and uses their alpha1 receptors on the afferent arteriole (as these have FAR MORE of these receptors), causing decreased GFR and RBF (redirecting blood flow during hemorrphaging for ex) --> Renin will be released due to activation of the beta1 receptors in the juxtamedullary cells as a response to NE, causing ATII production to vasoconstrict the efferent arterioles mainly to decrease GFR and thus RBF -TO INCREASE GFR: --> ANP will be released when the pressure increases in the atria (which should be around 0mmHg, usually due to increased blood volumes). ANP has an effect on both arterioles, but opposite -dilates afferent arterioles -constricts efferent arterioles --> this leads to decreased resistance, increased RBF and increased GFR --> PG I2 and E2 (made locally), vasodilates to counteract SY innervation and ATII!

8.10. Thermoreceptors. Thermoregulation. Regulation of the circulation of the skin.

THERMORECEPTORS: 3 classes of non-adapting receptors recognize thermal sensation, which results from difference between the external temperature of air/objects contacting the skin. These 3 receptors are cold, warm receptors and heat nociceptors. -Thermal stimuli generate special receptor potentials by activating distinct classes of NONSELECTIVE CATION RECEPTOR CHANNELS called TRP (transient receptor potential) channels. --Cold receptors: myelinated Adelta fibers, which are highly sensitive and encode cold with AP bursts -->TRPA1 receptors are activated at <17 degrees = cold and frigid, also respond to garlic -->TRPM8 receptors are activated at temp's below 25degrees, and they also respond to menthol --Warm receptors are carried by C fibers and encode rising temp's by increasing Ap firing rate until they saturate. They are less sensitive than cold receptors. --> TRPV4 activate at temps above 27degrees and are for normal skin temp and respond to touch -->TRPV3 are actviated at temps above 35 degrees --Heat nociceptors are carried by both C and adelta fibers and are inactivated by skin cooling (why it is dangerous when you are so cold that you can't feel the pain anymore) -->TRPV1+2 are activated at temps above 45 degrees and give the sensation of burning pain (THERE IS A GRAPH FOR THIS) THERMOREGULATION: The temperature of the body is not exactly the same throughout. The deep tissues of the chest, abdominal cavity and brain have a CORE TEMP OF 37 DEGREES. If you are in a cooler temperature, then the extremeties may have a much lower temp than the deep structures (can be as low as 28 degrees). If in a hot env, then extremeties are usually the same as the deep structures. -Regulating core temp to environmental temp has a SIGMOIDAL CORRELATION (like the reg of blood pressure by autoregulation). There is a platau where the body can handle variable environemental temp, but there are limits: --> 37 is the set-point value where the body functions as optimal. --It can vary between 30-42 in order to be COMPATIBLE WITH LIFE --> The heart is most sensitive to cold temperature which can cause arrytmia's --> The brain is most sensitive to heat and abnormal reflexes and CNS malfunction will occur. There is a cost to thermoregulation, and the energy requirement of regulation is measured in the CONSUMPTION OF OXYGEN (like BMR) -There is a range called the comfort zone where o2 consumption is lowest, (AMBIENT TEMP) and this is when humans doesn't have to exert any E in maintaining their core temp. With clothes this is between 21-23, and without this is between 27-30. -Below the comfort zone rangemt here is an increease in o2 consumption as we perform mechanisms to induce heat production -o2 consumption increases when in environmetnal temp's above the comfort zone. This is due to the activation of physiological processes that induce heat loss. PROCESSES THAT LEAD TO INCREASED BODY TEMPERATURE: -CHEMICAL HEAT PRODUCTION: metabolism of the organism produces heat --Non-shivering heat production: is done by the brown adipocytes + the body's major organs such as the heart, kidney, liver and brain (this is due to their high BMR's that significantly contribute to the core body temp.) Remember that brown adipocytes are more common for newborns and in adults we are talking about beige adipocytes --Shivering heat production is done by the skeletal muscle -PHYSICAL HEAT PRODUCTION: requires very high air temp's above 34 degrees because that's the temp of the skin. PROCESSES THAT LEAD TO DECREASED BODY TEMPERATURE: -PHYSICAL HEAT LOSS: consist of several passive processes. The determinant of this is the temp gradient that exists between the organism and the environment as heat is transferred from high to low, depending on surface area --Convective: depends on the velocity of the environment, example being the wind --Conductive: depends on the env temp, as heat is transferred to the env (ex, air, water etc) --Radiation: the IR is responsible for this type of heat loss -EVAPORATION: importantly, this does not depend on the temp gradient, but the HUMIDITY OF THE AIR --Persiperation insensibles: obligate persipitation caused by breathing (15%) and from the skin (85%). WE LOOSE ABOUT 1 LITER PER DAY IN THIS WAY. THIS CANNOT BE REG --Persipitation sensibles: sweating. This can be regulated Heat balance is when the processes that increase body temp equals the processes that lead to a decreased body temp. AKA: HEAT BALANCE when CHEMICAL HEAT PRODUCTION = PHYSICAL HEAT LOSS Another factor in heat balance is ISOLATION which includes adipose tissue, hair and clothing. SKIN CIRCULATION AND REGULATION: Normally, the basal blood flow of skin circulation is: -300-500mL/min, this equals to 5-9% of the cardiac output. -however, in a warm environment, the rate may rise to 8L/min and become 60% of the CO, aka increasing the Q x 25-30 times!!! -The acral skin refers to the non-hairy skin at the palms, soles, lips, nose, fingertips and has multiple arteriovenous anastemoses (AVA) which have high surface area and are regulated by SY innervation. In the presence of heat, these undergo vasodil (by downregulating the sympathetic tone) to increase skin circulation. -The non-acral skin refers to the hairy skin which have normal microcirulation (aka, normal arterioles with higher basal tone and local metabolite regulation). It is here where the sweat glands can be found. N.B!: Sweat glands are innervated by UNIQUE MUSCARINIC SY CHOLINERGIC NEURONS WHICH ACTIVATE SWEAT GLANDS, CAUSING VASODILATION. (If we give atropine, then body temp will increase as the vasodilatory effect exhibited by the MUSCARINIC SY neurons is inhibited!!!!) SWEAT GLANDS: -The primary secretion from the acinar cells use the key transporter Na+/K+/Cl- cotransporter to move the ions from blood and into the acinar cell and then they move to the luminal side by secondary active transport (na+ and h20 + cl- channels) -Primary and secondary secretion, where the primary secretion is isotonic and similar to plasma, and the secodnary is modified by reabsorption of Na+ and Cl- (which in cystic fibrosis, the Cl- channels do not work and thus, you have high conc's of these ions in the sweat). The Na+-reabsorption is controlled by aldosterone which increases it's activity, and Cl- follows due to the electrochemical gradient present. BUT NO WATER IS REABSORBED IN THE DUCTAL PART OF THE SWEAT GLAND, as the final product should by hyposmotic (having rel low conc's of solutes). Sweat regulation: Special muscarinic, sy cholinergic neurons are activated by Ach, which activates phospholipase C. The cells now produce KALLIKREIN --> bradykinin which is a local vasodilatory metabolite of local vessels in the skin. AKA, when sweating is activated, so is the skin circulation! CNS CENTERS OF THERMOREGULATION: -Hypothalamus: the most important regulator. Broadly, the effects are: --Stimulating regional vasoconstriction --> cold centers of teh body --stim reg vasodil --> warm centers of the body -Receptors: --Central receptors: are senetivie to changes in the CORE TEMP as these are situated in the deep structures of the body, hence they are the most important thermoregulators of the body! They are sensitive to both increase and decreased temp. Located: -Hypothalamus in the preoptic area -spinal bone marrow -liver --Peripheral receptors: Located in the: -skin -oral cavity Play an important role in detecting the air temp. These receptors belong to the TRP family and are the typical warm and cold receptors as talked about in the beginning of the topic. --> A major role of these is to modify the set-point value, which is how they impact core temp WHAT HAPPENS WHEN THERMOREG DOESN'T WORK?: -Heat exhaustion: Warm temperature causes vasodilation and increased sweating which leads to hypovolemia. Because we loose lots of Na+ and Cl- from sweating, meaning there is a HYPOSMOTIC HYPOVOLEMIA. This contributes to decreased CO, which means that it decreases BP and this is a form of circulatory shock. To treat this, we need to drinkwater and electrolytes to replenishthe Na+ and Cl- that were lost in sweating -Hyperthermia: if you are in a hot environment with high humidity, sweating is not effective and core temp increases --> CNS function becomes impaired and can't regulate vasodilation. Thus, core temp increases and creates a positive feedback loop of increasing core temp and worsening CNS function that may lead to death -Fever, which differs from hyperthermia, because thermoregulation is still functioning and is causing the fever by increasing the set-point value. Fever is induced by pyrogens: --Exogenous pyrogens: parts of bacteria and viruses, destroyed cells and high K+ values --Endogen pyrogens: usually cells of the immune system which produce molecules such as IL-1, IL-6, TFNalpha --> and synthesis of prostaglandins induces a + feedback loop that increases fever, and NSAIDS like aspirin reduce fever by inhibiting COX enzymes, which therefore inhibit pPG synth -Hypothermia: coe temp decreases, function of the heart is impaired via arythmia's and this can also lead to death.

7.2. The function of the adrenal cortex

The adrenal glands are located in the retroperitoneal cavity above the kidney. The glands are actually two different glands; the adrenal medulla and the adrenal cortex, which are both essential for life. The adrenal medulla is of neuroectodermal origin, while the cortex is of mesodermal origin. The cortex has three distincitve layers; zona glomerulosa (mineralocorticoids), zona fasciculata (glucocorticoids) zona reticularis (androgens). The adrenal cortex composes about 80% of the gland and differentiates in gestational week 8 (is responsible for production of steroid throughout intrauterine life). STRUCTURE OF THE HORMONES: They are all derived from cholesterol which enters the cell via LDL receptors, is endocytosed and esterified and stored in cytoplasmic vesicles until it is needed inside the adrenocortical cells. Cholesterol, progesterone, the glucocorticoids and the mineralocorticoids are all 21- Carbon steroids, the androgens are 19-carbom steroids and estrogens are 18-carbon steroids. SYNTHESIS OF STEROID HORMONES: (tegn det/memoriser det slik som på bildet) (NOTE THAT ALL OF THE ENZYMES ARE IN THE CYTOCHROME P450 FAMILY AND REQUIRES OXYGEN AND NADPH!!!!) The first step of the pathways, which are common for all three layers is the conversion of cholesterol to pregnenolone by cholesterol desmolase. The conversion of cholesterol from the cytoplasm and into the mitochondria of the adrenocortical cells are done by the STAR transporter (steroidogenic acute regulatory protein), so that it can be converted to progenonelone. Cholesterol desmolase is stimulated by ACTH, which activates a Gs-coupled protein --> incr cAMP --> PKA --> phosphorylation of star to incr transportation of cholesterol to the mitochondria. Each layer has specific amounts of enzymes which is what specializes each layer to produce their specific hormones. ZONA GLOMERULOSA (6 enz) (final product=aldosterone): This layer does not produce glucocorticoids because it DOESN'T CONTAIN 17ALPHA-HYDROXYLASE, and also corticosterone (a glucocorticoid) is converted to aldosterone because of the enzyme ALDOSTERONE SYNTHASE. -cholesterol desmolase -3beta-hydroxysteroid dehydrogenase -21-hydroxylase -11beta-hydroxylase -18hydroxylase -aldosterone synthase The zona glomerulosa is stimulated by other factors besides ACTH. These include ATII and high (K+)e.c, which means that even in the absence of ACTH, the zona glomerulosa will thrive and produce aldosterone. How does this work? -The ATII is formed by the renin-angiotensin system in response to low Na+ levels. ATII uses the AT1 receptor which is gq-coupled to produce a a calcium signal --> PKA --> phosphorlyate STAR to increase cholesterol transport into the mitochondria!! -increased extracellullar potassium acts depolarizing on the glomerulosa membrane, thereby ALLOWING INFLUX OF CALCIUM to cause increased cholesterol transport into mitochondria by STAR. -(ANP decreases aldosterone production in response to increased BP (vascular v) by the atria of the heart. The zona golmerulosa cells have ANP receptors to decrease cAMP and phosphorylation by PKA. ) ACTIONS OF ALDOSTERONE: -The actions of aldosterone are most important in the kidney, but are also significant in the colon and the sweat glands. -Aldosterone causes and increased activity and induction of the Na+/K+ ATPase - causing increased Na+ reabsorption through increased activity and presence of ENaC channels -increased K+ secretion by principle cells and H+ secretion of the alpha intercalated cells of the kidney. Meaning that OVERALL, aldosterone will CAUSE ECF VOLUMES TO INCREASED, INCREASE BP, DECREASE K+ LEVELS AND INCREASE NA+ LEVELS. An interesting problem arises with respect to the actions of mineralocorticoids in their target tissues. That is, the affinity of mineralocorticoid receptors for cortisol is, surprisingly, just as high as that for aldosterone. Because circulating levels of cortisol are much higher than circulating levels of aldosterone, it would seem like cortisol would overwhelm and dominate the mineralocorticoid receptors. However, this is solved by the RENAL CELL THEMSELVES!!! They contain the enzyme 11Beta-hydroxysteroid dehydrogenase, which converts cortisol to cortisone, which, in contrast to cortisol, HAS A LOW AFFINITY FOR THE MINERALOCORTICOID RECEPTORS. --> In this way, cortisol is effectively inactivated in mineralocorticoid target tissues. --> This inactivation of cortisol in mineralocorticoid target tissues also explains why, when cortisol levels are high, it still only has a very weak mineralocorticoid activity (despite it's very high affinty for the mc receptor)!!! ZONA FASCICULATA (the final product is cortisol, but corticosteroid could also be produced if for example the enzyme 17alpha-hydroxylase is blocked. So not producing cortisol is not deadly! But not producing ANY glucocorticoid is deadly!!!): -Cholesterol desmolase -3beta-HSD -17alpha-hydroxylase -21-hydroxylase -11beta-hydroxylase SECRETION OF CORTISOL: Cortisol is secreted in bursts in response to the pulsatile secretions of ACTH. The largest burst occurs 2 hours before waking up (opposite of GH which has the largest burst 1 hr before falling asleep). Cortisol is associated with higher stress and pain levels and it's effects are lower in people with high levels of endogenous opiates. There are two known glucocorticoid receptors, however, the first, glucocorticoid receptor 1 has the same affinity for both aldosterone and cortisol, but this is solved as explained above, by converting cortisol into cortisone. Thus, this receptor is usually called the mineralocorticoid receptor, since it binds aldosterone. The second glucocorticoid receptor is specific for cortisol and can be called the glucocorticoid receptor. Almost all cells have this receptor since cortisol displays catabolic effects in many different organs. --> What is important to remember about these receptors are that they are steroid receptors, aka they are NOT membrane bound, but CYTOPLASMIC!! Steroids diffuse across the membrane and bind to either type I or type II glucocorticoid receptors. These receptors then initiate transcription factors that upreg or downreg transcription of hundreds of genes. THE ACTIONS OF CORTISOL: Many of cortisol's effects are considered permissive, or so-called indirect, so it allows for a response to occur. An example is for ex that cortisol doesn't directly stimulate glycogenolysis, BUT it does enhance the glycogenolytic effects of glucagon. Cortisol is essential for gluconeogenesis (cortisol is said to have both catabolic and diabetogenic effects), vascular responsiveness to cathecolamines, supression of inflammatory and immune responses and modulation of CNS function. -Cortisol fascilitates gluconeogenesis, glycogenolysis and may help with glycogenesis. It is essential to survive during fasting/starvation, and has both glycogen storage and breakdown effects. -It has a paradoxial effect on fat metabolism, where it both enhances fat breakdown and fatty tissue deposits in the abdomen. People with CUSHING'S SYNDROME (excessive cortisol secretion) are extremely skinny, with low muscle tone in most of their body, but then have a surprising amount of abdominal fat -Cortisol is a KEY OPPONENT to insulin (the hormone which usually indicates well-fed state) -A basal level of cortisol is necessary to maintain muscle (as can be seen in cushing's syndrome). Too much cortisol will break this down and use it for gluconeogenesis. -Cortisol decreases bone formation and increase bone resoprtion by decreasing the vit D levels which decreases the differentiation of osteblasts (INDIRECT EFFECT). It also, directly acts on osteclasts to stimulate them and their production of cytokines for bone resportion. -Cortisol helps maintain BP by decreasing the permeability of the vascular endothelium -It increases the rate of GFR, by increasing flow of plasma into the glomerulus -Cortisol modulates alertness and emotional functions, and can in excessive amounts cause insomnia. ZONA RETICULARIS (produces DHEA and androstendion which are the precursors of testosterone and estradiol which are produces in the gonads) -cholesterol desmolase -17alpha-hydroxylation -3beta HSD NB! It is not easy to remember all the enzymes, so make it easy for yourself and remember where CYP17 (17ALPHA-HYDROXYLASE) and if 17,20-lyase levels are high or low!!!! Thumb rule: ZG: CYP 17 and 17,20-lyase is not expressed ZF: CYP17 is expressed and low levels of 17,20 lyase ZR: CYP17 is expressed and high levels of 17,20lyase as well! ADRENAL CORTEX DISEASES: -CUSHING's disease: Is caused by a chronic excess of cortisol either by a spontaneous overproduction or by a pituitary tumor which then upregulates ACTH which upregulates cortisol production as well. The symptoms include: hyperglycemia, increased proteolysis, so patient has thin extremeties with an excess of abdominal fat with striations (caused by a loss of CT), osteoporosis and hypertension caused by the weak mineralocorticoid activity of cortisol. -ADDISON'S DISEASE = PRIMARY ADRENOCORTICAL DEFICIENCY: caused by autoimmune destruction of all zones of the adrenal cortex. This causes an overall decrease of all hormones produces by the adrenal cortex. The decreased cortisol causes hypoglycemia, anorexia, weight loss, weakness and the lack of aldosterone causes hypotension and hyperkalemia and metabolic acidosis. Decreased androgens causes decreased pubic and axillary hair as well as decreased libido. -The disease is also characterized by skin pigmentation due to the increased levels of ACTH that contain the MSH. The increased ACTH can be explained by the lack of cortisol which will lead to a stimulation of the CRH-ACTH axis to produce more and more ACTH. Without cortisol's negative inhibition on this axis, ACTH is overproduced! MUST DRAW AND EXPLAIN THE REGULATION OF THE ADRENAL CORTEX!

8.4 Physiology of vision

The eye has three concentric layers. The outer layer which is a fibrous layer that includes the cornea, corneal epithelium, conjunctiva, sclera. The middle layer is a vascular layer and includes the iris and the choroid. The inner layer is the neural layer and contains the retina with it's 10 layers (they name 8). (Draw the eye and explain the structures!) Layers of the retina: -Pigment epithelium -> the epith cells absorb stray light and have tentacle like processes to prevent the scatter of light. They are also important as the epithelial cells CONVERT ALL TRANS-RETINAL TO 11-CIS RETINAL and delivers this to the photoreceptors. -Photoreceptor layer: the outer and innner layers of the rods and cones are found here (where they store rhodopsin) -(external limiting membrane) -outer nuclear: the nuclei of the rods and the cones (where they have mitochondria and other organelles to create the rhodopsin) -outer plexiform layer: synapse between the R&C and the bipolar and horizontal cells (the interneurons) -Inner nuclear layer: contain the cell bodies of the interneurons (bipolar, amacrine and horizontal cells) -Inner plexiform layer: the second synaptic layer. Synapse between the interneurons and the ganglion cells -Ganglion cell layer: contain the nuclei of the ganglion cells which are the output cells of the retina -Optic nerve layer: The axons of the retinal ganglion cells form this layer. These axons pass through the retina (avoiding the macula), enter the optic disc and leave the eye in the optic n Structure of the photoreceptors: Rods: There are two sensory receptors which differ slightly in structure and function. Rods have low tresholds, are sensitive to low-intensity light, and function well in darkness. This is because many rods synapse on a single bipolar cell, so they have lower acuity, but are much more sensitive. When light strikes any one of the rods, it will active a bipolar cell. The structure of the outer segment of the rod receptor contains a double membrane disc which is important because it can store large amounts of rhodopsin, and the rhodopsin is transferred from the inner to the outer segment by formation of a new membrane disc and shedding + phagocytosing of said disc Cones: Cone receptors are used in our daylight vision and can be used to see colour. They have a higher treshold for light and provide high visual acuity, but are less sensitive (to low intensity light). Only a few cones synapse on a single bipolar cell, except from the fovea where acuity is highest because one cone synapse on one bipolar cell. Their outer segment consist of membrane infoldings which doesn't hold as much rhodopsin as Rods, and the transport of newly synth rhodopsin does not occur via shedding, it is just randomly incorporated into the membrane folds. Steps of photoreception: Phtoreception is the transduction process in rods and cones that converts light E into electrical energy. Rhodopsin (photosensitive pigment) consists of opsin (g coupled protein) and retinal (an aldehyde of vitamin A). 1) Firstly, light strikes the retina and PHOTOISOMERIZATION of retinal occurs where 11-cis-retinal is converted to 11-TRANS-retinal. (Regen of 11-cis-retinal requires Vit A, which is why in vit a def, patients experience night blindsness). Due to conf changes, metarhodopsin II is formed 2)Metarhodopsin II activates a G-protein called transducin (gt) which catalyzes the conversion of cGMP to 5-GMP aka cyclic GMP levels are decreased 3) In the photoreceptormembrane, Na+ channels carry an inward current and this current is reg by cGMP. In the dark (when there is no light to decrease cGMP levels) there is some cGMP to produce the Na+ current called the DARK CURRENT and depol of the memb!. In light, this current is inhib causing hyperpolarization 4)This hyperpolarization (in the presence of light) causes a decrease in glutamate released (which is an excitatory NT) from the synaptic terminal of the photoreceptor 5)But remember that there are two types of glu receptors on bipolar and horizontal cells: Ionotropic receptors which are depolarizing (+) and metabotropic receptors are hyperpolarizing, BUT REMEMBER, that light causes HYPERPOL and a decrease in glu, which means that if the B or H cells has ionotropic receptors, then the decreased glu will cause hyperpolarization as it inhibits the excitatory receptors, and vice versa with metabotropic receptors. This is important in the phenomenon of on and off patterns of visual fields. VISUAL RECEPTIVE FIELDS: There are receptive fields for the photoreceptors, the B cells and H cells, ganglion cells, cells of the lat geniculate body in the thalamus and the cells in the visual cortex (brodmann area 17). At each higher level, the receptive field becomes increasingly complex. When light hits the photoreceptors they are ALWAYS hyperpolarized and the amount of glutamate is decreased. The photoreceptors synapse directly on bipolar cells, which is represented by the centre of the bipolar receptive field. If the bipolar cell have ionotropic glu receptors in the center, then the bipolar cell will be inhibited and vice versa with metabotropic rec. The surround of the bipolar cell's receptive field is determined by the adjacent horizontal cells. The surround of the receptive field shows the opposite response of the center because H cells are inhibitatory (they will REVERSE the direct response of the photoreceptor). Thus, two patterns are created: -ON-CENTER (off-surround): center is excitited because the bipolar center exhibits metabotropic glutamate receptors and the surrounding is inhibitory as H cells always inhibit -OFF-CENTER (on-surround): The center is inhibited by light because it has ionotropic glutamate receptors and the surround is excited by light. This is because the horizontal cell is inhibited by the photoreceptor (as always) and reverses the direct response of the photorec on the b cell to produce + surround. The amacrine cells have a mixture of off and on pattern receptive fields Ganglion cells depends lat geniculate cells of thalamus also dep It get's more complicated in the visual cortex. Has three cells: simple, complex and hypercomplex. Simple cells have similar rec fields like rods and cones. Complex responds best to responsive to a bar or edge oriented in a particular way anywhere within the receptive field. Hypercomplex: Hypercomplex cells are like complex cells except there are inhibitory flanks on the ends of the receptive field, so that response increases with increasing bar length up to some limit, but then as the bar is made longer the response is inhibited. This property is called end-stopping. optic pathways: just draw it and explain where they cross and the different lesions!

5.3. Function of the salivary glands and regulation of salivary secretion. Gastric secretion and its control.

The salivary glands include the sublingual glands (mostly mucous), the submaxillary glands(mixed) and the parotid glands(mostly serous). Their function is to start digestion of starches and lipids by salivary enzymes, dilute and buffer ingested foods and lubricate ingested food with mucous to aid it's movement down the esophagus. The glands are made up of acinar cells and ductal cells, which first produce the saliva and then alters it. There are myoepithelial cells present our the acini and the ductal cells, which contract when stimulated by a neural input. The acinar cells secrete an isotonic solution that has similar content as plasma. The ductal cells modify these concentrations by absorption of Na+ and Cl- and secretion of K+ and Hco3- done via the apical transporter: Na+/H+ echange, Cl-/Hco3- exchange and H+/K+ exchange. On the BL membrane NA+/K+ATPase is found and Cl- channels. There is a net absorption of solute, in which, under normal conditions, water would follow. HOWEVER, THE DUCTAL CELLS ARE IMPERMEABLE TO WATER and thus, water can't follow the absorbed NaCl. This makes the final saliva hypotonic. (The acinar cell also secretes organic constitutents such as alpha-amylase, lingual lipase, mucin glycoproteins, IgA and kallikrein. Kallikrein causes vasodilation which accounts for the high salivary blood flow during periods of increased salivary activity.) The flow rate changes the composition of saliva, because the ductal cells will have less time to modify the saliva, aka they will have less contact-time with the saliva. So at high flow rates, the saliva mostly resembles the plasma!!! There is one solute that doesn't follow this principle, the HCO3- concentration is proportional to the flow rate, since it is SELECTIVELY stimulated by for ex PSY stimulus. Regulation of salivary secretion: Salivary secretion is special because it is under ONLY NEURAL CONTROL, NOT HORMONAL!!!! And both PSY and SY are responsible for stimulating it's secretion, however, it is the composition of the saliva that changes. PSY= watery highly enzymatic saliva. Done by Ach -> M3 receptor on ACINAR CELLS ONLY -> Gq coupled -> IP3 -> increased calcium signal -> increased fluid and enzyme secretion VIP -> Gs coupled -> increase cAMP which will vasodilate and increase secretion further SY= NE --> beta2 --> increased cAMP, so increased mucin secretion also alpha1 receptors are stimulated to vasocompress and reduce the blood flow to the salivary gland. GASTRIC SECRETION: The 4 components of gastric juice include: HCL, pesinogen, intrinsic factor and mucous. Together, HCL and pepsinogen initiate the process of protein degradation. Intrinsic factor is THE ONLY ESSENTIAL component of gastric juice and is required for the absorption of VitB12. Mucus protect the gastric mucosa from the corrosive behavior of HCL and lubricates. The body of the stomach contains the gastric glands that contain the mucous neck cells(mucous and HCO3-), the parietal cells (HCL and intrinsic factor) and the chief cells(pepsinogen). The pylorus/antrum contains the pyloric glands which contain the G cells (secrete gastrin DIRECTLY TO THE CIRCULATION) and mucous cells. HCL SECRETION BY PARIETAL CELLS: HCL is important to reduce the pH of the stomach to a point between 1-2 so that the enzymes can work, and to activate pepsinogen into it's active form pepsin. This is done via the channels on the apical membrane which includes: -H+-K+ATPase -cl- channels and the BL membrane channels: -Na+-K+ATPase -cl-/HCO3- exchanger. and also the presence of carbonic anhydrase inside the partietal cell which provides for the HCo3- and the H+. (MUST BE ABLE TO DRAW IT) The net results, is secretion of HCL and absorption of HCO3-. SUBSTANCES THAT ALTER HCL SECRETION: 3 substances stimulate H+ secretion: -Histamine(released from ECL cells), a paracine. Uses H2 receptor and cAMP -Ach, a neurocrine. Use M3 receptors and IP3/Ca2+ as it's secondary messenger -Gastrin, a homrone. Uses CCKB receptor (same affinity for gastrin and CCK) and uses IP3/Ca2+. They all regulate H+ secretion directly, but they also have indirect effects. This is called potentiation which refers to the ability of two stimuli to produce a combined response greater than just one. One explanation for this is that all of the substances act on the parietal cells with different receptors and in the case of histamine, with different second messengers. DRAW THE CASCADE! The indirect inhibition is caused by prostaglandins and somatostatin via the Gi-coupled receptors. Explain what the different drugs does: -Cimetidine: have a great effect as it blocks the H2-receptors which have a direct effect on the H+ secretion. -Atroprine blocks the M3 receptors and both the direct and indirect potentiated effects of Ach. Gastric secretion has three stages: -Cephalic phase accounts for approx 30% of the HCL secretions and is stimulated by smelling and tasting in anticipation of the food. Two mechanisms promote HCL secretion in the cephalic phase: firstly, the direct stimulation of the parietal cell by the vagus nerve using Ach. Secondly, the indirect stimulation of gastrin by releasing GRP, releasing gastrin in the circulation to activate the parietal cells indirectly. -The gastric phase accounts for approx 60% of the HCL secretions. Which are stimulated by distension of the stomach (causing the direct and indirect stimulation of parietal cell like above) and small peptides and aa's. Caffeine and alcohol also stimulate HCL secretion. DUE TO THE INDIRECT PATHWAY WHICH IS NOT CHOLINERGIC, USING ATROPINE AS A DRUG WON'T INHIBIT HCL SECRETION COMPLETELY, BUT ONLY THE DIRECT PATHWAY! -Intestinal phase accounts for only 10% and is mediated by products of protein degradation. INHIBITION OF PROTON SECRETION: -The major inhibitory mechanism of proton release involve somatostatin. Somatostatin inhibits the gastric H+ secretion via a direct pathway, in which it binds to a Gi-coupled receptor to reduce the cAMP levels and antagonize the effects of histamine. The indirect pathway is achieved by inhibition of both histamine release from ECL and gastrin release from G cells. -Prostaglandin also inhibits the release of histamine by ECL cells GASTRIC ULCERS: Gastric ulcers are formed when the bacterium Hylobacter pylori infects the gastric antrum and breaks down the protective mucosal barrier and underlying cells. The treatment is giving proton-pump inhibitors to restore the pH (the pH is TOO acidic).

4.2. Tubular transport processes.

URINE FORMATION: Normal urine excretion is only 1-2 L/day, because 99% of the filtered water is reabsorbed! Formation of urine by the kidney consists of 3 processes: 1) Ultrafiltration: of plasma by the glomerulus 2)reabsorption: of water and solutes from the tubules into the interstitium + blood 3)secretion: of sulutes into the tubules PROXIMAL TUBULE, FIRST HALF: -The proximal tubule reabsorbs 65-70% of the filtered Na+ (TOTAL, BUT THE FIRST HALF ONLY 20%) in processes coupled with other substances. -About 65-70% of water is also reabsorbed here, because of all the solute reabsorption raises the osmolarity of the intracellular space with respect to the tubule --> Na+ reab wit bicarb -->Na+ reab with glucose -These SGLT transporters can be saturated at around 30mM (which is still very high as the normal glucose value is around 4-5mM) -->Na+ reab with aa's, lactate and Pi (Pi reab is inhibited by PTH, since PTH wants to increase the Ca2+ levels and pi forms complexes with Ca2+ thus decreasing it's free levels in the blood) OVERALL, ONLY ABOUT 20% OF THE FILTERED NA+ IS ABsorbed in the above meachanisms! The remaining will be reabsorbed PARACELLULARLY in the second half of the prox tubule! PROXIMAL TUBULE, SECOND HALF: -The tubular cl- conc is very high now and thus, drives paracellular cl- reab, leaving a positive potential in the tubule. -cations follow -increased osmolarity causes water to be reabsorbed through aq1 channels -some glucose is also absorbed here, but with the SGLT1 (highe capcity) -organic ions such as PAH, creatinine etc are secreted via pinocytosis into the prox tubule FACTORS AFFECTING THE REABSORPTION OF THE PROXIMAL TUBULE: -Acetazolamide: inhibits carbonic anhydrase, thereby inhibiting Na+/bicarb reab -Mercury components: INHIBITS AQUAPORINS! -Non-absorbed osmolytes: mennitol, glucose/ketone bodies can draw water back into the tubule, causing OSMOTIC DIURESIS seen in diabetes mellitus LOOP OF HENLE: -responsible for another 25% of the Nacl reabsorption -only exhibit passive transport of water and electrolytes -thin DESCENDING limb is highly perm to water and has lots of aq1 to let water through, but poorly perm to Na+. Osm increases from 300mosm to 1200mosm -thin ASCENDING limb: imperm to water (lack aq1), but perm to Nacl- and urea -THE THICK ASCENDING LIMB (TAL): active transport mechanisms to remove osmolytes occurs. Not perm to water as no aq1 channels, so it is said to be the DILUTING SEGMENT OF THE KIDNEY, and it leaves the tubular fluid at an osmolarity of 150mosm. (has Na+/K+/2Cl- cotransport <-- furosemide is a so called loop diuretic as it inhibits the above mentioned cotransporter, thus leaving more osmolytes in the tubular fluid -contains ROMK1 channels which causes K+ secretion DISTAL CONVULATED TUBULE: -resp for another 5-7% of Nacl reabsorption -Nacl cotransporter CONNECTING, CORTICAL, OUTER MEDULLARY COLLECTING DUCTS: -ENac channels on the luminal side for Na+ reabsorption which is further upregulated by aldosterone (prod by the zona glomerulosa) -Enac is decreased by ANP and amiloride -Water reab is regulated by ADH, which binds basolateral Gs-coupled V2 receptors inducing cAMP, to release aq2 proteins from vesicles to the luminal membrane -The collecting duct also contains alpha and beta intercalated cells which are important to regulate the acid/base balance

7.10. The function of adrenal medulla. Adaptation to environmental stress.

The adrenal medulla constitue about 20% of the adrenal glands and is derived from neuroectodermal origin. The medulla consists of chromaffin cells which have the potential to develop into postganglionic sympathetic neruons, which are innervated by preganglionic SY neurons and that can synthetize NE. DUAL BLOOD SUPLY: The medulla has dual blood supply medulla (coming from the cortex and down to the medulla). The medullary arterioles carry nutritious, oxygenated blood to the chromaffin cells and the cortical sinusoids which have high concentrations of steroids and more importantly CORTISOL bathes the chromaffin cells. These high levels of cortisol induces the expression of the PNMT enzyme which converts NE --> epinephrine, the PRIMARY HORMONAL PRODUCT OF THE ADRENAL MEDULLA! Instead of being secreted near a target organ and acting as NT's, adrenomedullary catecholamines are secreted into blood and ACTS AS HORMONES. About 80% of the cells secrete EPI, and the remaining secretes NE. BUT, although circulating epinephrine is only derived from the adrenal medulla, only about 30% of the CIRCULATING NE is derived from the adr medulla. This is because NE is also released from post-ggl SY n terminals and diffuses into the vascular system! So, because the adr medulla isn't the sole source of catecholamines, this tissue is not essential for life! SYNTHESIS OF CATECHOLAMINES: -Synthesis begins with the transport of the aa tyrosine into the chromaffin cells, where the first, RATE-LIMITING STEP takes place by the enzyme TYROSINE HYDROXYLASE to produce DOPA. -DOPA is then converted to dopamine by AAA decarboxylase and is transported into a secretory vesicle. -Within this vesicle, all dopamine is completely converted to NE by the enzyme dopamine- beta-hydroxylase. -The NE diffuses out of the granule and into the cytoplasm where the enzyme PNMT converts it to epinphrine which is stored in secretory vesicles until stimulated to be released. SECRETION: Secretion of NE and Epi is primarily regulated by descending SY signals in response to various forms of stress such as exercise, hypoglycemia and hypovolemia. The chemical signal for secretion of catecholamines is ACh which is secreted from SY preggl neurons, and which binds to nicotinic receptors on the chromaffin cells. Ach also increases the activity of tyrosine hydroxylase, which as mentioned is the RATE-LIMITING STEP of catecholamine synthesis. MECHANISM OF ACTION OF CATECHOLAMINES: -Adrenergic receptors are classified into alpha and beta receptors with different affinity for the two catecholamines and different densities in different tissues. The functions of the recpetors are also different, since the receptors are coupled to different g proteins which execute different cellullar responses via diff secondary messengers. SUMMARY (huskeregel er QISSS): -alpha1 --> NE> Epi --> Gq --> increases vascular smooth muscle contraction, also dilates pupil -alpha2-->NE>Epi --> Gi -->smooth m relaxation -Beta1 --> NE= Epi --> Gs --> heart and salivary glands. Increases contractability and saliva secretion -Beta2--> EPI> NE (IMPORTANT) --> Gs --> bronchioles, uterus etc. Decreases contraction, causes dilation -Beta3 --> NE>Epi --> Gs --> Liver, adipose --> increase lipolysis. ADAPTATIONS OF ENVIRONMENTAL STRESS: As mentioned above, environmental stress on the adrenal medulla could be cases of figh-or-flight response, hemorrhaging hypovolemia, hypoglycemia and exercise. Exercise is similar to the fight-or-flight response, just without the element of fear. However, it does involve a greater adrenomedullary response (because it is the endocrine action of EPI that used, rather than the NT role of epinephrine which is evoked by a SY nervous signal). Adrenomedullary responses are very rapid, because the adrenal medulla is DIRECTLY innervated by the ANS! The response of the catecholamines in response to exercise is the following: 1) Increased blood flow to the skeletal muscles is achieved by the integrated action of NE and Epi on the heart (beta 1 rec), splanchnic circulation and muscular arteriolar beds by aplha1 receptors 2) Epi promotes glycogenolysis in muscle, so that exercising muscle can utilize FFA's (EPI and NE promote lipolysis) and get the efficient production of ATP needed for exercise by beta2 receptors 3) They relax the bronchiolar smooth muscle for adequate supply of oxygen and exchange of gases to exercising muscle by beta2 receptors 4)They also decrease E demand by visceral smooth m such as decreasing the motility and thus E consumption of the GI tract and urinary tracts.

5.4. Exocrine secretion of pancreas and its regulation. Bile production of the liver. Metabolism and secretion of bile pigments.

The pancreas has both an endocrine (that aids in digestion and neutralization of acidic chyme from the stomach) and exocrine function (to reg blood sugar levels). Will only talk about exocrine functions in this topic. The exocrine pancreas secretes approx 1 L of product each day. The pancreas is really important to digest proteins, since the stomach only digests about 20% of it. The secretions consist of an aquous component that is high in HCO3-and an enzymatic component. This functions to neutralize the H+, and the enzymatic portion is used in digestion. ACINAR CELLS: The acinar cells produce the enzymatic component of the secretions, which is synthesized on the RER of the acinar cells. Amylase and lipase is secreted as active enzymes, while the proteases are secreted in inactive forms. The enzymes are stored in zymogen granules until a stimulus arrives (PSY or CCk) to trigger their secretion. CENTEROACINAR AND DUCTAL CELLS: Creates the aqueous component of pancreatic juice. The first solution produced is ISOTONIC. The Na+ and K+ concentrations are the same as their concentrations in plasma (Na+ =140mM, K+=3,5-5mM), however Cl- and Hco3- conc varies with pancreatic flow rate. This is due to the modification process that occurs in the ductal cells of the pancreatic duct. The apical membrane of the ductal cells contains a Cl-Hco3- exchanger and the BL membrane contains the Na+-K+-ATPase and Na+-H+ exchanger. In the presence of carbonic anhydrase, Co2 and H2o combine in the cells to form H2co3 which dissociates to HCo3- which is secreted into the pancreatic duct lumen by the HCO3-/Cl- exchanger. The H+ is absorbed into the blood by the Na+/H+ exchanger. THE NET RESULT IS HCO3- SECRETION INTO THE PANCREATIC JUICE, ABSOPRTION OF H+ CAUSING ACIDIFICATION OF PANCREATIC VENOUS BLOOD. (DRAW THE GRAPH, CONC VS FLOW RATE) The effect of flow rate on the composition of pancreatic juice affects the Cl- and HCO3- concentration. These two ionic concentrations have a reciprocal relationship, due to the CL-/HCO3- exchanger. At high pancreatic flow rate, the HCO3- conc of pancreatic juice is highest and CL- conc the lowest. The pancreatic secretion has two functions: -to secrete the enzymes necessary for digestion of proteins -and to neutralize the chyme coming from the stomach. The pancreatic secretions, like gastric secretion is divided into three phases; cephalic, gastric and intestinal. -The cephalic phase is initiated by smell, taste and is mediated by the vagus nerve. The cephalic phase produces mainly an enzymatic secretion -The gastric phase is initiated by distension of the stomach and is also mediated by the vagus nerve. The gastric phase produces mainly the enzymatic secretion -The intestinal phase is the MOST IMPORTANT and accounts for almost 80% of the secretion. During this phase, BOTH ENZ and Aq solutions are secreted, which is regulated by both hormonal and neural regulation as explained below: (There is a drawing for this) What is important to understand is that CCK stimulates enzymatic secretion and secretin stimulates aqeous secretion using different recptors and different secondary messengers! Pancreatic acinar cells have receptors for CCK (CCKa receptors) which, due to stimulus by presence of aa's, I cells secrete CCK to make the acinar cell secrete enzymatic pancreatic juice. In addition to this, Ach potentiates this via the vagovagal reflexes. The ductal cells have receptors for CCK, Ach and secretin. Secretin is secreted by S cells in the duodenum in the presence of H+. These actions are potentiated by both CCK and Ach. Overall, CCK causes enzyme rich pancreatic secretions (via CCKa rec) Secretin causes bicarbonate rich pancreatic secretions and Ach potentiates both. (via secretin rec) BILE PRODUCTION AND SECRETION: Bile is necessary for the digestion and absorption of lipids in the small intestine. This is because they solve the problem of lipids being insoluble, by wrapping around them in micelles. Bile is produced continously and secreted in the liver by hepatocytes. The components of bile includes, bile salts (primary cholic adic, chenodeoxycholicacid. Secondary: deoxycholic acid and lithocholic acid), cholesterol, phospholipids, bile pigments, ions and water. Bile flows out of the liver and into the gallbladder where it is stored and further concentrated by absorbtion of water and ions. When chyme reaches the small intestine, CCK is released which has 2 functions: -to stimulate contraction of the gallbladder -and to relax the sphincter of Oddi so that the bile can flow into the duodenum and mix + emulsify the fats. When the lipid absorption is complete, the bile salts recirculate to the liver via the enterohepatic circulation.(DRAW AND EXPLAIN THIS CIRCULATION) This step involves the absorption of bile salts from the ileum into the portal circulation via the Na+/bile salts cotransporter, delivery of bile salts back to the liver and then extraction of bile salts from the portal blood by the hepatocytes --> aka, the liver must only replace A SMALL AMOUNT OF THE BILE SALTS THAT ARE NOT RECIRCULATED (600mg/day lost in fecal matter). The liver "knows" how much new bile acids to synthesize daily as bile acid synthesis is under negative feedback by bile salts. It is the rate-limiting step catlyzed by the cholesterol 7alpha-hydroxylase that is inhibited by bile salts. Bile acids is produced from cholesterol, which is taken up by LDL-receptors. Primary bile acids are produced by cholesterol 7alpha hydroxylase and is conjugated with the amino acids taurine and glycine. This conjugation step causes the bile acids to be much more water soluble and become amphipathic. When the primary bile acids are secreted from the liver, into the intestinal luman, the intestinal bacteria produce two secondary bile acids by dehydroxylation at C7. Metabolism and secretion of bile pigments: Bilirubin is a yellow pigment and the major bile pigment (a byproduct of Hbg). Bilirubin is conjugated in the liver to give bile it's yellow colour, and is secreted into the intestine together with bile. Here, in the intestine, it is converted back to bilirubin, which is THEN CONVERTED TO UROBILINOGEN by intestinal bacteria. Some of it is recircled, some of it is excreted in urine and some is oxidized to urobilin and stercobilin which is excreted with feaces and is what gives it it's dark colour

8.11. Electroencephalogram (EEG); sleep phenomena. Learning and memory.

EEG: electroencephalogram is the recording of neuronal electrical activity that is produced in the cerebral cortex -Electrodes are placed on the skull and the SYNAPTIC POTENTIALS DIPOLES ORIGIANTING FROM THE PYRAMIDAL CELLS ARE PERPENDICULAR TO THE ELECTRODE RESULT IN THE EEG WAVES -the waves recorded are NOT AP's! -We use EEG's to measure brain rhytm and to measure epileptic seizures IMPORTANT: -alpha wave: 8- 13Hz, eyes closed, calm -beta wave: 13- 30 Hz, eyes open, mental activity, excitement, thinking -delta rhytm: 0,5-4 hz, deep sleep -theta wave: 4-7 Hz, sleep, drowsy, frustaration, dissapointment, sometimes PATHOLOGICAL in adults SLEEP PHENOMENA: -Sleep is powered by the circadian rhytm which is about every 25 hours, however the suprachiasmatic nuclei adjusts this according to light and darkness. --> it is NOT a loss of consciousness or brain activity --> sleep is an actively controlled mechanism -->the cortex is still active during sleep SLEEP STAGES: 30-45 min -stage 1: alpha and theta waves -stage 2: slower EEG waves with small bursts of activity known as sleep spindles and K complexes -stage 3: delta -stage 4: delta waves and no spindles During sleep, the body's phsyiology changes: --> posture is adjusted --> muscles relax --> HR, BP and breathing decrease --> GI tract increases motility --> metabolism is highly active during sleep TO WAKE UP, THE PERSON MUST PASS THROUGH THE STAGES IN REVERSE! --REM: EEG becomes desynch and most similar to alpha waves. Person is hard to wake up. MUSCLE TONE IS LOST EXCEPT EYE MUSCLE. Penile erection can occur, loss of thermoreg. REM occurs most freq in youth and then decreases with age LEARNING is a change in the reaction to stimuli whereas memory is the storage of what has been learned. Can be: -IMPLICIT: unconscious, expressed in behavior, automatic behavior like reflexes, not verbally expressed EXPLICIT: can be short term, intermediate, long term -storage of past life events -can be verbally expr such as feelings or ideas

1.2. Structure, permeability and transport functions of the cell membrane. Transepithelial transports

FUNCTIONS OF THE CELL MEMBRANE: 1) they keep toxic substances out of the cell; (2) they contain receptors and channels that allow specific molecules, such as ions, nutrients, wastes, and metabolic products, that mediate cellular and extracellular activities to pass between organelles and between the cell and the outside environment; and (3) they separate vital but incompatible metabolic processes conducted within organelles. STRUCTURE OF THE CELL MEMBRANE: -PHOSPHOLIPIDS: most abundant kinds are the choline-containing phospholipids; lecithins and sphingomyelins. Some of them play a crucial role in SIGNAL TRANSDUCTION (for ex phospholipase C). They have heads made of glycerol which are hydroPHILIC and tails made up of 2 FA's which are hydrophobic, OVERALL MAKING THEM AMPHIPHATIC -CHOLESTEROL: make the membrane more rigid, creating lipid rafts -GLYCOLIPIDS: function as receptors and antigens -PROTEINS: --> integral (in the membrane), allowing contact between ECF and ICF (transmembrane), for ex; g-coupled proteins, Na/K+ pumps, hormone-binding receptors etc -->glycoproteins with a covalently-bound carbohydrate side chain facing e.c. They have a role in communication between the e.c matrix and the cell's cytoskeleton, + adhesion TYPES OF TRANSPORT ACROSS THE CELL MEMBRANE: -Lipid soluble molecules can cross the plasma membrane, like O2, CO2, steroids etc -But water soluble molecules cannot and needs help to be transported across (Na+, Cl-, glucose) -Some of the molecules requires transport proteins in which it is important to differentiate between a carrier protein and a channel: -CARRIER: is an eznyme, which turn active and passive in a cyclic manner, and can be saturated. Has a slow rate of transport -CHANNEL: are gates that can only alter between blocking or ALLOWING PASSIVE TRANSPORT to take place. The transport is much faster and doesn't show saturation like with the carrier! TRANSPORT PROCESSES: -SIMPLE DIFFUSION: gases are transported in this manner, and no protein is needed. The driving force is the concentration difference between two compartments. Simple diffusion is fast over short distances, and very slow over long ones. Follow fick's law of diffusion where the diffusion coefficient depends on the size of the molecule and the distance the process is occuring over. J= D*A/x * conc difference -FASCILITATED DIFFUSION: works with the concentration gradient and does not require energy, but the transport protein can dramatically increase the rate of diffusion. For ex: GLUT 4 transporter. H20 undergoes fasc diffusion via aquaporins (more rapid diffusion of h20 than just simple diffusion) -PRIMARY ACTIVE TRANSPORT: uses ATP, and is linked to metabolic energy in some way, usually GOING AGAINST THE CONCENTRATION GRADIENT. Examples: Na+/K+ATPase, PMCA (Ca2+ ATPase pumps Ca2+ out of cell), SERCA, H+/K+ ATPase in parietal cells and alpha-intercalated cells -SECONDARY ACTIVE TRANSPORT: uses the POTENTIAL ENERGY stored by the concentration gradient created by primary active transport to power another ion to cross the PM. Can be either a symport or an antiport. Examples: SGLT (sodium glucose transport in the kidney which is driven by the Na+/K+ATPase), or Na+/K+/2Cl- cotransporter also driven by the Na+/K+ATPase Countertransport ex: Ca2+/Na+ exchanger in heart., Na+/H+ exchanger in proximal convulated tubule, and collecting tubule ----> One important transporter which is imp to mention is the CFTR (cystic fibrosis transmembrane conductance regulator protein), which, if mutated, will cause a retention of Cl- inside the cell and thus, not inhibiting the EnaC, leading to increased Na+ conductance and thus, salty cellular secretions. VESICULAR TRANSPORT: -Endocytosis: 1)pinocytosis: nonspecific uptake of small molecules and water 2) phagocytosis for larger molecules like bacteria, is usally receptor-mediated via ag's 3)receptor mediated endocytosis by clathrin-coated pits -exocytosis: 1)constitutive: always active for a particular cell type 2)regulated: requires an external signal to begin secretion, for example, ca2+ signal. Describes secretion of endocrine cells, neurons, exocrine cells which secrete hormones, NT's at regulated intervals. WATER TRANSPORT AND PERMEABILITY: -passive transport of water via simple diffusion is called osmosis. -Osmolarity= concentration *number of dissociated particles -tonicity= ONLY takes into account total concentraion of NON-PENETRATING solutes (aka, just Na+, urea etc) -The reflection coefficient used in the Van't Hoff equation for osmolar pressure can be used to calculate if a solute is a good or a bad osmole. -refl coeff = 0, can diffuse so is a bad osmole -refl coeff= 1 cannot diffuse so is a good osmole ( VAN'T HOFF: Used to calc osmotic p - symbol is pi Pi= i(vant hoff factor) RTnc

6.1. Hematopoiesis. The composition of the blood

Hematopoesis is the formation of blood cells and how they get into the circulation. The blood is compromised of: -RBC's (F: 3,9-5,3*10^6/uL, M: 4,5-5,5*10^6/uL) -WBC's (3-12*10^3/uL) -Platelet's (2,5-3*10^5/uL) There are two forms of hematopoeisis: -CONSTITUTIVE: or housekeeping, is a daily production to maintain steady levels in which 10^11 cells are produced a day. -75% WBC -25% RBC (BUT, there are more RBC's due to their lifespan which is 120 days, which are much longer tgan most WBC's) -STRESS HEMATOPOESIS: is induced by an event such as anemia or an infection in which case the appropriate blood type of cells are made Hematopoesis occurs mainly in the liver in the developing fetus and as it grows, the location is slowly changes to the bone marrow. After birth, the hematopoetic organs are the axial skeleton and some in the long bones. The lecture insists that the spleen doesn NOT produce blood cells in humans. The bone marrow have a structure of active (red) and inactive (yellow = fatty) states. The active states refers to the hematopoetic stem cells, stromal cells (for structural support). Hematopoetic stem cells are the mothers of all blood cells. They have some important characteristics: -They are self-renewing (when they divide, some remain stem cells and other go through the cell differentiation to become specialized) -multipotent (can form a variety of cell types) -thei divison is assymetric (as described with some cells specializing and others remaining stem cells) -and they have two specific surface markers: --> c-kit (a receptor tyorsine kinase that binds "stem cell factor") and CD34 (migration/adhesion molecule) MUST EXPLAIN AND KNOW THE STEPS OF ALL THE CELLS ETC. HSC--> omnipotent --> oligopotent --> unipotent FACTORS RESPONSIBLE FOR MATURATION: -Cytokines which are glycoproteins that induce transcriptional gene regulation via the tyrosine-kinase mechanism. --> Il-3 usually moves cells down the myeloid line --> IL-6 is a regulator of stem cells which is secreted by T cells and macrophages --> erythropoetin --> form of RBC's -The environment: The environment of the cell (cellto cellconnections) is important in the differentiation of blood cells in the bone marrow. Cells in contact with certain stromal cells will take on certain differentiation/specialization routes (an area dedicated to a certain function like this ="niche"). therefore chemokines exist in the bonemarrow to induce cell movement to different parts of the bonemarrow (via chemotaxis, which is driven by chemokines)and regulate the differentiation process. An example of a specialized niche is a osteblast. The idea of niche leads to the suggestion that cell differenatiation can be limited by asymetrical division and environmental asymmetry. ERYTHROPOESIS: Proerythroblasts--> basophilic erythroblasts (incr RER to produce ribosomes) --> polychromatophilic erythroblast (acc of Hbg) --> orthochromatic erythroblast (nuclei shrink and move to the side) --> reticulocyte (still contain RER for hbg synth) --> erythrocyte! Erythrocytes ​form from the myeloid lineage that become proerythroblasts and then erythroblasts. Slowly they gain more hemoglobin and their nuclei shrink until they are orthochromatic erythroblasts. These orthochromatic erythroblasts begin to localize their nucleus on one side of the cell and a macrophage becomes attached to that side and absorbs the nucleus. Now the cell is called a reticulocyte, which is anuclear and has also lost its mitochondria. [It is called a reticulocyte because it is not quite mature yet and there is a special staining technique which stains the RNA for hemoglobin synthesis, making it reticulated] Hemoglobin is the main component of mature erythrocytes, and most other organelles are absent or are in small quantities. REGULATION OF ERYTHROPOESIS: Erythrocyte production is regulated by erythropoietin (EPO) , which is mainly produced in the kidney (90%) by interstitial fibroblasts, with some minor production also in the liver (10%). The production of erythropoietin is a negative feedback mechanism that is regulated by oxygen concentration in the kidney. Low O2 content in the kidneys causes hypoxiainducible factor(HIF) to activate , causing increased transcription of the erythropoietin gene and production of erythropoietin. This will increase erythrocytes and thus o2 content in kidney's. It is also dependent on folic acid, vit B12 and iron. THROMBOPOESIS: Thrombocytes ​are initially formed the same myeloid path as erythrocytes, but instead become promegakaryoblasts → megakaryocytes → thrombocytes/platelets. This is done when the megakaryocyte processes grow through the intercellular space of the endothelial cells of the vessel wall and platelets begin "budding off" of the process into the vessel. platelets are continuously used up in injuries in the vasculature, thus daily use and production occurs. LEUKOPOESIS (will talk about this in immuno topics), but some important info: granulocytes take 912 days to mature, but this can be sped up to 2 days in cases of infection, thanks to cytokines. Mature granulocytes exit the bone marrow and either freely circulate (these granulocytes are called the "circulating pool") or they attach to the endothelial cells of blood vessels (these are called the "adherent pool"). They change between these two roles until finally they find a spot where they will burrow into the interstitium.

2.7. Functional organization of microcirculation and its control. Control of interstitial fluid volume, Starling forces.

MICROCIRCULATION: Refers to the functions of the smallest blood vessels, the capillaries and the lymphatic vessels (own topic) -Arteries undergo DICHOTOMOUS ARBORIZATION, meaning that they contineously divide into 2 branches as they transition into capillaries. -Capillaries ARE THE FUNCTIONAL UNIT OF MICROCIRCULATION --> it's the site of exchnage of nutrients, waste prodcuts and fluid between the vascular and intestinal fluid compartments -Metaarterioles can also direct blood from arterioles to venules, but without nutritive flow (shunting= skipping the capillaries) -Smooth muscle cells form a layer of the arteriolar wall which control flow in the arterioles, but NOT in the cap wall. --> it is the PRE-CAPILLARY SPHINCTERS which control the flow to the capillaries, and since they do not posess Sy innervation, they are only regulated by local control. When the pre-cap sphincters close they shunt the blood via metarterioles so that the blood won't go through the capillaries! --> Both the pre-cap sphincters and the smooth muscle cells in the arteriolar wall are responsive to many different signals such as NT's, hormones and metabolites. Most of which are produced by endothelial cells during shear stress to release vasodilators like prostacyclin and NO! --> autoreg/Bayliss effect explain -Vasomotion: vascular smooth muscle in arterioles undergoes cyclic contractions and relaxations (oscillations in diameter) --> the mechanisms behind this is the cyclic change of calcium signal --> this improves flow in the periphery and gives the blood a little push -> more efficient Due to the small diameter of the capillaries, RBC's must go through a severe deformation while they travel through the capillary. --> The RBC and plasma flow through the capillary single-file, each RBC is a "plug" followed by a plasma "bolus" between another RBC --> enhances molecular exchange! --> The RBC's never come into contact with the wall because of the wall's GLYCOCALYX LAYER which covers the int. surface of the endothelium Even WBC's, which are quite larger than RBC's, can pass through the capillary. But in a much slower flow of course, which sometimes block the capillary and needs a pressure gradient to build up for it to push it through. --> Luckily, there are much less WBC's than RBC's, but if WBC count increases then this can cause blood flow problems! STRUCTURE OF CAPILLARY AND IT'S EXCHANGE: -CONTINEOUS: tight, very specific to what they let through for ex in BBB -FENESTRATED: allows a lot more kinds of molecules through, in absorptive tissues -DISCONTINEOUS: few limitations, even lets some cells go through, like in the spleen and liver (filtration of RBC's in spleen) -The exchange of the solutes and gases across the capillary wall occurs via SIMPLE DIFFUSION -Some solutes diffuse through endothelial cells, others diffuse between them --> TRANSCELLULAR PATHWAY: lipid-soluble substances, like gases, O2, CO2) diffuse through the endothelial cells, depending on the partial pressure of the gas and the surface area --> PARACELLULAR PATHWAY: water-soluble substances like water itself, ions, glucose etc cannot cross the endothelial membranes so they travel in aqeous clefts between the endothel cells. Proteins are usually unable to pass CONTROL OF INTERSTITIAL FLUID VOLUME: Fluid moves between the plasma and the interstitial fluid compartments through the capillary wall iva osmosis, as long as aquaporins are present and also that there is a pressure gradient present across the membrane. --> THESE PRESSURE DIFFERENCES ARE WHAT IS CALLED STARLING FORCES!!!!!!!! STARLING HYPOTHESIS: states how fluid across a capillary wall is dependant on the balance between the hydrostatic pressure and the oncotic pressure difference across the capillary (so the pressure difference between the plasma in the capillary and the interstitium). -Results in an outflow of fluids at its arterial end with an increasing inflow toward its venous end. Jv= Kf ((Pc-Pi) - (pic - pi,i)) STARLING FORCES: -CAPILLARY HYDROSTATIC PRESSURE (Pc): (32-15mmHg) --> favours filtration --> it drops in pressure due to the dissipation of E via the filtration of fluid. The only one with a drastic p drop -INTERSTITIAL HYDROSTATIC PRESSURE: --> opposes filtraton -->value is often negative rel ti atm. Normally, near 0 -> -5 mmHg -CAPILLARY ONCOTIC PRESSURE (25mmHg) --> opposes filtration (but if +, like in kidney, it will favour filtration) --> this value can be effected by the plasma proteins. An increase in plasma protein conc's increases cap oncotic p (also called colloid osmotic pressure) and leads to less fluid movement into the interstitium (less filtration) ----> "Relative coefficients is a mathematical way to show what can pass through the membrane. H20 = 0 because it passes freely, while albumin =1. This is region -specific. In the brain for example it is 1 for proteins, while in the liver = 0 for proteins. -INTERSTITIAL ONCOTIC PRESSURE: --> favors filtration --> determined by the interstitial protein concentration. Normally there is a LOW AMOUN TOF PROTEIN IN THE INTERSTITIUM, so this P SHOULD BE LOW. --> starts at 0 and will increase slightly on the venular end THE NET PRESSURE OF THE STARLING FORCES, is the sum of all the four Starling force pressures. --> if sum is + then there will be net filtration OUT OF THE CAP --> if sum is - then there will be net absorption into the capillary

5.6. Energy balance of the body. The quantitative and qualitative requirements of food. The regulation of food intake. Control of body weight.

Metabolism refers to the chemical reactions in the body, which generally requires some sort of fuel/E to be maintained. There are 3 sources of E: fats, carbs, protein. The amount of E that they provide is measured in J/calories. E content: carbs= 17kJ/gram fats= 39kJ/gram protein=17kJ/gram Neutral E balance (when calorie intake vs usage is equal) is called TOTAL ENERGY EXPENDITURE(TEE). Negative E balance is typical for weight loss (consume less calories than used) and positive E balance is typical for weight gain (consume more calories than they use). TEE is directly measured by measuring a person's heat production which corresponds to the rate of metabolism. TEE= HEAT PROD + EXTERNAL WORK However, this is not a very pratical way of measuring as a person would have to sit in a room full of ice and see how fast the ice melts to be able to measure it, hence, we measure the rate of metabolism via the INDIRECT way by measuring the oxygen consumption (as most metabolic processes require ATP through oxidative phosphorylation). ! 1 liter of o2 is roughly equivalent to 21kJ of E released! BMR= Basal metabolic rate is the minimal E expenditure required to exist. It refers to the E used in an awake state and without PE. TEE= BMR + DIT (diet induced thermogenesis) + E expenditure in PE. So to measure BMR, the person must not be moving nor be digesting food (as this accounts for around 8-15% of the TEE and uses a lot of E.) BMR of women are usually lower than men as women have more body fat, and men have more muscle. Women: 6000kJ/day Men: 7000kJ/day BMR is also influenced by: -body size -age (declines with age) -body temp (BMR is high when you have a fever) -climate -thyroid hormones and catecholamines increase the BMR -drugs, stress etc BMR IS NORMALLY 50-70% OF TOTAL ENERGY EXPENDITURE. Heat production is usually just a side effect of the metabolic processes of our body, but some tissues are specialized for heat production. For example the brown adipose tissue. (Highest in newborns, very low conc in adults). What is special about brown adipose is the abundance of mitochondria, which has the UCP1 transmembrane protein that allows H+ ions to flow from the intermembrane space into the matrix, which again, decreases the H+ gradient necessary for ATP synthase. UCPs are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. Basically, UCP1 allows for the dissipation (E being transformed from one state to the other) of the proton gradient in the inner mitochondrial membrane to yield heat at the expense of ATP production. So heat is produced and not ATP! Exposure to cold and catecholamines stimulate the cell differentiation of beige adipose cells which contain this uncouple protein 1. Specialized areas of the hypothalamus analyze incoming afferent signals, and through various efferent pathways, they coordinate food-seeking and thermogen to maintain appropriate long and short-term E needs. We have two main centers in the hypothalamus that get their information from the arcuate nucleus: -the satiety center which inhibits appetite even in the presence of food -the feeding center which has the opposite effect The arcuate nucleus communicates with the centers via neurons that project into them, these being called ANOREXIGENIC NEURONS (they release POMC that decreases appetite) and OREXIGENIC NEURONS (that release neuropeptide Y that causes increased appetite). These factors act on the arcuate nucleus to influence hunger and feeding: -increased adipose tissue mass increases leptin (can cross BBB) which decreases huger by stimulating the anorexigenic neurons. These effects are long-lasting -insulin will also stim anorexogenic neurons and inhibit orexigenic neurons, plus indirectly support leptin secretion -Some neuropeptides released from the GI will also aid this: HUNGER DECREASED BY: -GLP-1 (stim insulin secretion) -petide YY -CCK -CART HUNGER INCREASED BY: -ghrelin -orexins Draw the added picture to aid explanation

3.5. Cardiopulmonary adaptation during change in the body position and during physical exercise.

-REMEMBER: PCO2 AND PO2 NEVER CHANGE DURING EXERCISE, ONLY VENTILATION AND MORE EFFICIENT GAS EXCHANGE CHANGES TO KEEP THE PCO2 AND PO2 LEVELS GOOD. -Venous pCO2 will increase since the skeletal muscle produce a lot of CO2, thus we need to increase the respiration to decrease these levels and that's why we respirate even when we are done lifting -The muscle and joint receptors (proprioceptors) will send signals to the medullary inspiratory centre to increase ventilation due to increased movement in the body. They are activtaed early in exercise, and can sometimes also be activated by conscious anticipation before exercise begins -CO will increase during exercise to deal with the increasing demand for O2 from the metabolism, therefore the pulmonary blood flow increases, which causes a decreased resistance in the capillaries so perfusion of the lungs becomes more even (not a big difference between the top and bottom like it usually is) -The hbg affinity will change as we need to unload a lot more O2 in the tissues. Many of the inhibitors for Hbg are produced during exercise, which causes an increased unloading of O2, by shifting the hbg curve to the right -There are also stretch receptors in the lungs which will be activated when ventilation is increased, which activates the HERING-BREUER REFLEX to make sure our lungs don't overinflate, even though our respiration increases to meet the demands of our body during exercise

1.6. The development of the action potential in excitable cells: similarities and differences between distinct cells. Conduction of the action potential.

An action potential is an electrical messaging phenomenon of excitable cells (nerve and muscle), characterized by a rapid depolarizatio followed by repolarization of the resting membrane potential Characteristics for AP's: -All-or-nothing phenomena: of the treshold potential is met, then an AP of the stereotypical amplitude is produced, if not, then no AP -Propagation without decrement: an AP at one site causes adjacent sites to depolarize, bringing them to the treshold as well, without decreasing the AP amplitude -Stereotypical size and shape: each normal AP of a GIVEN cell type look identical and de/repolarizes to the same values, depending on that cell type's ion channels. -Treshold potential: different cell types have different treshold voltages that must be met for their depolarizing cascade to commence -has absolute and relative refractory time Characteristc for electrotonic potentials: -Strength is proportional to the stimulus as no treshold is needed -passive conduction -decays with distance from source -multidirectional -can be both depolarizing and hyperpolarizing -summation --> temporal and spatial -no refractory time -ligand-gated channels (while, AP's have ONLY voltage-gated channels. DEVELOPMENT OF AP'S: Generally, APs develop as the result of graded potentials (electrotonic potentials) which reaches the treshold voltage and stimulate an ion-channel cascade that depolarizes and repolarizes the membrane potential. IN NERUONS: (draw each AP) -At rest, K+ permeability is high and Na perm low, leading to a membrane potential of -70mV -Due to an incoming signal, Ach is released in the synaptic cleft and ligand-gated Na+ channels open, the membrane to become more positive and closer to treshold --> -50mV -This activates voltage-gated Na+ channels, increasing the Na+ permeability above that of K+ -Na+ influx depolarizes the cell membrane to +40mV (in about 1ms) -Repolarization occurs as the Na+ channels close and voltage-gated K+ channels open, leading to K+ efflux -Hypoerpolarization occurs due to the increasing permeability for K+.--> -85mV As the K+ channels close, Em is returned to normal values IN SKELETAL MUSCLE: -Em is at -90mV -The basis of an AP is similar to the neuron, the only differences is that skeletal muscle is under voluntary control and the AP lasts longer (1-2ms) and has a very brief refractory period --> which is why tetanus can occur for example (more on this in the skeletal muscle topic). -AP's in the muscle cell membrane are propagated to the T tubules (contineous with the sarcolemmal membrane) by the spread of local currents from the surface to the interior of the muscle fiber -This depolarization of the membrane causes a confirmational change in the voltage-sensitive dihydropyridine receptors (which are actually L-type Ca2+ receptors), and they open Ca2+-release channels called Ryanodine receptors on the nearby sarcoplasmic reticulum -When this occurs, Ca2+ is released from it's storage in the SR to increase the i.c ca2+ conc. -Ca2+ binds to troponin C on the thin filaments and causes a conf change to move the tropomyosin from hiding the myosin head binding site and the cross-bridge model can occur. (IF, the muscle is stimulated repeatedly, in such a case where the SR doesn't have time to reaccumulate Ca2+, then the high Ca2+ levels will cause the continuation of the cross-bridge model and sustain contraction = TETANUS, rather than just a single twitch) (DRAW)! AP IN VENTRICULAR, CARDIAC MUSCLE: (-85/-90mv) -it has a very long duration (200msec ++) -The refractory period is also very long as we can't have tetanus in the cardiac muscles -has a long platau of depolarization happening. -The depolarization enters via electrical synapses between the gap junctions. -Depolarization of the membrane occurs by the opening of the voltage-gated Na+ channels, in which they become inactivated at around +20mV -As the Na+-channels inactivate, both electrical and concentration gradient's favor K+ efflux, so the membrane repolarizes slightly -The platau is caused by the opening of L-type voltage-dependent Ca2+ channels that open during the end of deplarization (+20mV) and increase the Ca2+ conductance. There is now an inward current of Ca2+ and to balance this, K+ effluxes out of the cell -When the K+ efflux begins to exceeds the Ca2+ influx, and Ik (inwardly-rectifying K+)-channels open to allow the outward K+ current, this restores the Em to it's normal value. AP'S IN SA/AV NODE: (nota stable resting memb, but is around -60mV) -The most important differences here is that there is NO RESTING MEMBRANE POTENTIAL, as these cells are what drives our heart beat, and act as pacemaker cells. -They also lack a platau -They have more of a positive Em, because they lack the inwardly rectifying channels -Depolarization happens slowly with a Na+-influx current created by the If (funny channels), and at a treshold voltage T-type VDCCs and L-type VDCCs activate and Ca2+ influx depolarizes the nodal cells. -INITIAL DEPOL AND PLATAU PHASES ARE ABSENT IN NODAL CELLS -Repolarization occurs due to the increased K+ permeabilty caused by the delayed rectifier K+ current (iK), which repolarizes the cell to about -65mV after the upstroke is complete. COMPARE AND CONTRAST CARDIAC M VS SKELETAL M: (Cardiac / skeletal) - both are striated - T-tubules present, 1 per sarcolemma / 2 T-tubules per sarcolemma - involuntary contraction /voluntary contracton -Gap junctions / no gap junctions -Requires extracellular ca2+ for contraction to occur which is supplied by the L-type Ca2+ channels /requires intracellullar ca2+ for contraction -AP compromises both Na+ and Ca2+ inflow /AP compromises ONLY inflow of Na+ -AP duration is for 150-200ms so refraction period is longer / AP lasts only 2-5ms and can be tetanized REFRACTORY PERIODS: (DRAW GRAPH) During the refractory periods, excitable cells are incapable of producing normal AP's, no matter how great the stimulus. The duration of the absolute refractory period lasts almost the entire duration of the AP. During this period, an AP CANNOT be elicited, no matter the strength of the stimulus. This is because of the different configurations of the Na+ and K+ channels. They are both voltage gated, and open accordingly. The Na+-channel, however, has 3 configurative states: open (caused by the depolarization of the Em), closed and INACTIVATED (which is the cause of the absolute refractory period). The K+ channel only has 2 configurations: open and closed. When the K+ channels open during repolarization, relative refractory period begins, which, due to the increased K+ conductance, can elicit an AP, if the stimulus is stronger than the usual depolarizing current needed! CONDUCTION OF AP'S: Ap's are unidirectional and usually travels from the soma down the axon. The axon hillock is most dense with voltage-gated Na+ channels. 2 factors increase the conduction velocity of neurons: -the nerve diameter - velocity increases with the nerve diameter becasue R is inv prop to cross-sectional area -Myelination --> provides insulation which increases the membrane resistance and thus forces current to flow down the lower resistance pathway of the axon, rather than flowing out through the membrane. --> Fast nerve fibers are the myelinated A alpha motor neurons at 75-120m/s. Slowest are unmyelinated fibers at 0,4-2m/sec

8.5. Physiology of hearing

Audition is the sense of hearing and involves the transduction of sound waves into electrical energy, which can be transmitted to the nervous system. Sound is produced by waves of compression and decompression which is transmitted in an elastic media such as air or water (it differs from light, which doesn't need a media to propagate in. Sound requires a media!!). These sound waves are associated with increases or decreases in pressure and the units for sound is in decibel (dB), which is on a relative measure on a log scale. The sound frequency is measured in hertz. A pure tone results from sinusoidal waves of a single frequency. The human ear is sensitive to tones with frequencies between 20Hz and 20 000Hz, however, human speech usually range between 300-3500Hz (sound intensity around 65dB). Sound intensity above 100dB can be damaging and painful to human ears. The structure of the human ear includes: -THE EXTERNAL EAR: which consists of the pinna and the external auditory meatus, and it's function is to direct sound waves into the auditory canal. It is an air-filled space -THE MIDDLE EAR: consists of the tympanic membrane and a chain of auditory ossicles called the malleus, incus and stapes. The tympanic membrane separates the external and the middle ear and contain the oval and the round window, and creates an amplification of the sound. The foot of the stapes inserts itself into the oval window and when sound waves arrive, it will create pressure waves from the oval window into the fluid-filled space of the inner ear. The middle air is also air-filled. -THE INNER EAR: consists of a bony labyrinth and a membranous one. The bony labyrinth consists of the semicircular canals(lat, post, sup) which are important in the vestibular system. The membranous labyrinth consists of the a series of ducts called the scala vestibuli, scala tympani and scala media. The first two are filled with perilymph which has a similar ionic composition like the extracellular fluid, while the scala media is filled with endolymph which has a HIGH K+ CONC and low Na+ conc. Making it appear more similar to the intracellular fluid, than the extrecellular, eventhough it is characterized as the latter. From the two labyrinths, the cochlea and the vestibule is formed! The cochlea contain the organ of corti that contains receptor cells and is the site of auditory transduction. The inner ear is fluid-filled. (Endolymph is produces by the stria vascularis. This is a transepithelial transport that uses the Na+/K+/Cl- transporter to pump all 3 ions from the perilymph across the epithelium, however, only K+ will make it all the way to the endolymp as Na+ is pumped back due to the Na+/K+ ATPase, and Cl- via it's own channels. This system produces the high K+ endolymph and the high Na+ perilymph. THE STRUCTURE OF THE ORGAN OF CORTI: (maybe draw it?) The organ of corti is the transduction apparatus of the human ear. The cochlea, where we can find the organ of corti is divided into three chambers, by two membranes: The REISSNER'S MEMBRANE DIVIDES the scala vestibuli and the scala media, and the BASILAR MEMBRANE divides the scala media from the scala tympani. The organ of corti is located in the basilar membrane of the scala media. It consists of receptor hair cells which contain cilia that are embedded into a gel-like substance called the tectorial membrane, and the base of the hair cells synpase on the axons of CNVIII. The organ of corti consists of two types of receptor cells. The inner hair cells which are fewer (3500) and are arranged in single rows. And the outer hair cells which are more numerous (16 000) and arranged in parallel rows. STEPS IN AUDITORY CONDUCTION: In cochlea, there is a VERY IMPORTANT voltage difference between the different chambers. The endolymph in the scala media has a membrane potential of +80mV, while the hair cell potential is -40mV. This causes a potential difference of +120mV, aka it's a huge difference. Why this is important is because there isn't really much K+ difference between the hair cell and the endolymph, so the electrochemical gradient is important to drive K+ from the endolymph onto the hair cell to depolarize it. ( OBS! KAN VÆRE FEIL! ) The outer hair cells are embedded in the tectorial membrane, while inner cell cilia have some distance between the two. The inner cells are the primary auditory receptors. THE MECHANISM OF ACTION: When the stapes moves, it creates pressure differences in the perilymph. The p in the scala vestibuli will decrease and the p in scala tympani will increase. Because of these pressure waves, the stereocilia in the tectorial membrane will tilt and open K+ channels and depolarize the outer cells. The outer hair cells have a motor protein: PRESTIN, present that can cause contraction without the aid of ATP. Depolarization leads to contraction of the outer hair cells, THIS IS WHY THE OHC ARE CALLED ELCETROMECHANICAL TRANSDUCERS (they convert electrical signals of depolarization into mechanical signals). The contraction of the outer hair cells causes cochlear amplification and endolymph flow which causes the stereocilia of the inner hair cells to bend and therefore, the inner hair cells are ALSO ACTIVATED resulting in K+ influx and depolarization. Due to this depol, the VD-Ca2+ channels open and this causes an increased exocytosis of glutamate from the hair cell into the synaptic cleft and the afferent neurons are activated and generate AP's. The type of receptor in the stereocilia are mechano-sensitive and part of the TRANSIENT RECEPTOR POTENTIAL (TRP) A1 FAMILY, which are non-specific cation channels that conduct K+, Na+, Ca2+. These channels are always active at a certain level when resting, but with a positive mechanical deformation, they open even more. So the membrane potential of the hair cell is always oscillating between depolarizing potentials and hyperpolarizing potentials. ENCODING SOUND: (remember to distinguish between the frequency of the AP's which correspond to the intensity of the sound, and the frequency the sound waves down the basilar membrane which corresponds to the displacement of the waves on the membrane) Encoding of frequencies occurs because different auditory hair cells are activated by different frequencies. The freq that activates a particular hair cell depends on the POSITION of that hair cell along the basilar membrane. The base of the membrane is closest to the stapes and is narrow and stiff, hair cells located here respond best to high frequencies. The apex is wide and complient and the cells here respond best to lower frequencies. AKA THE BASILAR MEMBRANE ACTS AS A SPIMD FREQUENCY ANALYZER. AUDITORY PATHWAYS INNERVATION: 95% of afferent fibers are from the inner hair cells. The body of the neurons forms the spiral ganglion which is the first order neuron. The second order neuron is in the superior olivary nuclei and then it goes to the cortex of brodman area 40/41. Some fibers cross, while others remain IL. This means that central unilateral lesions of the auditory pathways does not cause deafness as some of the fibers transmitting info from that ear have already crossed. IMPORTANT: the OHC receive efferent fibers (the inner hair cells do not). They receive Ach as a NT, and the OHC have nicotinic receptors in which the Ach lead to depol --> ca2+ influx --> activation of CALCIUM-DEP K+ CHANNELS --> CAUSING HYPERPOL to prevent from future depol. Aka the electromechanical transduction is decreased.

4.3. Concentration and dilution in the kidney. The function of the urinary bladder and the regulation of the urination.

Concentrating capcity is related to . medullary thickness; a thicker medulla, means a lomger looå of henle and thus a greater concentrating capacity. This is due to the greater ability of a longer loop to perform the process of COUNTERCURRENT MULTIPLIFICATION which is an active process which creates a high osmotic gradient between the cortical and papillary regions of the kidney. The urea recycling also contributes to the concentration gradient developemtn, and is highly dependent on ADH. -ADH increases cortical/outer medullary colecting duct water permeability, BUT THE UREA PERM IS NOT INCREASED, so the tubular urea concentration increases. --> BUT, IN THE INNER MEDULLARY COLLECTING DUCT, ADH DOES INCR TUBULAR UREA PERM (via UT1 transporters) --> urea now diffuses from its high tubular conc to the interstitium of the medulla, which increases the osmotic gradient from the outer to the inner medulla (so the osmotic gradient is huge for the thin limbs of the loop of henle) --> the urea is then recircled back into the tubular fluid in the thin limb of henle (asc) ----> the urea circulation can cause a 600mosm build up in the interstium COUNTERCURRENT EXCHANGE: is a process occuring between the vasa recta and interstitum that differs from the multiplying process in that is is: -passive -only MAINTAINS the gradient rather than creates it (I have a drawing that helps in understanding, but basically, whatever the TAL is reabsorbing is taken up, and then the opposite goes to the interstitum. CONCENTRATION OF THE KIDNEY: When water needs to be conserved, higher levels of ADH are released and the kidney produces HYPEROSMOTIC urine. The driving force of conc (and dil) of urine is Na+ reabsorption in the TAL DILUTION OF THE KIDNEY: When water must be excreted ADH secretion decreases. --> When this happens, the interstitial omsolarity of the inner medulla is also lower (600mosm, rather than 1200mosm), since there is no ADH-induced urea reabsorption from the distal collecting duct as urea accounts for about half of the osm of the inner medulla. DIABETES INSIPIDUS: a defect in either production of or response to ADH resulting in high urine production: --> central diabetes insipidus: due to lack of ADH prod/secretion by the hypothalamus/pituitary --> nephrongenic DI: due to lack of response by the nephron to ADH DIURETICS: -Furosemide (inhibits Na+/K+/2Cl- cotrs) and thiazide (Nacl cotransporter) inhibits Na+ reabsorption, so when more Na+ is delivered to the tubular cells, the Na+/K+ ATPase acitivty is increased leading to incr K+ secretion -K+-sparing diuretics: such as amiloride counteracts aldosteron's effects on principal cells decreasing K+ secretion

4.5. The acid-base balance. The role of the lung and kidney in the regulation of the pH and in the compensation of acid-base imbalances

DEFINITIONS: ACID: any chemical that can donate H+ (can affect enzymes, receptors, ion channels, transporters, proteins etc --> In the body, there are two types of acid: volatile acid (which refers to acids easily evaporated/respirated, so CO2 is a common example), and fixed acids which are produced from aa's with sulphur and phospholipids. They are called fixed acids because they CANNOT be respirated, and have to be buffered in the body and excreted in the urine. BASE: any chemical that can accept H+ -pH: the negative logarithm of hydrogen ion concentration (-log(H+)) pH i.c= 7,2. pH e.c= 7,4 -Henderson-hasselbach equation: is used to determine the pH of a buffer: pH = pK (dissociation constant) + log (conjugated base (A-)/weak acid (HA)) --> The smaller the pKa, the more acidic/strong the acid is. -BUFFER: is a mixture of weak acid and it's conjugated base, or a weak base and it's conjugated acid. Buffers are really important becasue they can resist large changes in the pH when there is an acid or base added to the system. THE NORMAL BLOOD pH IS 7,37-7,42 (40nM H+) and these buffers are essential for keeping the blood in this range. BUFFER SYSTEMS OF THE BODY: Bicarbonate is the most important buffer system of the body since it allows for quick adaption to changes in the pH due to its buffering capacity as well as the ability for respiratory compensation. Other buffers cannot do this, and thus are less effective buffers, but here is a list of them: H2SO4 + 2 NaHCO3 ↔ Na2SO4 + 2 H2CO3 ↔ Na2SO4 + 2 CO2 + 2 H2O HCl + NaHCO3 ↔ NaCl + H2CO3 ↔ NaCl + CO2 + H2O INTRACELLULARY: bicarbonate and protein buffers (especially Hbg) are important because they have a's that have the capacity to become protonated. Also, in acidic conditions, proteins, which usually bind Ca2+, will bind H+ instead, increasing the free Ca2+ concentration. In alkaline solution, more Ca2+ is bound and hypocalcemia occurs as less Ca2+ is free. EXTRACELLULARY, PLASMA: bicarbonate+protein EXTRACELLULARY, INTERSTITIUM: bicarb + some interstitial protein buffers EXTRACELLULARY, CSF: only bicarb as NO protein cross the BBB! URINARY TRACT: phosphate is an effective buffer in the kidney, because it's pKa is around 6,8 (so it allows for more H+ to buffered before the pH gets too low). Creatinine is also a buffer in the urinary tract, but it's pKa is a bit lower than phosphate (around 5) so it does not buffer urine as well, since the pH of urine is around 4,4-7,4 (DRAW THESE GRAPHS!). Uric acid is also used and ammonium (mostly for proton trapping) ACID/BASE DISORDERS: There are 4 conditions that arise when there is an acid/base imbalance in the body. Metabolic disturbances deal with an imbalance of HCO3-, whereas respiratory imbalances deal with an imbalance i CO2. If the problem is respiratory, then it cannot be fixed with the lungs, only the kidney's can compensate this imbalance. If the imbalance is metabolic, then it must be fixed both through respiration and kidney regulation. RESPIRATORY ACIDOSIS: is caused by hypoventilation which leads to CO2 retention and decreased pH as CO2 acts as an acid. We need to compensate this in the kidney by increasing the reabsorption of HCO3- in the proximal tubule (where it is reab with Na+) RESPIRATORY ALKALOSIS: is caused by hyperventilation and the loss of too much CO2, and an increased pH. The kidney needs to compensate this by increasing the H+ reabsorption done by increasing the activity of the K+/H+ cotransporter in the beta-intercalated cells (K+ is secreted with the urine) METABOLIC ACIDOSIS: this is due to a decrease in bicarbonate levels which can be caused by an increase in fixed acids (so there isn't enough HCO3- to neutralize them all) or simply bicarb loss. Chemoreceptors will be triggered to increase respiratory rates so that CO2 levels decrease. Renal correction is done via the alpha-intercalated cells which increase HCO3- reabsorption, by secreting Cl- into the urine. METABOLIC ALKALOSIS: Due to an increase in bicarbonate which can be caused by loss of fixed acids or simply by too much bicarb gain. Which can be fixed either by decreasing the respiratory rate to retain some CO2 to neutralize the blood HCO3 levels or by the beta-intercalated cells in the collecting duct in the kidney which increase the H+ reabsorption (and K+ secretion). We use a special technique to DIAGNOSE METABOLIC ACIDOSIS: -Because the blood is electroneutral (cations =anions), we measure the chief cation (Na+) and the chief anions (cl- and HCO3-) and compare the two values. -TYPICALLY; due to plasma proteins, phosphate, citrate and sulfate, there is an "ANION GAP" of anions which are not measured, but that we know are there since the laws of electroneutrality are never broken! -This gap is normally around 8-16mEq/L. -If the gap GROWS however, this indicates a loss of HCO3- which could be a sign for metabolic acidosis! --> The gap grows as the other anions from the gap come to replace the HCO3- loss, creating a greater gap! (LOOK AT PICTURE FOR A BETTER UNDERSTANDING)

7.7. Endocrine physiology of sexual development. Male reproductive physiology.

DIFFERENTIATION OF THE GONADS: The gonads are endocrine glands responsible for secreting sex determining hormones. In week 5, it is not possible to distinguish them between male and female. The differentiation occurs via the presence/absence of the Y chromsome which has the SRY (sex determining region of Y) which encodes for the testis-determining factor. This factor induces transcription of SOX9, which helps the indifferent gonad in becoming the testis. Once the testis is formed, the leydig cells secrete testosterone and the sertoli cells secrete anti-mullerian hormone (AMH) to enhance the differentiation and degrade the mullarian duct. Testosterone helps support the wolffian duct which will develop into the epididymis, vas deferens and seminal vesicles and DHT (converted testosterone) will drive the differentiation of the male genitalia. WITHOUT THE Y CHROMOSOME, Wnt4 stimulates an inhibitory effect on the SOX9 and helps transform the indifferent gonad into an ovary. Since there is no anti-mullarian hormone released from sertoli cells (NOT PRESENT OFC), the mullarian duct develops into the oviduct and uterus. (draw summary) In the early sexual development, both male and female gonadal function is driven by the HYPOTHALAMO-PITUITARY AXIS: --> arcuate nucleus secrete GnRH into the ant pit. Ant pit responds by releasing LH and FSH. The secretions of GnRH, LH and FSH are low UNTIL PUBERTY!!! PUBERTY: At puberty, the pulsatility of GnRH kicks in, and now LH > FSH (in childhood FSH>LH). The pulsatile secretion is REQUIRED FPR RECEPTOR SENSITIVITY THAT ALLOWS FOR NORMAL REPRODUCTIVE HORMONE LEVELS. If the secretion is contineous, then the receptors are desensitized. For males, there are 2 major testosterone peaks before puberty: one within the first couple of months of gestation for genital development and at birth for development of male-type CNS. Later in life, the receptors are desensitized again and so testosterone levels drops in spite of high FSH/LH levels. (draw this graph). REGULATION OF HYPOTHALAMIC AXIS: The arcuate nucleus is stimulated by light, stress, emotional stimuli, glucose and leptin. It is important to note that it is NOT testosterone which inhibits the arcuate nucleus in releasing GnRH, but the aromatase enzyme PRESENT BOTH IN THE SERTOLI CELLS AND IN THE ARCUATE NUCLEUS ITSELF, which converts testosterone into estradiol which iNHIBITS THE arcuate nucleus. The inhibition of FSH is driven by estradiol and inhibins (produced by the sertoli cell); and the actual inhibition of LH is driven by testosterone and DHT (produced by the leydig cells) Sertoli cells also produce inhibin which inhibits the ant pituitary. (MUST ALSO DRAW THIS) MALE REPRODUCTIVE PHYSIOLOGY: -The testis are located in the scrotum, which is essential as the testicular temperature must be at 35-37 degrees to maintain the countercurrent arrangement of testicular artery's and vein's which FASCILITATE HEAT ECXCHANGE COMPOSITION OF TESTIS: -80% is composed of the semiinferous tubules which produce the sperm. The epithelial lining the tubules consists of --spermatogonoa --spermatocytes --sertoli cells --> which have 2 important functions: --> to provude nutrients for the developing sperm --> to create the blood-testis barrier -->and to secrete an aqeous fluid to the lumen of the tubules to help move the sperm to the epididymis -the remaining 20% of the testis consists of CT and leydig cells which synth and secrete testosterone. SPERMATOGENESIS: -Occurs contineously through the lifetime of a male -2 MILLION SPERMATOGONOA BEGIN THE PROCESS DAILY AND AT THE END 128 MILLION SPERM ARE PRODUCED EACH DAY! Spermatogonoa undergo meiosis to become haploid spermatozoa (look at pic!) -SPERMIOGENESIS includes: --> the Golgi phase (increasing the mitochondria since the sperm needs it to have E to swim far) --> the cap phase (getting the acrosome cap) --> formation of tail --> the maturation stage where the sertoli cells removes most of it's cytoplasm TESTOSTERONE PRODUCTION: -The differences between the synthesis of testosterine un the adrenal cortex vs the leydig cells is that: --> testis lack the enzymes 21beta-hydroxylase and 11beta-hydroxylase which inhibits them in creating meneralocorticoids and glucocorticoids --> the leydig cells possess an ADDITIONAL ENZYME (17-beta hydroxysteroid DH) which is responsible for converting DHEA --> testosterone (so the end product is testosterone and not DHEA like in the adr cortex) TESTOSTERONE ACTIONS: -responsible for development of the internal male genitalia -increase muscle mass during puberty -growth spurt -libido -closure of epiphyseal plates -growth of penis -deepening of voice -spermatogenesis DIHYDROTESTOSTERONE PRODUCTION (produced in the target tissues since they posess the enzyme 5alpha-reductase)! ACTIONS OF DHT: -development of external male genetalia (penis, scrotum, prostate) -hair distr -responsible for baldness -sabecous gland activity -growth of prostate SPERM, SEMEN AND EJACULACTION: -Once sperm are mature they leave the semiinferous tubules --> rete testis -->efferent tubules --> epididymus (they can be viable here for months) -They become 100% activated by CAPACITATION which occurs inside the female genital tract. It includes washing off inhibitory factors, acrosomal reaction etc to isolate as many motile spermatozoa and remove the dead /non-motile ones) SEMEN: -90% of the volume of semen is composed of secretions from the male sex accessory glands (prostate, seminal vesicles) and the secretions include fructose, citrate, fibrinogen, ca2+, enz and PG's (Prostaglandins are secreted to aid peristalsis of the sperm forward and to make the cervical mucous more penetrable for the sperm. -the remaining 10% is the spermatozoa. (sperm) MALE SEX ACT: Divided into 3 steps: Erection, emission, ejaculation There's two types of reflexes that exist: -->unconditional reflex where stimulation of the penis, without brain input aka how paralysed men get an erection --> conditional reflex: where the male sex act can be controlled and stopped via input from the CNA ERECTION: -under PSY control, causes endothelial NO release --> cGMP inr --> PKG --> ca2+ pumps increase and the ca2+ channels are decreased SINCE WE DO NOT WANT SMOOTH MUSCLE CONTRACTION, we just want the vessels to dialate. EJACULATION: -under SY control in which contractkon of the vas deferens, accessory glands, inner urinary sphincter and a DECREASE IN ALPHA1 RECEPTORS to decrease the sympathetic tone of the vessels --> incr Resistance and to vasoconstrict. Sy will also increase the HR and BP EMISSION: -Important to relax the outer urethral sphincter and close the inner urinary sphincter to prevent retrograde ejaculation where semen enters the bladder. (both int and ext urinary sphincters are closed during this phase) ERECTILE DYSFUNCTION: -Lower testosterone levels may lead to lower amount of ejaculate, decreased fertile sperm, decreased libido, and the causes can be: -type 2 DM -cardiovascular disease -smoking -stress/anxiety -hypogonadism --> treatment is done by giving viagra which inhibits the smooth muscle contractions and increasing cGMP levels

2.2. Electrocardiography, the human electrocardiogram.

ECG stands for electrocardiogram and indicates the electrical activity of atrial and ventricular muscle (the potential from SA node and the conduction system themselves are not powerful enough to be detected, so ECG uses the depol and repol of cardiac myocytes). It detects this by using surface electrodes to measure changes in potential that results from heart activity. But this activity can only be detected if a large number of synchronized cell perform the elcetrical activity. So it can be used for: -ECG: atrial + ventricular myocytes -EMG: skeletal muscle fibers -EEG: cortical neurons The surface electrodes detect changes in voltage over time, meaning the ions that flow in or out of the myocytes. When there is no large net change in ion flow, then the electrodes do not detect any voltage change and the baseline (0mV) can be detected. The ECG uses either unipolar or bipolar leads UNIPOLAR: 1 pole/electrode + the reference point. The unipolar leads reflect the potential difference between one of the three limb electrodes and an estimate of zero potential - derived from the remaining two limb electrodes. These leads are known as augmented leads. The augmented leads and their respective limb electrodes are: -->aVR lead: right arm -->aVL lead: left arm -->aVF lead: left leg BIPOLAR LEADS: The bipolar limb leads reflect the potential difference between two of the three limb electrodes: -->lead I: right arm-left arm -->lead II: right arm-left leg -->lead III: left leg-left arm CARDIAC AXIS: The electrical activity of the heart starts at the sinoatrial node then spreads to the atrioventricular (AV) node. It then spreads down the bundle of His and then Purkinje fibres to cause ventricular contraction. Whenever the direction of electrical activity is towards a lead you get a positive deflection in that lead. Whenever the direction of electrical activity is away from a lead you get a negative deflection in that lead. The cardiac axis gives us an idea of the overall direction of electrical activity when the ventricles are contracting. In healthy individuals you would expect the axis to lie between -30° and +90º. The overall direction of electrical activity is towards leads I,II and III. As a result you see a positive deflection in all these leads, with lead II showing the most positive deflection as it is the most closely aligned to the overall direction of electrical spread. You would expect to see the most negative deflection in aVR. This is due to aVR looking at the heart in the opposite direction to the overall electrical activity. (Look at the pic) EINTHOVEN'S TRIANGLE: He invented the first ECG and created the systems of lead I, II and III, as a down-ward facing triangle. He chose these leads based on the way that all 3 WILL SHOW A POSITIVE INFLECTION DURING THE R WAVE (VENTRICULAR DEPOL). THE HEART VECTOR: (must draw) Changes during cyclic activity. The magnitude and direction (what makes up a vector) depends on: --> the number of fibers de-or-repolarizing in a unit time --> the direction of spread of de/repol The ventricular depolarization loop is bigger than the ventricular repolarization loop. Atrial repol and ventricular depol overlaps in time. Because LEAD II follows a diagonal trajectory from the right arm to the left leg, it most cloecley resembles the direction of cardiac depolarization The normal heart should have the highest R wave in lead II. ECG WAVES: -P WAVE: 0,08s --> The P wave is a small deflection wave that represents atrial depolarization. -PR INTERVAL: 0,12-0,2s -QRS DURATION: 0,06-0,1s, Amplitude should be 2mV The three waves of the QRS complex represent ventricular depolarization -->Q: depol of interventricular septum -->R: depol of the main mass of the ventricles -->S: ventricles of the base of the heart -ST SEGMENT: It reflects the period of zero potential between ventricular depolarization and repolarization. IS ISOELECTRIC = 0mV. If this is elevated then this is a strong sign of a MYOCARDIAL INFARCTION (STEMI) -T WAVE: T waves represent ventricular repolarization (atrial repolarization is obscured by the large QRS complex) AUGMENTED LIMB LEADS (GOLDBERGER'S): already talked about. Most imp is that they are unipolar, use a reference line. --> The electrical vector of the heart cycle is close enough to aVf and aVl to make positive inflections with the P, R and T waves, however, the aVr vector is nearly OPPOSITE that of the heart vector and thus, the infelctions should be negative (it looks like the opposite of lead II). CHEST LEADS/WILSON'S LEAD'S: -6 unipolar leads cover the anterior chest in a horizontal plane -These electrodes are very close to the heart meaning that they give A BETTER PICTURE OF SPECIFIC REGIONS OF THE HEART (can be used to localize the specific place of a myocardial infarction) NORMAL SINUS RHYTM, DISEASE RELATED TO THIS! -Regular sinus rhythm should range between the frequency range of 60-100 beats per minute -This frequency is calculated from the RR distance. If the RR distance is 0,8s, then the frequency is 75/min. -The heart frequency will increase during inspiration since the stretching of the lungs activate the baroreceptors and firing of the vagus nerve -Every P wave should lead to a QRS complex wave and this complex should last 0,12-0,2 s -P wave should be + in lead II, neg in aVr and have a size of approx 3*3mm If heart rate/frequency is > 100/min = tachycardia if HR/frew is < 60/min = bradycardia!

2.11. Circulation of the skeletal muscle. Circulatory effects of physical exercise. Splanchnic circulation.

SKELETAL MUSCLE CIRCULATION: -The mass of our muscles is about 40% of our total body mass -It's flow at rest, Q= 1L/min (20% of CO) --> BUT, at max Q it can incr x20 times and become 20L/min -AVDO2 = 60mL O2/L at rest --> max AVDO2 = 150mL/L AKA THERE IS A 50X INCREASE IN O2 DELIVERY TO MUSCLES Blood flow to the skeletal muscle is controlled by both LOCAL METABOLITES AND SYMPATHETIC INNERVATION of its vascular smooth muscle. Because of the vast weight of the skeletal muscle, the vasoconstriction of the skeletal muscle arterioles is A HUGE DETERMINANT OF TPR! AT REST, SY innervation is the primary regulator of skeletal muscle! The vascular smooth muscle of skeletal muscle arterioles are densely innervated with alpha1 receptors, with some beta2 receptors present as well (beta2 can be activated by epi to cause vasodil). Usually, NE dominates and binds to the alpha1 causing vasoconstriction BUT, during exercise, or FIGHT-OR-FLIGHT, epinephrine is released in high doses to activate beta2 receptors and vasodil so that you can use your muscles to their max! CIRCULATORY EFFECTS DURING PHYSCIAL EXERCISE: DURING EXERCISE, local metabolites are the PRIMARY REGULATOR! The most important local vasodilators are: -lactate -adenosine -K+ -NO -pO2 decreased -decreased pH --> When you exercise, you cause mechanical compression of your blood vessels and thus causing brief periods of occlusion and reactive hypermia, which needs to be vasodilated and compensated THERE ARE 2 TYPES OF MECHANICAL EXERCISE: --> dynamic like running causing contineous contraction, relax and contraction again. -Aids venous pump and causes arterial occlusion --> static exercise like when lifting a weight and keeping it there in that position. Causes contraction and resistance in vessels increase, so TPR incr and since sk muscle mass is so big and such a big determinator of the mean arterial BP, it will overall increase the TPR of the body! SPLANCHNIC CIRCULATION: Hepatic Q = 1,5L/min, where 75% of it is from portal veins and 25% of it is from hepatic artery (to supply hepatocytes with nutrients) REGULATION: Locally ONLY by the hepatic artery as portal blood is not regulated, but hepatic is the buffer and regulate the portal indirectly. So if there is an increase in portal blood flow then hepatic artery blood flow is decreased. Neurally: by SY and adrenal gland Alpha1 rec will reg the blood pressure and shunt blood via smooth m constriction Beta2 rec will cause smooth m relaxation Gastrointestinal circulation: --> POSTPRANDIAL HYPEREMIA --> FLOW IS INCREASED AFTER A MEAL. locally up to 7-8 times more increase in flow. After a meal, blood is diverted from muscle to the GI tract to subserve the metabolic needs and to reomve absorbed nutrients

7.5. Glukagon secretion and the regulation of the secretion. Endocrine mechanisms protecting from hypoglycemia. Endocrine and metabolic changes related to starving and physical exercise

GLUCAGON SYNTHESIS: Is the primary "counterregulatory" hormone that increases the blood glucose levels through it's effects on the liver glucose output. Glucagon promotes the production of glucose through: -elevated glycogenolysis -elevated gluconeogensis -decreased glycolysis -decreased glycogenesis GLUCAGON SECRETION: -Preproglucagon contains the aa sequences for glucagon, GLP-1 and GLP-II ( glucagon like peptide). The latter 2 go to the intestine, while the preproglucagon is proteolytically cleaved in the alpha cells into glucagon. Glucagon enters the portal circulation from either the gut or the pancreas, it is carried to the liver before reaching the systemic circulation. A lot of it never does reach the systemic circulation since the liver is it's main target where it increases glycogenolysis and gluconeogenesis in the liver to produce increased glucose levels to the systemic circulation. The liver breakds down aprox 80% of the glucagon, thus very little of it reaches the periphery. REGULATION OF SECRETION: Glucagon is activated by: -hypoglycemia -basic aa's -Sy -catecholamines -cortisol -GH INHIBITED BY: -glucose -insulin -somatostatin -FFA's EFFECTS: The glucagon receptor is expressed primarily in the liver, but can also be found on pancreatic beta cells. In the liver, glucagon's effects are the opposite of that of insulin. It's MAIN GOAL is to make transport of more nutrients available in the blood. Done so by: Glucagon --> Gs --> adenylate cyclase --> cAMP i.c increases PROTECTION AGAINST HYPOGLYCEMIA: Done by a network of different hormones. -CATECHOLAMINES are released from SY nerve endings in the adrenal medulla in response to decreased glucose concentrations, stress and exercise. (The sensing of hypoglycemia is mainly done by hypothalamic neurons which signal the release of catecholeamines) --> catecholamines will effect the liver, muscle, adipose and increase the secretion of glucagon -CORTISOL (the fasting hormone): will be released in response to a stressful stimulus. It's main consequence is proteolysis --> It will increase glucagon secretion and beta-adrenergic receptor expression via it's indirect effects -GROWTH HORMONE: will increase blood glucose levels by increasing glucagon secretion and by desensitize the target organs of insulin. THE ORDER OF SECRETION OF THE HORMONES TO PROTECT FROM HYPOGLYCEMIA: -4,6mM glucose : decreased insulin -3,8mM glucose: increased glucagon and increased adrenalin -3,7mM : increased growth hormone -3,2mM : increased cortisol Insulin>glucagon + EPI > GH > cortisol FASTING: the main aim is to keep the blood glucose levels in a normal range for the organs that CAN ONLY UTILIZE GLUCOSE AS IT'S FUEL: -RBC -LENS -CORNEA -neurons (until they adapt to using ketones) This means that we have to find other ways to fuel the more flexible: 1) EARLY FASTING: (0-24 timer) -decreased insulin and increased glucagon. The liver's glycogen storage provides for most of the glucose (75%) and the liver's gluconeogenesis provides for the rest (25%). -The muscle provides lactate for the liver (gluconeogenesis) -the adipose provides glycerol for the liver's gluconeogenesis 2)EARLY FASTING (24-72): -Together with the insulin and glucagon levels, adrenalin, cortisol and GH hormones are present -The liver glycogen storage is now empty, and the body has to rely solely on the glucose produced via the gluconeogenesis process in the liver. The other organs aid the gluconeogenesis with substrates, such as muscle --> lactate and aa's, adipose --> glycerol etc 3)LONG-TERM FASTING (>72 hrs): this leads to inactivity and decreased BMR. - Now, even the T3 levels are decreased which causes major metabolic problems (thyroid hormones are not regulated by blood glucose so this is dangerous) PHYSCIAL EXERCISE: The metabolic response to PE is similar to that of fasting, but with the ADDITION OF GLUT-4 TRANSPOSITION IN THE PLASMA MEMBRANE OF ACTIVE MUSCLES, even though the insulin levels are low! --> this allows the muscle to receive a sufficient amount of glucoe for ANAEROBIC ENERGY PRODUCTION.

6.6. The physiological role and function of T lymphocytes.

T cells are part of the ADAPTIVE IMMUNE RESPONSE, also called the cellular immune response. They originate in the bone marrow under the lymphoid cell line along with B cells, BUT, UNLIKE THE B CELLS, they travel to the thymus for later development and differentiation. There are 2 types of T cells (the CD's are surface glycoproteins that are used to identify different cells in the lab, but they may also carry out important functions): -T helper cells (CD4+) --> which helps B cell activation and secretion of ab's --> T helper cells are actually divided into two subgroups. -->Th1 cells activate macrophages and is a important link between the innate and the adaptive immune response -->Th2 cells to activate B cells (most imp function of helper cells) -Cytotoxic T cells (CD8+) --> destroys virus infected cells and tumor cells with its granzymes and perforins STAGES OF T CELL MATURATION: 1) PRO-T CELL (bone marrow) -no TCR -CD4-/CD8- (double negative thymocytes) -Rag-1, Rag2 recombinase expression -rearrangement of the TCR beta chains start 2)PRE-T CELLS -posess the pre-T cell receptor (TCR beta chain+preTalpha+ CD3+ + zeta chain (for itam)) --> survival -->proliferation expansion -->TCR beta chain allelic exclusion --> initiation of TCR alpha chain gene recombination 3)DOUBLE POSITIVE THYMOCYTE -CD4 and CD8 expression -TCRalphabeta heterodimer The double positive cells move into the corticomedullary junction where they undergo pos/neg selection 4) SINGLE POSITIVE CELL(thymus): When the DN thymocytes goes into the cortex of the thymus they start interacting with epithelial cells that have MHCI and MHCII markers on them. The thymocytes MUST bind to one of these to be able to live, or else they would go through apoptosis. This also determines their fate -Cd4+ if it binds to MHCII -Cd8+ if it bids to MHC I ^the above described mechanism is the positive selection, but the thymocytes must also go through a negative selection prosess: -where the cells that bind too strongly to their MHC complex will be marked for apoptosis. With this mechanism, we want to kill any T cells which might attack the bodies own antigens and become autoreactive! T-CELL RECEPTOR: -TCRalpha + TCR beta + variable region + constant region -They only have 1 ag-binding site (unlike the BCR) -DOES NOT have an excreted form (unlike B cells) -contains ITAMs MHC = major histocompatability complex -Important in proper recognition of cells by the immune system --> MHC I: present on every nucleated cell in the body (so NOT RBC's) -->MHC II: present on the surface of ag presenting cells such as dendritic cells, macrophages and B cells NK CELLS: ARE NOT t-cells ofc, but they also descend from the lymphoid lineage and they crucially use MHC I. -Their job is to check that EVERY CELL that they come across has the MHC I receptor (aka is self). If the cell doesn't then the NK cell immediately kills it -The NK cells can use the same mechanism as cytotoxic T cells with perforins and granzymes, as well as secrete inflammatory cytokines CLINICAL RELEVANCE: --> DIGEORGE'S SYNDROME: congential malformation affecting the development of the thymus, thus t-cell def -->BARE LYMPHOCYTE SYNDROME: a lack of MHCII expression -it will decrease the antigen presented to the T cells and thus decrease the positive selcetion process in the thymus, altering the T cell mediated responses - can be fatal if not teated with bone marrow -->Aquired immunodeficiency syndrome (AIDS) -caused by HIV (human immunodeficiency virus) which affects the CD4+ Th cells -->GRAFT-VS-HOST DISEASE: -after transplantation -mediated by donor T cells + NK cells and must be treated with immunosupression

2.8. Venous circulation, factors determining venous pressure and flow. Control of capacity vessels. Lymph flow.

LYMPH FLOW: The lymphatic system is responsible for returning interstitial fluid and proteins to the vascular compartment of the blood. To receive these components, lymphatic capillaries exist within the interstitial fluid, close to the vascular capillaries. Then, the lymphatic capillaries drain through lymphatic vessels to the thoracic duct or right lymphatic duct into the venous system. --> Lipids from the GI travel through the lymphatic system in the form of chylomicrons -120mL of lymph is produced PER HOUR -In about 1 day, about as much lymph is transported as there is plasma volume The lymph Q back to the venous system is promoted by: -the lymphatic capillaries and other vessels containing one-way flaps to PREVENT BACKFLOW (--> the interstitial pressure builds up and pushes through the flaps) -weakly contracting smooth muscle in the lymph vessels -compression via contracting skeletal muscle in the region around the lymph vessels. EDEMA OCCURS WHEN THERE IS AN INCREASE IN INTERSTITIAL FLUID VOLUME = pathological. -The interstitial fluid V exceeds the capacity of the lymph system to recirculate it -Occurs when filtration increases and when lymph drainage is impaired --> lYMPHATIC DRAINAGE IS IMPARIED WHEN: -lymph nodes are damaged/infected -when there is a lack of muscular activity like in long periods of standing and sitting -->INCREASED FILTRATION OCCURS WHEN: -incr capillary hydrostatic pressure -decreased capillary colloid osmotic pressure ------> the common example is KWASHIORKOR, when ascitis develops from low protein content and malnutrition in kids in afrika VENOUS CIRCULATION: is the way out of microcirculation, and, by the time blood reaches the venules and veins, pressure is less than 10mmHg. It decreases even further in the SVC and IVC to approx 0mmHg. The pressure in the vena cava and right atrium is also called THE CENTRAL VENOUS PRESSURE=0mmHg CAPACITANCE: An important feature of the veins. Their capacitance makes them able to adjust blood volume returning to the heart (preload) based on the needs of the body. This is due to the venous walls are very compliant and can store large V's of blood. --> Compliance varies with region. The walls of the lower extremity veins are much thicker and less compliant since it would be harder to push blood up against gravity with very compliant walls. --> compliance declines with age, as with arteries -->helps control the filtration(absoprtion of capillaries by adjusting postcapillary resistance --> assist in the cardiovascular adjustments that occur when the body position changes (e.g sitting to standing) VEINS CONSTITUE THE LARGEST RESERVOIR OF BLOOD IN THE CIRCULATION, CONTAINING ROUGHLY 64% OF THE TOTAL BLOOD VOLUME. THIS IS BECAUSE OF THEIR HIGH COMPLIENCE! VASCULAR FUNCTION CURVE AND VENOUS RETURN: DRAW! --> CARDIAC FUNCTION CURVE: when the right atrial pressure increases (via higher venous return), cardiac output increases due to higher EDV (according to the frank-starling law) --> VASCULAR FUNCTION CURVE: Because the driving force of blood flow is the pressure gradient (fluid flows from high to low p). SO, if atrial pressure increases, venous return decreases because of a smaller gradient between the atria and veins occurs and this cannot happen. Decreased blood returning to the heart means that CO is also decreased. THE FLAT PORTION ON THE GRAPH IS DUE TO THE FACT THAT THE VEINS COLLAPSE AT NEGATIVE ATRIAL PRESSURE, so even with a very high p gradient, the collapse of the vein will impede the the venous return. --> where the two curves intersect = CO AND VENOUS RETURN! FACTROS DETERMINING VENOUS PRESSURE AND FLOW: - increasing skeletal muscle movement which compresses the veins -gravity causes a large blood pool in the lower extremities and if the body can't compensate this when standing up, then the patient will suffer what is called ORTHOSTATIC HYPOTENSION -increased ionotropy (contractability) of the heart leads to increased CO, decreased atrial pressure (because there is less blood remaining in the heart) and increased venous return -An INCREASE IN TPR decreases CO, which increases right atrial pressure (as more blood remains in atria), but an increased TPR also leads to decreased venous return, which decreases right atrial pressure so it usually stays unchanged -increased blood volume or vasoconstrictions (pushing blood out of the venous storage) will incr CO, incr venous return, incr atrial pressure ---> THE VALSALVA1S MANEUVER, occurs when there is a forceful exhalation against a closed glottis, which increases intrathoracic pressure and thus impedes venous blood return to the heart which stimulates baroreceptors to increase heart rate to get more blood back to the heart --> leads to a short increase in cardiac output to fix low venous return VENOUS PUMP AKA THE "VENOUS HEART": -Aids mostly the lower extremeties in pumping the low pressure venous blood against gravity which wants to keep it in the extremeties. --> As we walk, the leg muscles undergo repetitive contractions and will compress against the deep vein compartment, and because of the venous valves, blood CAN ONLY GO UPWARDS --> meaning that during muscle relaxation when the blood isn't being pumped upwards, the valves keeps the blood from running back down and aids them refilling themselves. If the valves are insufficient, then VARICOSE VEINS may develop. This means that when skeletal muscles are contracting, the blood is forced basckwards as well as forwards, causing a high increase in venous pressure. This backflow leads to poor interstitial fluid drainage and thus edema. (COMPARE THE VENOUS HEART AND EXPLAIN THE ANALOGY)

1.4. Classification, function and main features of ion channels. Voltage-gated Ca2+ channels. Cellular calcium metabolism.

MAIN FEATURES: -pore, forming, transmembrane proteins -passive, let ions down their electrochemical gradient -selective based on ion size and charge -gated, so a confirmational change causes them to open/close -not saturated -they are very fast, up to 4 times faster than carriers FUNCTIONS: -establishing resting membrane potential -shaping ap's -control ion flow of secretory/epithelial cells -regulate cell volume CLASSIFICATION: 1)VOLTAGE-GATED -activated by changes in the Em (depol/repol) -important in excitable cells like neurons and muscles for rapid and coordinated cell depol Ex: - VD- Na+ channels, has 3 configurations, open, closed but activatable, closed and non activatable - V-D K+ channels (GIRK in cardiac myocytes) - VD ca2+ channels at synaptic terminals NMJ 2) 2ND MESSENGER GATED -controlled by changes in intracellular secondary messengers (IP3, cAMP). -sensors are located i.c Ex: IP3 mediated ca2+ channel on the SR for ca2+ release in smooth muscle contraction 3)LIGAND-GATED CHANNELS -controlled by hormones, NT's etc -sensors are located e.c ex: nicotinic channel receptors on skeletal muscle (ach is ligand, Na+/K+ goes through) 4)MECHANOSENSITVE: -responds to mechanical deformation in membrane Ex: touch receptors in skin 5)Heat/Light sensitive receptors: -Rhodopsin channels in eye -TRPV1 heat receptors in skin VOLTAGE-GATED CA2+ CHANNELS: -alpha1 unit forms the ion pore and then there are different combinations of the others (alpha2, delta, beta) that functions in gating modulation -these channels are very important in: --Ca2+ dependent K+ channel activation (important in hearing) --muscular contraction --hormone/NT release --gene expr regulation types: L-lasting --> skeletal, smooth muscle and ventricular myocytes T-type --> SA node N-type --> brain and PNS

2.4. Pump function of the heart. Cardiac output and its control.

PUMP function: The right side of your heart receives oxygen-poor blood from your veins and pumps it to your lungs, where it picks up oxygen and gets rid of carbon dioxide. The left side of your heart receives oxygen-rich blood from your lungs and pumps it through your arteries to the rest of your body. CARDIAC OUTPUT: The volume of blood being pumped BY THE LEFT VENTRICLE and into the aorta per minute! -resting CO should be: 5600ml/min! CO= HR * SV MABP= CO* TPR -In steady state, the Co is equal to the venous return STROKE VOLUME: the difference between the volume of blood in the ventricles BEFORE ejection (end-diastolic volume = 140ml) and the volume remaining after EJECTION (end-systolic volume = 60ml) SV = EDV- ESV = 80ml! EJECTION FRACTION: the fraction of blood that was available for systole (EDV) that is ejected in one stroke volume. It tells you about the effectiveness of the ventricles in ejecting blood EF= SV/EDV = approx 55% REGULATION OF CARDIAC OUTPUT: -There are 4 factors which affects CO --> heart rate --> myocardial contractability -->preload --> afterload -Temp, ion concs (increased e.c ca2+, incr e.c K+), hypoxia and CARDIAC GLYCOSIDES all affect ionotropy. Cardiac glycosides have a positive ionotropic effect in which the inhibition of the Na+/K+ ATPase leads to less Na+ being pumped out of the cell which makes less Na+ available for the Na+/Ca2+ exchanger, thus it is less active AND MORE CA2+ REMAINS IN THE CELL! -HETEROMETRIC REG -Refers to the regulation of CO when the muscle fiber length is changed! -increasing the length of the fibers also increases the forcefulness of the contraction --> thus, when the heart receives more blood (PRELOAD) and and the myocardium muscle fibers are strecthed more, it will lead to a more forceful contraction -Heterometric regulation is an INTRINSIC PROPERTY of cardiac muscle as the Ca2+ sensitivity of troponin C is altered by changing the initial fiber length --> incr m length --> incr Ca2+ sensitivity INCREASED PRELOAD: --> FRANK EXPERIMENT: showed that, during an isovolumetric contraction (he clamped the aorta of fish hearts), so the volume stayed the same, but the ventricle filled with blood and the myocardium was stretched, leading to more forcecul contraction -->STARLING EXPERIMENT (eventually what became frank-starling hypothesis) If you increase the preload and the contraction is not forceful enough to pump it all out, then there will be an increase in ESV, so during the next cycle, the EDV will also be larger (since not all of the blood was pumped out in the first place). The fiber lengths will adapt and thus the EDV and SV also increase. -----> CONCLUSION: if an isolated heart is filled with more blood than it is accustomed to, then the heart will adapt and compensate to eject more volume (FRANK-STARLING LAW), but the V cannot be so large that it overstrecthes the heart. --> SO IF PRELOAD INCREASES, THEN EDV AND SV ALSO INCREASES TO COMPENSATE FOR THIS AND TO INCREASE THE FORCEFULNESS OF THE CONTRACTION! INCREASED AFTERLOAD: -Afterload is the end load at which the heart needs to contract against to eject. Aka, it is the aortic pressure at which the heart pumps against. -If this pressure increases, then less blood is ejected from the ventricle, so the SV decreases and the ESV increases (cannot push all of it out) -HOMOMETRIC REGULATION: -force of contraction is changed REGARDLESS of the fiber length. -N.B: CONTRACTABILITY OF THE HEART IS DEP ON I.C CALCIUM LEVELS -so, when there are more calcium available, then there is a greater ionotropic effect --> occurs with SY innervation, where the b1 receptors --> Gs --> cAMP --> PKA activated which PHOSPHORYLATES THE FOLLOWING: -L-type voltage gates Ca2+ channel; allowing for a large influx of ca2+ -Ryanodine receptor: responsible for much of the ca2+ from the lumen of SR -phospholamban will be activated which regulates the Ca2+-ATPase pump that brings Ca2+ into the SR which decreases the i-c ca2+ causing faster relaxation -troponin I, which is much needed to downregulate the others, as it decreases the ca2+ sensitivity and thus leads to less ca2+ binding. Needed to prevent over-contraction of the heart

7.9. Endocrinology of pregnancy, delivery, and lactation.

Pregnancy occurs after an ovum is fertilized and is now called an ovum, in which the zygote begins to divide and will become a fetus. A pregnancy is said to last 40 gestational weeks. In early-pregnancy (the first trimester), the source of steroid hormones is the corpus luteum, in mid-to-late pregnancy, the placenta is the source of steroid hormones!! EVENTS OF PREGNANCY: -ovulation --> o day -fertilization --> 1 day -entrance of blastocyts into uterus --> 4 days -implantation --> 5 days -formation of trophoblast and attachment to endometrium --> 6 days -onset of trophoblast secretion of HcG --> 8 days -hcG rescues corpus luteum (if not fertilization then corpus luteum will regress and die) --> 10 days!!! (There is a graph I should draw for the hormones during pregnancy which shows the increase and decline of hcg and increasing levels of prolactin.) Synthesis of progesterone during pregnancy (draw out) -During the first trimester, the corpus luteum (being rescued by hcg) maintains progesterone and estrogen levels -But in the second and third trimester, it is up to the placenta to maintain these hormonal levels. -It is done by cholesterol entering the placenta from the maternal circulation, it is converted to prognenolone in the placenta which is then converted to progesterone in the placenta. (draw out) Synthesis of estriol (the major form of estrogen during pregnancy) is produced through an interplay of the mother and the placenta, but, importantly it REQUIRES THE FETUS!!! Just like above, cholesterol is supplied to the placenta through the maternal circulation and is converted to progenolone, WHICH ENTERS THE FETAL CIRCULATION AND IS CONVERTED TO DHEA-sulfate IN THE FETAL ADRENAL CORTEX!!!! DHEA-sulfate is hydroxylated into 16-OH DHEA-sulfate in the FETAL liver and is then crossed back to the placenta where sulfatase removes the sulfate and aromatase converts it to estriol! PARTURITUON/DELIVERY: Delivery of the fetus occurs approx 40 weeks after the onset of the last menstrual period. -When the fetus reaches a critical size, it distends the uterus and increases it's contractability. This is the reason for the fake contractions called the Braxton-Hicks 1 month before delivery -Near term, the FETAL hypothalamic-pituitary axis is ACTIVATED to increase the activity of the fetal adrenal gland to produce cortisol and to increase the ESTROGEN/PROGESTERONE RATIO. This increases the sensitivity of the uterus to contract (NB!: Estrogen increases the contractability, while progesterone decreases it!) -The high levels of estrogens stimulate local production of prostaglandins PGE2 + PGF2, which increase the intracellular calcium levels causing increasing smooth muscle contractions of the uterus -Oxytocin is a powerful stimulant for uterine contractions and its receptors are upregulated towards the end of pregnancy. LACTATION: Prolactin is a hormone synthesized by the lactotrophs in the anterior pituitary. It consists of 198 aa's in a single polypeptide chain with 3 disulfide bridges. What is important to mention is that prolactin is TONICALLY INHIBITED BY DOPAMINE (released by all the dopaminergic neurons in the hypothalamus) in people who are not pregnant or lactating!!! Throughout pregnancy, estrogen and progesterone stimulate the development and the growth of the breasts, preparing them for lactation. Estrogen also stimulates prolactin secretion by the anterior pituitary and the prolactin levels steadily increase over the course of the pregnancy. HOWEVER, although prolactin are high during pregnancy, lactation does NOT OCCUR because estrogen and progesterone BLOCK THE ACTION OF PROLACTIN until the baby is delivered! Lactation is maintained by the suckling of the nipple by the baby, where afferent fibers from the nipple carry information to the hypothalamus and inhibits the dopaminergic neurons!!! As long as lactation continues there is a suppression of ovulation, since prolactin inhibits release of GnRH by the hypothalamus and also the release of FSH and LH by the ant pit. ORAL CONTRACEPTIVES AND HOW THEY WORK: Oral contraceptives contain combinations of estrogen and progesterone, or just progesterone alone (can never be estrogen alone as this can cause blood clotting and has proven to be cancerous). What they do is that they exert negative feedback effects on the anterior pituitary by inhibiting FSH and LH, aka inhibiting ovulation. Progesterone only pills mostly decrease the motility of the fallopian tubes and makes the cervical mucous a hostile environment.

8.8. Supraspinal regulation of muscle functions. Postural reflexes.

SUPRASPINAL CONTROL: -Based in the medulla, midbrain, cerebellum, basal ganglia and motor cortex. -The movement can be conscious in which the information travels down the pyramidal/lateral pathways tract, or unconscious (extrapyramidal/medial pathway) --> PYRAMIDAL TRACT: DRAW both lat and ant corticospinal tract - lateral corticospinal CROSSED (motor cortex --> spinal cord) -rubrospina (red nucleus --> spinal cord) --> EXTRA PYRAMIDAL TRACT (unconscious, postrural reflexes, coordination and such) -anterior corticospinal tract (UNCROSSED) draw -corticoreticular -vestibulospinal -pontine-reiculospinal -medullary reticulospinal -tectospinal POSTRURAL REFLEXES: -Are automatic movements that control the equilibration we require once upright and moving, and with combatting gravity. -They maintain our posture, balance and fluidity of movement -The localization of these reflexes can be visualized via the DECEREBRATION and DECORTICATION which is a damage to the brainstem, either at the level of the ponto-medullary junction or above the red nucleus! DECEREBRATION: Decerebrate posture is an abnormal body posture that involves the arms and legs being held straight out, the toes being pointed downward, and the head and neck being arched backward. The muscles are tightened and held rigidly. This type of posturing usually means there has been severe damage to the brain. --> if we apply this in the lab, then we can use it to ONLY VISUALIZE THE REFLEXES THAT ORIGINATE IN THE MEDULLA, SUCH AS: -tonic labyrinthine reflex: a primitive reflex found in newborn humans. The presence of this reflex beyond the newborn stage is also referred to as abnormal extension pattern or extensor tone. -Neck proprioception: mostly seen in animals, but can also be seen in babies. When baby's head turns to one side, her arm on that side will straighten, with the opposite arm bent as if she's fencing. DECORTICATION: Decorticate posture is an abnormal posturing in which a person is stiff with bent arms, clenched fists, and legs held out straight. The arms are bent in toward the body and the wrists and fingers are bent and held on the chest. This type of posturing is a sign of severe damage in the brain. --> if we were to apply this in the lab, we can visualize the MDIBRAIN contributions to the postrural reflexes. The red nucleus is present in this type of posture and thus, it contributes majorly as the rubrospinal tract stimulates FLEXOR reflexes in the upper limbs -Muscle rigidity decreases because the red nucleus inhibits muscle tone in upper limbs -eyemovements such as nystagmus and vestibulo-ocular reflexes -and righting reflexes in which the orientation of the body is corrected with the vestibular system and the vestibulospinal tract. CEREBRAL CORTEX: for sliten til å skrive inn

1.8. The physiology of smooth muscle. The functions of different types of smooth muscle

Smooth muscle consists of uninucleated, small cells, which lack striations, because their thin and thick filaments are not organized into sarcomeres. The sarcoplasmic reticulum is present, but not T-tubules. Smooth muscle is found within hollow organs such as the GI, urinary tract, uterus, bronchioles, uterus, vasculature and some eye structures. Smooth muscle functions either to propel substances through tubes or to create tension on those tubes. TYPES OF SMOOTH MUSCLE CELLS The two types of smooth muscle cells are classified base don how the cells are electrically coupled. -SINGLE-UNIT SMOOTH MUSCLE CELLS (present in GI, bladder, uterus and ureters): --has gap junctions which allow easy electrical conduction between the cells, and also allow large regions to contract in unison --they are innervated indirectly --> one nerve for many cells --these cells are characterised by showing "spontaneous pacemaker activity" called slow waves which show peristaltic movement -MULTI-UNIT SMOOTH MUSCLE CELLS (present in iris and ciliary muscles + vas deferens) --Each cell is directly innervated and thus, behaves as a separate motor movement. --Allows for fine motor control SMOOTH MUSCLE AP: -Compared to neuronal Aps, smooth m Ap's have smaller amplitude, longer duration and different ion currents (they are HIGHLY ca2+ dependent) -The resting membrane potential is NOT CONSTANT, but rather oscillates between -40- -80mV, in so-called "small waves" (in the GI, these slow waves are initiated by the intestinal cells of Cajal -Lasts for about 200ms SMOOTH MUSCLE CONTRACTION: Smooth muscle is able to contract without changing the Em, as only ONE of the 3 sources of Ca2+ is voltage-dependent. There are 3 possible sources of increased intracellular calcium as a signal to contract: -Voltage-gated Ca2+ channels in the sarcolemma that open during cell membrane depolarization taking in EXTRACELLULAR CA2+ (unlike skeletal muscle) --> Ca2+ that enters the smooth muscle cells from voltage-gated Ca2+ channels releases additional Ca2+ from the sarcolplasmic reticulum -ligand-gated Ca2+ channels also in the sarcolemma membrane. They are NOT regulated by membrane potential, but by receptor-mediated events resulting from hormones or NT's. Cell takes in e.c Ca2+. -IP3-gated Ca2+ channels are present in the sarcoplasmic reticulum (SR) membrane. These are Gq-coupled to stimulate IP3 and calcium release out of the SR. Smooth muscle doesn't contain troponin like skelelal muscle, HOWEVER, ca2+ is still the key signal, and smooth muscle regulates contraction via a pathway involving calmodulin. --> Ca2+ binds to calmodulin, which activates myosin-light-chain kinasem which phosphorylates myosin light chain, increasing its ATPase activity, leading to activation of the cross-bridge cycle --> additionally, MLCK phosphorylates CALPONIN and CALDESMON, which, when not phosphorylated, bond actin and therefore PREVENT THE CROSS-BRIDGE CYCLE TO OCCUR. CROSS-BRIDGE CYCLE: The thin filaments consist of the proteins: -actin -troponin C, T and I -tropomyosin The thick filaments consists of myosin which is composed of 1 pair of heavy and 2 pairs of light chains. And a tail, hinge and head which is essential for the ATPase activity. There are 4 binding sites for Ca2+ on troponin C. 2 with high affinity which binds Mg2+ in resting state and 2 with low activity. Relaxation will occur when the intracellular calcium levels falls which can occur due to several factors such as hyperpolarisaton, direct inhibition of the ligand-gated Ca2+ channels by cAMP. These 3 channels are involved in decreasing the Ca2+ intracellular levels: -Membrane Ca2+-ATP-ase - Membrane Na+/Ca2+ antiporter - SR - Ca2+-ATP-ase MODULATION AND REGULATION OF SMOOTH MUSCLE: Smooth muscle is regulated by the phosphorylation of myosin light chain, done by the MLC kinase. This can be inhibited by increased camp levels (where PKA phosphorylates the enzyme MLCK itself) or increased cGMP (which activates the enzymes myosin phosphatase which dephosphorylates the myosin light chain). Contraction can also be increased tho, by Rho-GTP --> rho-kinase which enhances myosin light chain phosphorylation and also further increases Calcium's sensitivity. Also, NE and Epi can modulate sm contractions via their alpha1 receptors --> CONTRACTION and beta2 --> RELAXATION

5.1. Regulation in the gastrointestinal tract: enteric nervous system and gastrointestinal hormones.

The GI is regulated by the ANS, which has an extrinsic and one intrinsic component. The extrinisc component is the SY and PSY. The intrinsic component is the ENS, which is contained wholly within the submucosal and myenteric plexuses in the wall of the GI. It communicates extensively with the PSY and SY. (MUST KNOW THE LOCAL REFLEX PATHWAYS OF ENS) The ENS consists of 10^8 neurons and innervates the lower 1/3 of the esophagus until the out er rectal sphincter. It is mainly for reflexes and local control of motolity, secretion, blood flow. Because of the presence of ENS, regulation of the GI functions are well preserved in the absence of CNS regulation. ENS receives regulating input from the extrinsic branch of the nervous system and sensory information FROM the chemo and mechano receptors. The messages from these are sent to smooth m, endocrine and secretory cells. The neurotransmitters of the ENS include: -Ach -NE -VIP -Gastrin-releasing peptide -Opiates -Neuropeptide Y -Substance P The extrinsic branch includes the PSY and SY system. PSY: consists of the vagus nerve until the CANNON-BOHM POINT for the upper GI tract, and the pelvic nerve for the lower GI tract. The postggl NT used is either Ach or another petidergic NT like VIP. The preggl fibers synapse in the wall of the GI. Because the vagus nerve is mixed aff and eff fibers, it both senses the need to digest via chemo/mechanorec as well as sending the efferent signals to the target muscles. When both of the limbs are used, it's called the VAGOVAGAL REFLEX. PSY effect on the GI will have an excitatory effect, SY inhibitory. SY: The presyn ggl synapse in ganglia outside the GI (celiac, sup mesenteric, inf mesenteric, hypogastric). The postganglionic fibers are adrenergic and uses NE. They either indirectly affect the target organ by synapsing on the ENS, or directly by synapsing on smooth m, endocrine or secretory cells. Also the SY is both aff and eff. Gastrointestinal hormones: What is different about the GI hormones is that they are not located in clusters, but as single cells/group disperses over large areas. -GASTRIN: is produced by G cells of the stomach and stimulates release of H+. It is stimulated by vagal stimulation, distension of the stomach or presence of aa's. It is INHIBITED by secretin and GIP. -CCK: is for overall fat, protein, carb digestion and absoprtion. It is produced by I cells of the small intestine and is released when detection of nutrients is present. It has several functions, mainly related to pancreatic secretion. It causes contraction of the gallbladder, with simultaneous relaxation of the sphincter of Oddi. It also results in secretion of pancreatic lipases and amylases, secretion of bicarb from the pancreas, growth of the gallbladder and the pancreas. and it INHIBITS gastric emptying. -SECRETIN: is made in the S cell of the duodenum and is stimulated by acidic chyme and FA's. It's function is to aid CCK with pancreatic secretions, bile secretions. It inhibits gastrin as it wants to neutralize the chyme. -GLUCOSE-DEP-INSULINOTROPIC PEPTIDE (GIP): is produced in the duodenum and jejunum and is created when glucose, FA's or aa's are near. GIP increases insulin secretion of the pancreas beta cells and decrease the gastric H+ secretions. There are not only hormones that regulate the Gi, but also paracrines and neurocrines such as somatostatin, histamine, ach, vip, GRP, neuropeptide Y and substance P

7.1. The hypothalamus-pituitary gland system. Growth hormone and somatomedins

The hypothalamus and pituitary gland function in a coordinated fashion to rochestrate many of the endrocine systems. The hypothalamus-pituitary unit regulates the functions of the thyroid, adrenal and reproductive glands as well as growth, milk production, ejection and osmoregulation. The pituitary gland (hypophysis) consists of two lobes with different embryological origin. The posterior lobe is derived from neural tissue and secretes two peptide hormones; ADH and oxytocin, which act on their respective targets the kidney, breast and the uterus. The hormones released by the posterior lobe is actually neuropeptides as they are peptides released from neurons. The cell bodies of the ADH and oxytocin secreting neurons are located in the supraoptic and paraventricular nuclei (both produce both hormones, however, SON is primarily associated with ADH, and PVN with oxytocin). The anterior lobe is derived from the primitive foregut (Ratchke1s pouch). Unlike the posterior lobe, the anterior is a collection of endocrine cells that secretes 6 peptide hormones: TSH, FSH, LH, GH, prolactin, ACTH. (What is special about peptide hormones is that they are stored in secretory vesicles unlike steroid hormones!) The hypothalamus and the ant pituitary are linked directly by the HYPOTHALAMIC-HYPOPHYSIAL PORTAL BLOOD VESSELS which provide most of the blood supply to the anterior lobe. The portal blood supply is important because it makes it so that the hypothalamic releasing hormones can be delivered directly to the ant lobe in HIGH CONCENTRATION, without them appearing in the systemic circulation in high concentration. A good example in explaining the hypothalamic-hypophyseal relationship is illustrated using the TRH-TSH-thyroid hormone system. TRH is synthesized in the hypothalamus and released by the neurons, where it enters the portal blood through fenetrated capillaries. It is delivered to the anterior lobe by the hypothal-hypophyseal portal vessels, where it stimulates TSH secretion. TSH then enters the systemic circulation and is delivered to its target tissue, the thyroid gland, where it stimulates secretion of thyroid hormones. As mentioned, each anterior lobe hormone is a peptide and all peptides are synthesized in the same way: -transcription of DNA into mRNA in the nucleus -translation of the mRNA to a preprohormone on the ribosomes -postranslational modification of the preprohormone on teh ER and the golgi to produce the final hormone. -The hormone is STORED in secretory granules for subsequent release. When the anterior lobe is stimulated by a hypothalamic-releasing hormone or a release-inhibiting hormone there is exocytosis of the granules and the hormone is released to the systemic blood circulation and to it's target. The hormones of the anterior lobe are organized into families according to their structure or function. -TSH, FSH and LH are alle GLYCOPROTEINS with sugars covalently linked to their asparagine residues. Each hormone has two subunits, which alone are inactive. The alpha subunit is the same for all and is 92 aa's long. While the beta subunit changes for each hormone. TSH: b=112 FSH: b=114 LH: b=121 Gonadotropin is structually related to this family and has a beta subunit of 145 aa's. Each hormone of the anterior lobe is secreted by a different cell type (EXCEPT for LH and FSH). -TRH is secreted by thyrotrophs -FSH and LH is secreted by gonadotrophs -GH by somatotrophs -prolactin by lactotrophs -ACTH by corticotrophs ACTH (adreno-cortico-tropic hormone) family is derived from a single precursor, the POMC (pro-opiomelanocortin). The family includes an opiod called beta-endorphin and a melanocyte-stimulating hormone. POMC is transcribed from a single gene and is cleaved like all peptide hormones in the ER. What is important to note is that MSH activity is and darker pigmentation of the skin can be a symptom of addison disease (PRIMARY ADRENAL INSUFFICIENCY) where POMC and ACTH levels are increased by negative feedback. (more on this on adrenal topic). Growth hormone is secreted throughout life in a pulsatile pattern, and is the single most important hormone for normal growth. It is synthesized by the somatotrophs in the ant lobe and is stimulated by GHRH. It consists of 191 aa's in a straight polypeptide chain with 2 disulfide bridges, which is structually similar to prolactin (198 aa straight-chain polypeptide with 3 disulfide bridges). GH has a big burst of secretion every 2 hours, with the largest burst being 1 hour before falling asleep. At puberty, there is an enormous secretory burst, induced by female and male sex hormones, which stabilizes after puberty and hits the lowest values at sensecence. The major factors that alter GH secretions are hypoglycemia (low blood glucose) and starvation ( it increases it's secretion). Exercise and stress also increases Gh secretion. REGULATION OF GH (this must be drawn): -GHRH acts (+) directly on the somatotrophs via it's special gs-coupled receptors which uses both cAMP and IP3 as secondary messengers. GHRH inhibits it's own secretion from the hypothalamus in a very short-loop feedback. -Somatostatin (ALSO CALLED SOMATOTROPIN RELEASE-INHIBITING HORMONE) is also secreted by the hypothalamus and acts on the somatotrophs in an inhibitory way via it's gi-coupled receptors, to decrease cAMP levels and GH vesicular secretions. -Somatomedins (insulin-lige-growth factors; IGFs) are by-products of the GH action on target tissues, and inhibit secretion of GH by the anterior pituitary. - Lastly, there is an important negative feedback loop which is mediated by both GH and somatomedins to secrete somatostatin (which is inhibitory of GH). ACTIONS OF GROWTH HORMONE: Some of the actions of GH are direct, meaning mediated by GH itself, or indirect, aka mediated by somatomedins. The direct actions include: -lipolysis -decreased glucose uptake (diabetogenic effects as they cause insulin resistance by counteracting insulin's actions aka the above mentioned effects are ANTI-INSULINIC) -protein production, this is an action which is pro-insulinic The indirect actions, done by somatomedins include: -linear growth=bone lenghtening and thickening -increased chondrocyte differentiation -collagen synth -organ growth In GH excess, different diseases may occur depending on when the excess of GH is. If, the excess is before puberty, then the excess of GH causes GIGANTISM where there is an increased linear growth because of intense hormonal stimulation at the epiphyseal plates. After puberty, when the epiphyseal plates have closed, linear growth can no longer be affected, thus the periosteal bone growth is increased in excessive GH AFTER PUBERTY. This causes a disease called ACROMEGALY, where the hands and feet are increased in size, same with the organs, the tongue is enlarged, coarsening of facial features, insulin resistance and glucose intolerance. Somatomedins: -IGF1/somatomedin C is special because it is an inhibitor of GH release. It is produced by the liver in response to GH and it's receptor is special as it has intrinsic tyrosine kinase activity. -IGF2/somatomedin A is produced in theca cells and acts as a growth factor in utero growth. NB!!!!! During fasting, GH is increased as the metabolic actions of GH (direct pathway) are needed to maintain blood sugar levels normal, however, GH does NOT induce growth during fasting. Fasting inhibits somatomedins production. This means that even though growing children which are not fed enough, but still have high levels of GH; they are not growing properly since somatomedins which mediate the growing effects of GH indireclty are inhibited!!! (Can also talk about prolactin and such, however, this will be written about in the pregnancy topic)!

1.10. Parasympathetic and sympathetic efferent mechanisms.

The main function of the ANS is to maintain constant internal environment (homeostasis). The ANS unconsciously receives sensory input and sends signals to the effectors, which include smooth muscle, cardiac muscle and glands. The ANS is divided into SY and PSY. The neuro-effector junction is analogous with the NMJ in the somatic nervous sytem, the biggest difference is that so-called VARICOSITIES are the site of NT synthesis, storage and release, and are therefore analogous to the presyn-terminal of NMJ. Most organs have both SY and PSY innervation. These innervations operate reciprocally/synergistically. Examples include the heart, the smooth muscle of the GI and bladder. PARASYMPATHETIC DIVISION = THE OVERALL FUNCTION OF THE PSY DIVISION IS RESTORATIVE AND TO CONSERVE ENERGY. -preganglionic neurons originate in the brain stem and sacral spinal cord (craniosacral divison) -in contrast with SY, PSY has long pre-ganglionic neurons which synapse in ganglia close to the effector organ. -The preggl neurons are cholinergic and release Ach which bind to nicotinic receptors. The postggl neurons are also cholinergic, thus they use Ach as well, but it binds to muscarinic receptors on the effector organs. (However, the varicosities (presyn neuron) can also synthetize and release VIP and NO) -The PSY cranial nuclei include: --Edinger-Westpahl --sup and inf salivatory nuclei --dorsal vagal nuclei --nucleus ambiguus and the PSY fibers coming from the sacral nuclei travel through the SPLANCHNIC NERVE Muscarinic receptors are located in all of the effector organs of the PSY: heart, GI, bronchioles, bladder and male sex organs. M1, M3, M5 = Gq --> activation of phospholipase C --> IP3 + DAG, IP3 releases Ca2+ M2, M4 = Gi --> inhibits adenylyl cyclase --> decreased cAMP levels M2 is a bit unique because the alpha unit will inhibit adenylyl cyclase, but also, the betagamma subunit will have a function. It will stimulate Ik(Ach) GIRK channel to further hyperpolarize the cell resulting in negative chronotropic effects alpha subunit binding direclty to K+ channels in the heart and smooth muscle, causing the channels to open and hyperpolarize the cell, thus slowing the rate of depolarization and decreasing HR. So, the target of PSY is: -Slow heartbeat with M2 receptors -Smooth muscle contraction via M1, M3, M5 receptors --> contraction of bladder, GI, constrict airways etc M1: neural, found in exocrine glands and autonomic ganglia M2: located in atria and conducting tissue of the heart M3: glandular, located in exocrine glands and smooth muscle M4: CNS M5: Substantitia nigra SYMPATHETIC PATHWAY: -Thoracolumbar origin of preganglionic fibers -The preganglionic fibers are short and they synpase in ganglions either paravertebrally (sympathetic chain) or prevertebrally (celiac, sup mesenteric, inf mesenteric and hypogastric) -The preganglionic neurons are ALWAYS cholinergic and uses Ach, while the postganglionic neurons are adrenergic in all of the effector organs EXCEPT in the thermoregulatory sweat glands (where they are cholinergic). -The adrenal medulla is a specialized ganglion within the SY division of the ANS. The preganglionic neurons are located in the thoracic spinal chord and synapse on the chromaffin cells of the medulla where they release Ach. Then, the chromaffin cells secrete catecholamines into the circulation. Adrenergic receptors can be activated by either norepinephrine or epinephrine, with the receptor types having different affinty to them (B1 in the heart has equal affinity, while B2 has higher affinity for epinephrine than NE! -Alpha1 receptors: Gq-coupled so leads to increased Ca2+. It is found in vascular smooth muscle of skin, skeletal muscle and splanchnic region, sphincters of the GI tract and radial muscle of the iris. Causes vasoconstriction and contraction -alpha2 receptors: Gi-coupled. Found in nerve terminals as it inhibits release of NE, to inhibit prolonged SY stimulation. In the GI, alpha2 receptors cause inhibition of Ach release and inhibition of GI function -Beta1 receptors: Gs-coupled. Heart, both atrial AND ventricular. Also located in the salivary glands, adipose tissues AND KIDNEY'S (to promote renin secretion) -Beta2 receptors: Gs-coupled. Found in vascular smooth muscle within the heart and bronchioles + bronchiolar smooth muscle as well. LEADS TO RELAXATION/DILATION OF SMOOTH MUSCLE I BOTH BRONCHIOLES AND BLOOD VESSELS to provide increased blood flow and oxygenation -beta3 receptors: Gs-coupled. For lipolysis in adipose tissue and thermogenesis in skeletal muscle. Some organs are only innervated by SY, these include: -vascular smooth muscle -sweat glands -arrector pili -liver -adipose -kidney The regulation of these are done, not by competing between PSY and SY stimulation, but by the presence/non-presence of the SY stimulus

8.2. The somatovisceral Sensory System: properties of the receptors, afferent pathways, role of the thalamus and the cerebral cortex. Tactile sensations.

The somatovisceral sensory system analyzes sensory events relating to the mechanical, thermal or chemical stimulations of the body and face. There are 4 properties of coding sensory information: -Modality --> type of stimulus. For ex: touch, temp, light, smell, pressure -Intensity -Duration -Location Sensations starts with some sort of receptor, which varies based on the modality (quality). There are 11 major sensory modalities: -Classic senses: Vision, hearing, taste, smell, touch -Other imp sensory modalities: flutter-vibration, cold, varmth, proprioception, linear and rotational acceleration, pain The sensory system uses the concept of labelled line code. This means that the sensory modality is encoded starting at the receptor, then including all the nerves that carry sensory information, all the way to the cortex where the information is received. A stimulus must reach a certain TRESHOLD to be able to be sensed. The treshold is defined as the point where in 50% of the cases we sense, and 50% of cases we do not. The treshold depends on the intensity of the stimulus which can be coded in different ways: -AP frequency: higher freq of AP's = larger intensity -population coding: with a higher intensity stimulus, more sensory nerves are activated -Different receptors are activated, but they are related: mechano and noicoreceptors when you add enough pressure so that it becomes painful?? The duration of the perceived sense can be altered by adaptation. When a stimulus continues to last, the AP freq may slow down. The location of a stimulus is interpreted by somatotopic organization (when there is a point-for-point correspondance between peripheral receptors and cortical neurons). Two-point discrimination is the phenomenon based on the distance between two distinct receptors, and the interpretation of the relative location of one stimulus to another. Separation of the two is harder where the receptor density is lower like your back for ex compared to your fingers. Sensory neurons are usualyy pseudopolar, EXCEPT in the olfactory tract, retina and vestibular apparati where there are bipolar neurons. All sensory information passes through the thalamus (remember this is afferent tracts), except the majoroity of olfactory stimuli. A receptive field defines an area of the body that when stimulated results in a change in firing rate of a sensory neuron. The firing rate can either increase (excitatory) or decrease (inhibitory). Receptive fields vary in size. The smaller the receptive field, the more precisely the sensation can be localized/identified. Typically, the higher the order of the neuron, the more complex the receptive field since more neurons converge on relay nuclei here. In the lower neurons, we have something called lateral inhibition ai us to define the boundaries and further localizing the stimulus on the skin. The somatosensory system processes information about touch, position, pain and temp. The receptors involved in transducing these sensations are mechanorec(touch and proprioception), thermorec, and nocireceptors (pain). Intensity of these is based on electrotonic potential. Sensory receptors adapt to stimuli which can be observed when a constant stimulus is applied for a period of time. -"Rapdily adapting receptors" can only detect a signal if it is quickly on and off. They detect changes in the stimulus, therefore detect changes in velocity. Rapidly adapting receptors are surrounded by a capsule, and because of this capsule, the energy from an impact with the skin is quickly dissapated. If pressure comes periodically, as in vibration, then the receptor capsule is not allowed to restructure itself, and so vibration, tapping or flutter are detected -"slowly adapting" receptors don't have a layered capsule, so there is not the same dissipation of mechanical energy applied to them, and stimulus will last longer. These receptors respond more to intensity and duration of the stimulus. Receptors: *Pain and temp: free nerve endings *Touch and position: Meissner (fine), Merkel (deep) *Pressure: Pacinian, ruffini, Merkel. REMEMBER: that those receptors associated with fingers adapt slowly, except meissner, and the rest adapt more quickly. MNEMONICS: "I can feel pain and temperature, free all over the skin"--> thermorec and nociceptors "MeiSSner --> hairleSS" --> for touch, superficial, rapidly adpating, small R. fields, lips, fingertips "Merckel's superficial fingers" --> for pressure, superficial, slowly adapting "Ruffini- my fingers and joints are touching the roof" --> deep, slowly adapting for stretch "The pacinian (pacific ocean) is so deep, that I can feel the pressure and vibration of the ocean" --> deep, subcutenous, encapsulated, rapidly adapting, large R. fields -Pacinian corpuscles: deep, rapidly adapting, for vibration. They are encapsulated receptors found in the subcutanous layer of the skin and m. They have large receptive fields as the sensations they detect, vibration and deep pressure disappears more. -Meissner corpuscle: superficial, rapidly adapting, for touch. They are also encapsulated found in the dermis of non-hairy skin, especially fingertips, lips and other places where tactile sensation is strong. They have very small receptive fields, and can be used for two-point discrimination -Ruffini corpuscle: deep, slowly adapting, for stretch. Located in the dermis of skin, and joint capsules. They have large rec fields and are stimulated when the skin is stretched. -Merkel receptors: superficial, slowly adapting, for pressure. Found in non-hairy skin and have very small receptive field. They detect vertical indentations of the skin, and their response is prop to stimulus intensity. (Tactile disks are similar to merkel rec, but are found in hairy skin). -Thermoreceptors: free nerve endings with no capsule -slowly adapting. Located at the boundary between the dermis and the subcut. Cold receptors use myelinated Adelta axons (pretty fast), while warm receptors use unmyelinated C fibers (slow). Above and below certain temp's, these receptors become inactivated and only pain receptors are functioning. Transduction of warm temp1s involve transient receptor potential (TRP) channels that are activated like substances like such in spicy food. Transduction of cold temperatures involve a different TRP channel, (TRPM8) which is activated by for ex menthol. -Noiceptors: respond to stimuli that can cause tissue damage. There are two major classes. Thermal/mechanical noiceptors are supplied by finely tuned Adelta aff n fibers and respond to mechanical stimuli such as sharp, pricking pain. Polymodal noiceptors are supplied by unmyelinated C fibers and respond to hot and cold stimuli. There are two pathways for transmission of somatosensory information to the CNS: the dorsal column and the anterolateral/spinothalamic system. THE DORSAL COLUMN SYSTEM- cross in medulla = medial leminiscus pathway. -uses mechanoreceptiors and proprioceptors -responsible for detection of fine touch, vib, proprioception, two-point discrimination -consist mostly of group 1 and group 2 n fibers. -Path: The 1st order neurons have their cell bodies in the dorsal root ganglion cells and ascend IL to the nucleus gracilis (lower limb) or nucelus cuneatus (upper limb) in the medulla of the brain stem. In the medulla, the 1st order neurons synapse on the 2nd order neurons, which CROSS THE MIDLINE, and ascend CL to the thalamus. This tract is called the medial leminiscus. Information from the body goes through the VPL, while information from the head goes through VPM. The 3rd order neurons are in the thalamus and the 4th in the somatosensory cortex (brodmann 3, 2, 1) THE ANTEROLATERAL PATHWAY - spinothalamic tract - cross in spinal chord -uses warm and cold thermoreceptors plus noiceptors for pain -ant spinothalamic tract carries info about crude touch -posterior carries info about pain and temp Path: 1st order neurons have their cell bodies in the dorsal horn and synpase on thermorec and nociceptors in the skin. They then synapse with the 2nd neuron in the spinal chord. The 2nd neurons then cross the midline and and ascend CL into the thalamus (3rd order) and goes to the somatosensory cortex (4th order). Central projection of tactile information = senses of touch: Goes to post-central gyrus for the somatosensory cortex, where a complex somatosensory map is formed and called a homunculus. This takes place in Brodmann area 3, 2, 1 (which makes up a region called S1). The regions corresponds not to their body size, but to how well those areas may receive tactile stimuli. The lips and fingers are very large on the homunculus map.

7.3. Production and effects of thyroid hormones (T3/T4). The regulation of their secretion.

Thyroid hormones are synthetized and secreted by epithelial cells of the thyroid gland. They have effects on virtually every organ system in the body including those involved in normal growth and development. The two active thyroid hormones are TRIIODOTHYRONINE (T3), and TETRAIODOTHYRONINE/THYROXINE (T4). The two differ only by a single atom of iodine. Although T3 is more active than T4, almost all hormonal output of the thyroid gland is in the T4 form. This is solved by the target organs however, which contain the enzyme 5'-iodinase which converts T4 back to T3, the active form. A third compound called the reverse T3 has no biological activity. SYNTHESIS OF THYROID HORMONES: As mentioned, the hormones are synthetized by the follicular epithelial cells that are arranged in circular follicles of 200-330um diameter. (Follow the steps in the drawing from the book, attached. Should maybe draw it to aid myself in explaining it?) 1) THYROGLOBULIN, a glycoprotein which contains large amounts of tyrosine is synthetized on the RER + golgi of thyroid follicular cells. 2) "I-TRAP". On the BL membrane of the follicular epithelial cells, there is a Na+/I-contrasnporter, which transports I- from the blood into the epithelial cell against it's electrochemical gradient. This is a form of active transport and it can be inhibited by PERCHOLATE and THIOCYANATE. This step is ofc, regulated by the I- levels in the body. Done by negative feedback. (If the iodine levels are low, the pump tries to compensate by increasing its activity, but if the iodine deficiency is severe enough, then it cannot be compensated for and thyroid hormone synthesis is decreased. (Minimum iodine intake for hormone synthesis: 50100 μg/day.​ Avg. daily intake = 400 μg.) 3) Oxidation of I- to I^2. This step is catalyzed by thyroid peroxidase (catalyzes this step + the next two as well) and is inhibited by propyl thiouracil (PTU), which is a very effective medicine to treat hyperthyroidism. 4) Organification of I^2, where I^2 combines with thyroglobulin to form MIT and DIT. MIT and DIT remain attached to TG until the thyroid gland is stimulated to secrete it's hormones. Iodine usually stimulates thyroid hormone synthesis, but too high levels of I- (over 2mg per day) inhibit organification and synthesis of thyroid hormones = Wolff-Chaikoff effect. 5)Coupling effect: while still atatched to TG, two coupling reactions occur between, either 2 x DIT to form T4, or, 1x MIT and 1 x DIT to form T3. THE FIRST RXN IS FASTER AND AS A RESULT, APPROX 10X MORE T4 IS PRODUCED THAN T3. This is what stays in the colloid until stimulation 6)When the thyroid gland is stimulated, iodinated TG ( with it's T3, T4, MIT or DIT) is endocytozed by PSEUDOPODS and TG is re-used 7)Hydrolysis of T4 and T3 from TG: TG will fuse with the lysosomal membrane, so that lysosomal proteases can hydrolyze the peptide bonds to release T3/T4/MIT/DIT from TG. The released T3 and T4 goes into the systemic circulation. 8) Deiodination of MIT and DIT: catalysed by thyroid deiodinase. The released I- generated by this reaction is recycled. DIFFERENT FORMS OF THYROID HORMONES AND THE BINDING OF THEM IN THE CIRCULATION: In circulation, the majority of T3 and T4 are they are bound to proteins because they are not watersoluble. 80%​ bind to thyroxinebinding globulin (TBG),​ (15%​ to transthyretin ​(AKA thyroxinebinding prealbumin, TBPA​), and 5%​ to albumin.) 0.02% of T4 is free​ and 0.5% of T3 is free​ in circulation, so significantly more T3 is free. Since only the free hormone is active, TBG acts as circulating reservoir of thyroid hormone that can be utilized by dissociation from the bound proteins. REGULATION OF THYROID HORMONES: -Major control of the synthesis and secretion of the thyroid hormones is via the hypothalamic-pituitary axis. (MUST DRAW!) -TRH--> thyrotrophs --> TSH --> T4 and T3. -The actions of TSH on the thyroid gland are initiated when TSH binds to a membrane receptor which is Gs-coupled which increases the cAMP levels to increase the synthesis and release of the thyroid hormone synthesis steps. --> TSH also has a trophic effect on the thyroid gland, which can lead to hypertrophy if TSH levels are elevated over time. -The TSH receptor on the thyroid cells also is activated by THYROID-STIMULATING IG'S which are antibodies to the TSH receptor. When the Ig's bind to the TSH receptor they stimulate the same response as TSH itself. --> GRAVES disease is a common form of hyperthyroidism, which is caused by increasing circulatin glevels of thyroid-stimulating Ig's. The actual TSH levels are lower than normal, but the Ig's stimulate an increased release of thyroid hormones, which further lowers TSH levels by negative feedback. ACTIONS OF THYROID HORMONES: n almost every tissue, thyroid hormones act with growth hormones and somatomedins to promote bone formation, increase metabolism, and thus oxygen consumption and heat production, and alter cardiovascular and respiratory systems to increase blood flow and oxygen delivery to tissues. The first step is converting T4 to T3 as mentioned above with 5' iodinase. Once in the T3 form, T3 will bind to thyroid hormone receptor o​ n the nuclear membrane. This complex enters the nucleus and finds the thyroid responsive element (TRE) ​on the DNA and with RXR (retinoid X receptor)​. The complex will stimulate gene expression, translation and production of several proteins such as K+/Na+ ATPases, transport proteins, β adrenergic receptors, etc. as listed below. Basal Metabolic rate​: Thyroid hormone increases the oxygen consumption in all tissues except the brain, gonads and spleen by increasing synthesis and activity of Na/K ATPases, among other mechanisms. This increased oxygen consumption will increase the basal metabolic rate and thus increase the body heat. Thyroid hormone also stimulates uncoupling protein that makes adipocytes burn fuel for the purpose of heat production. -Metabolism​: thyroid hormones increase glucose absorption, gluconeogenesis, glycogenolysis, protein synthesis and degradation, and strengthen other hormones like glucagon, GH, etc. Thyroid hormones give a general catabolic (degradative) effect thus certain enzymes like cytochrome oxidase, malic enzyme, and proteolytic enzymes are upregulated. Muscle weakness is a symptom of hyperthyroidism because usually the net effect is proteolysis, even though there are also some mechanisms to stimulate protein formation. Lipolysis occurs via a permissive effect that enhances effects of epinephrine. -Cardiovascular effects​: Because of the high demand for oxygen to fuel the high metabolic activity, there is a need for increased cardiac output through both increased stroke volume and heart rate. This is done by permissive effects that induce β​1​ adrenergic receptors in the heart tissue to increase the sympathetic effects of the heart. Thyroid hormones also alter the expression of myosin and sarcoplasmic reticulum Ca2+ ATPases to increase inotropy. These effects lead to increased systolic blood pressure, but the increased oxygen demand in the periphery means that there is also vasodilation and a decrease in TPR, which correlates to lower diastolic blood pressure. So, hyperthyroid patients may present with a high systolic and low diastolic blood pressure, translating to a wider pulse pressure. -Respiratory effects​: Both rate and minute volume are increased, and erythropoietin is stimulated so that RBC production increases. -Growth:​ Thyroid hormones work with GH and somatomedins to promote general growth, and TH is particularly important in bone formation. TH stimulates chondrocyte differentiation, promotes linear growth and bone remodeling. With connective tissue, TH stimulates degradation of glycoproteins and proteoglycans. This degradation alters the osmotic gradient of the interstitial space. Lack of TH during development ⇨ cretinism​, which includes stunted physical growth and mental retardation. -Central nervous system​: Lack of thyroid hormones in the perinatal period results in a failure to properly develop the CNS and thus mental retardation/cretinism. In development, TH aids in myelination, synapse formation, dendrite arborization, and cell migration. In adults, they main proper cognitive and motor functions. In adults, hypothyroidism causes slowness, impaired memory, and decreased mental capacity. Hyperthyroidism creates irritability, hyperexcitability, and hyperreflexia. -Autonomic nervous system:​ Thyroid hormones interact with the sympathetic nervous system in ways described above with the heart, heat production, lipolysis, and gluconeogenesis. They induce expression of α and β adrenergic receptors PATHOPHYS OF THE THYROID HORMONE: *Talked about hyperthyroidism above with Graves disease! *Hypothyroidism: ​low free T3/T4 Causes: iodine deficiency (most frequent), genetic issues (TPO/DUOX), inflammation Symptoms: --in infants: -cretinism​ mental retardation, decreased height (dwarfism), facial abnormalities, big tongue --in adults: - Myxoedema​: edema which develops because proteoglycans and glycoproteins are high in the CT (TH normally breaks these down) Observed in the face, organs, vocal cords Hoarse voice: myxoedema of vocal chords Dry, cool skin: decreased BMR; dry because TH role in secretion Weight gain: decreased metabolism Sensitive to cold: decreased heat production Slow speech: slow mental function Depression: a symptom or can be a separate disease developing independently Panda bears carry mutation in DUOX2 > they have hypothyroidism; it's not their fault they are lazy.

3.4. Localization and function of the respiratory control centers. Neural and chemical control of the respiration.

-The respiratory control centers are located in the brain stem, and they control the frequency of normal and involuntarilty breathing via 3 centers: 1)MEDULLARY CENTERS IN RETIUCULAR FORMATION: -inspiratory center/pre-bottzinger complex control basic rhytm of breathing. It sends repetitive APs to the phrenic nerve. Gets it's input signals from chemoreceptors and apneustic center -expiratory center: controls expiration but since expiration is mostly passive, it is mostly used in exercise 2) APNEUSTIC CENTER: abnormal breathing center. Controls intensity of breathing. Gets afferent fibers from vagal stretch receptors in lung 3)PNEUMOTAXIC CENTER LOCATED IN THE UPPER PONS: turns of inspiration, to limit the size of the tidal volume and to reg resp rate --> The cerebral cortex can override all of these centers up to a certain point as a person can decide to hold their breath or hyperventilate etc CHEMORECEPTORS: regulate respiration, stimulate respiratory centers and increase the ventilatory drive, but also changes blood pressure through changes in SY and PSY output. Operates mostly against the dramatically low blood pressures but via detecting low O2, high CO2 and or metabolites that build up during poor perfusion. CENTRAL CHEMORECEPTORS: in brainstem -Are most sensitive to the partial pressures of CO2, and pH. -If there is a decreased rate of cerebral blood flow, there is an immediate increase of pCO2 and decreased pH due to the H+ formation which increases SY outflow --> causing an intense arteriolar vasoconstriction throughout the body to incr TPR to REDIRECT THE BLOOD FLOW TO THE BRAIN THE CUSHING'S REFLEX ILLUSTRATES HOW THE CENTRAL CHEMORECEPTORS WORK: The combination of a slowing pulse, due to PSY activation, rising blood pressure due to activation of SY to overcome the increased intracranial pressure, and erratic respiratory patterns; a grave sign for patients with head trauma or cerebrovascular accident. --> basically, when people hit their heads and the intracranial pressure is increased, firstly the central chemoreceptors are activated to increase blood pressure and redirect the blood flow to the brain, but the arterial baroreceptors detect this high BP and thus slows the HR down to compensate PERIPHERAL CHEMORECEPTORS: Located: -Near the bifurcation of the common carotid arteries -aortic arch -Sense changes to pO2, but also increase pCO2 and pH changes. --> When the pO2 decreases, there is an increased firing rate of sensory nerves from the carotid bifurcation and aortic arch to activate the SY which will cause vasoconstriction of the arteries in the skeletal muscle, renal and splanchnic vascular systems (to redirect to brain), and vasodil in cerebral circ.

1.1. Body fluid compartments and their determination. The extracellular and intravascular fluid

70kg man! COMPARTMENTS: -TOTAL H20 CONTENT = 0,6* BW = 42L -->INTRACELLULAR FLUID = 0,4*BW =28L -->EXTRACELLULAR FLUID = 0,2*BW= 14L ---->INTERSTITIAL FLUID = 3/4 OF ECF = 10,5L ----> PLASMA = 1/4 OF ECF = 3,5L ----> TRANSCELLULAR FLUID = 1L (-CSF, OCULAR FLUID, SYNOVIAL FLUID) -The intracellular and extracellular compartements are separated by the cell membrane -the interstitial fluid and plasma are seperated by the capillary wall COMPOSITION OF THE ECF AND ICF: ECF ICF -Na+, 140mM 12mM -K+, 4mM 130mM -Cl- 100mM 25mM -Hco3- 25mM 15mM -Ca2+ 2,5 tot 100nM <-- 1,3free -pH 7,4 7,2 -osm 290 290mosm DETERMINATION OF THE V OF THE DIFFERENT FLUID COMPARTMENTS: -DILUTION METHOD to measure plasma V: Done by injecting radioactive labelled albumin (which, due to its size will stay in the plasma as it cannot cross the cell membrane nor the capillary membrane) -EVANS-BLUE METHOD DYE to measure plasma V: Is a protein bound dye that has a high affinity for albumin and with it we can measure ENDOGENOUS PRODUCED ALBUMIN! -DEUTRIUM (HEAVY WATER) to find total fluid compartment: The technique works because of the difference between the molecular composition of heavy water and regular water. An H2O molecule has two atoms of hydrogen that each are built of a single proton and a single electron. A D2O molecule, by contrast, has two atoms of a hydrogen isotope known as deuterium, which differs in that each atom has a single neutron in addition to a proton and an electron. This makes a heavy-water molecule significantly more massive than a regular water molecule. --> The heavy water goes everywhere were normal water goes, it is just easier to measure! -INULIN to measure ECF V To measure ECF we need something that can cross the capillary wall to get to the interstitium, but that doesn't cross the plasma membrane. Therefore, we use a smaller, but slightly big molecule. Can also use saccharose for example. -WE CANNOT DIRECTLY MEASURE ICF, SO WE MEASURE THE TOTAL FLUID VOLUME AND SUBSTRACTS ECF TO GET ICF!

1.7. Physiology of nerve cells. Synaptic transmission and its regulation. Neurotransmitters

A synapse is a site where information is transmitted from one cell to another. The information can be transmitted either electrically or via a chemical transmitter. An electrical synapse allows current to flow from one excitable cell to the next via low-resistance GAP JUNCTION pathways. This allows for: -very fast conduction -bidirectional transmission -has no delay (as we have with chemical synapse as the NT must be degraded and Ca2+ must trigger the exocytosis cascade) -found in cardiac ventricular muscle, single-unit muscle cell, uterus -allows for synchronized contraction of many neural cells A chemical synapse involves a synaptic cleft, a pre-ganglionic neuron, a post-ganglionic neuron and a NT. The NT is released by the pre-ggl terminal and binds to receptors on the postsynaptic terminal which produces a change in membrane potential of the post-ggl n. This can either be excitatory or inhibitory, depending on the nature of the NT. -The chemical synapse is UNIDIRECTIONAL and a synaptic delay time (1-5ms) is required for the multiple steps in chemical neurotransmission to occur. An example of a chemical synapse is the NMJ transmission (explained steps in topic 1,9). They can regulate this by different drugs: - Giving botulinus toxin to block the complete release of AcH from pre-synaptic terminal. Causing paralysis of skeletal muscle. (Arrows africa) -Curare can be given to block the ACh nicotinic receptor on end-motor plate to decrease the size of the EPP. Tubocurarine is used therapeutically as a muscle relaxant during anasthesia. -Anticholinesterase drugs like neostigmine prevents the degradation of ACh in the synaptic cleft and prolong + enhance the action of ACh. This drug is given to treat myasthenia gravis (when muscarinic receptors are blocked by antibodies which causes muscle weakness) -Hemicholinium blocks choline reuptake into presyn terminals, thus depleting choline stores and decreasing the synth of Ach. Definition/requirement of substances to be categorised as a neurotransmitter: -must be synthesized by presynaptic neuron -must be released upon stimulation of presyn neuron -must have a receptor on the post synaptic terminal and induce a response Excitatory NT's: Ach (it is the ONLY NT that is used in the NMJ. It is also the NT released by ALL preganglionic neurons in both PSY, SY and adr medulla). -Dopamine -Glutamate -NE -Seretonin Inhibitory Nt's: -GABA, -glycine In a many-to-one synaptic arrangement, many pre-synaptic cells might converge on a single postsynaptic cell, with the inputs being both excitatory and inhibitory. The postsyn cell integrates all the converging information, and if the sum of the inputs is sufficient to bring the postsyn cell to the treshold, then an AP is fired. EPSP's: excitatory postsynaptic potentials will depolarize (0,1-5mV) the postsyn cell, bringing them closer to the treshold level and closer to firing an AP. -they are produced by the opening of ligand-gated non-selective cation channels and the NT is usually glutamate -AMPA: permeable to univalent cations (na+, K+) -NMPA: permable to univalent AND divalent so calcium influx occurs. IPSP's: Causes hyperpolarization (0,1-5mV9 and/or stabilization of a more neg resting membrane pot. This is caused by the opening of the ligand-gated chloride channels or by opening of K+ channels (IRK). -NT is usually GABA -GABA a: ligand-gated chloride channel -GABA b: gi-coupled, involved in opening the inwardly rectifying K+ channels. These postsynaptic potentials are summated to see which will have the dominant effect, or they will just cancel each other out. -Temporal summation can occur, in which case two potentials from the same origin occur close together in time or -spatial summation, where to synapses of different origin are close to another and may add together both of their effects. REMEMBER: -There is a high density of voltage gated Na+ channels on the axon hillock which means that this is the final site of decision on whether the neuron can fire an AP or not. -NT's are taken into the synaptic vesicle by the NT-H+- antiporter and H+ is first brought into the vesicle through the V-type proton pump which requires ATP

6.5. The physiological role and function of B lymphocytes.

B lymphocytes are part of the adaptive, immune system, and helps create immunological memory in response to a pathogen, leading to a faster, more specific response with future encounters of said pathogen. --> The primary function of B lymphocytes are secretions of Ab's! The B cells are synthetized with the T cells in the bone marrow via the lymphoid lineage and then, the secondary lymphoid organs are sites of B CELL ACTIVATION! REMEMBER THE SPECIAL FEATURES OF THE ADAPTIVE IMMUNE SYSTEM: -Specificity due to specific epitopes being recognized by the surface receptors on adaptive immune cells -diversity is high in the variability of the structures of ag-binding sites on lymphocyte receptors --> 10^7-10^9 distinct epitopes recognized by each individual's immune system. This is the result from many different clone-specifiv receptors formed by the VDJ recombination that distinguish subtle differences in epitope structures -Memory -clonal expansion --> an increase in the number of cells that express IDENTICAL RECEPTORS for an antigen ANTIBODIES STRUCTURE: -are ag-specific soluble proteins produced by B lymphocytes in preparation and in response to lymphocytes -They can be: --> membrane bound to B cells --> or secreted and be present in the plasma, mucosal secretions and interstitial fluid MUST BE ABLE TO DRAW THE STRUCTURE! -2 identical light chains --> kappa or lambda -2 identical heavy chains --> mu, alpha, delta, gamma, epsilon --> these are connected by disulfide bridge --> hinge to regulate the two ag-binding sites - The N terminal has the variable domains that make-up 2 ag-binding sites -The C terminal makes up the constant domain which mediate the effector functions of the ab --> If we were to proteolytically cleave the ab at it's hinge region, we will be left with 3 distinct pieces: -2 Fab which consists of whole light chain and the C terminus of the heavy and V of the light --> it retains it's ag binding sites -Fc --> will self-crystallize AB DIVERSITY AND RECOMBINATION --> The COMBINATORIAL and JUNCTIONAL RECOMBINATION of the ab structure (gene level) leads to a huge diversity of ab's: 5*10^13 total receptor diversity!!!! - COMBINATORIAL DIVERSITY: VDJ recomb. There is a rambly assembly of 50V, 25D and 6J gene segments - JUNCTIONAL DIVERSITY: imprecise addition/removal of NT's TYPES OF AB'S: -IgG: monomer has high conc in plasma. Takes part in opsonization --> activates complement system -capable of neutralizing bacterial toxins --> ABLE TO CROSS PLACENTAL MEMBRANE!! -IgD: monomer used as B cell receptor -IgE: monomer, activates mast cells (via fcRe receptor) part of allergic reactions. Also provides defense against parasitic worms -IgA: dimers, involved in mucosal immunity -IgM: pentamers, the largest ab type. Used as NAIVE B CELL RECEPTOR, and inv in compliment activation B LYMPHOCYTES: Pro-B --> Pre-B --> immature B cells that have IgM receptor --> mature(naive) B cells will have both IgM and IgD receptors that migrate to the peripheral lymphoid organs, it also has a receptor composed of IgA and IgB subunit with an i.c ITAM (with tyrosine-based activation) --> once exposed to an ag the B cell will activate and become either memory cell or plasma cell B CELL ACTIVATION: -occurs in secondary lymphoid organs like the spleen and lymph nodes. -Activation occurs when the B cells is exposed to an ag, either free floating or via APC cells --> T CELL DEPENDENT ACTIVATION: (if they lack Th cells= AIDS, body doesn't have an adaptive response to the ag's) ----->When a B cells binds to a T-cell dependent ag, the ag is taken up into the cell by receptor-mediated endocytosis, then degraded and presented to T cells as peptide pieces in a complex with MHC-II molecules. The helper T cells recognize these aag's and bind the MHC II + peptide complex with their T receptors, stimulating secretion of IL-4, which facilitate B cell activation ---> B cells grow and differentiation is dramatically enhanced with the factors that T cells secrete. B cells MAY UNDERGO ISOTYPE SWITCHING, meaning they transition from producing IgM ab's into produces smaller IgG's ---> T-cell independent activation: ag's do not T cells to activate B cells, are so called TI ag's (T-indep). The response to these ag's are very rapid, BUT THE AB'S PRODUCED TO FIGHT THESE ARE USUALLY WEAKER THANT WITH T-DEP ACTIVATION, usually IgM's are produced

8.9. The role of the cerebellum and basal ganglia in motor functions.

BASAL GANGLIA: -STRIATUM = ptuamen + caudate -PALLIDUM = globus pallidus internus + externus -subthalamic nuclei -substantia nigra --> these components form a cortical-cortical loop in which the input comes from the cortex and the output also goes to the cortex. -MEANING: that the basal ganglia act to activate or inhibit motion, but more specifically it functions to: -provide background for fine movements -helps to generate movement patterns -allows us to learn different movements like how to play tennis or an instrument until the action becomes automatic and unconscious DIRECT AND INDIRECT PATHWAYS: (included pic's in graph segment) DOPAMINE WILL ALWAYS HAVE A POSITIVE EFFECT ON MOVEMENT, BUT THE NIGRASTRIATAL FIBERS USES DIFFERENT RECEPTORS FOR THE DIRECT (GS) AND INDIRECT (GI). (remember that 2 negative = positive, 3 negative = negative, 4 negative = positive) But basically, in the direct pathway there will be an EXCITATORY effect on the muscles, because we have + - - = + and the substantitia nigra will, through it's D1 receptors (gs-linked) cause a greater inhibition of the globus pallidus internal, which causes it to NOT inhibit the excitatory thalamus leading to overall excitatory effects In the indirect pathway, the overall effect will be inhibitory and the substantitia nigra aids this by using it's D2 receptors (Gi-coupled) is indirectly decreasing the inhibition of the globus pallidus externus INJURY AND PATHOLOGY OF THE BASAL GANGLIA: -The matabolism of basal ganglia is very high and requires a lot of blood since they are constantly working, therefore the most common injury to the basal ganglia is hypoxia -Pathologies to the basal ganglia can be characterized as either hypokinetic or hyperkinetic to describe the decreased or increased muscle tone and action associated with them -HYPoKINETIC DISEASES: --> Parkinson's - (can actually be characterized as both) due to the loss of nigrostriatal pathways and decreased in dopamine production. Can be treated with L-dopa -HYPERKINETIC DIEASES: -huntington's: involuntary movements that cannot be modulated intentionally, problems with voluntary movement and execution -athetosis: problems with the putmain, slow, invol, worm like movements -Hemiballismus: decrease in activity of subthalamic nuclei CEREBELLUM: -the cerebellum has NO DIRECT INFLUENCE ON THE SPINAL CORD, but accounts for 15% of the mass of cerebrum -MAIN FUNCTIONS: --reg muscle tone --ensure postural background of fast movements --cont control of small movements --reg automatic movements -We divide the cerebellum into 3 functional differences: -VESTIBULOCEREBELLUM (flucculonodular lobe/archicerebellum) - functions with balance and processes info from the vestibuli -SPINOCEREBELLUM - modulate movements with emboliform, globuse, fastigial nuclei -NEOCEREBELLUM -movement planning with modulation with dentate nuclei CEREBELLAR DISEASE/INJURY SYMPTOMS: -delay in movement or tremos -lack of coordination -ataxia - inability to initiate movements -atonia - decrease muscle tone -dysmetry - cannot judge distances of objects

8.1. Physiology of nerve and glia cells

BASIC STRUCTURE AND MYELINATION: Neurons is the functional cellular unit of the n system. Human brain has approx 10^12 neurons (10 times more glial cells, but will talk about them later). A neuron consists of a body (soma), usually several dendrites and a single axon. Nerve fibers that are myelinated are faster than unmyelinated fibers, because myelin is a lipid that increases the membrane resistance (R=8*l*viscosity/pi*r^4) which forces the current to flow along the path of least R which is inside the axon interior. It also decreases the membrane capacitance, and because of this, the conduction velocity is increased. It is important to have the nodes of Ranvier, which are 1-2mm breaks for AP's to be fired across the membrane, or else none would be. Due to R being inversely proportional to cross-area, nerves with larges diameter are faster. Therefore, the largest fastest nerve fibers are large, myelinated Aalpha motor neurons. The slowest type is unmyelinated, type C fibers used to transmit dull, aching pain. Must know velocity of different type of nerves: -Aalpha (motor neuron) : 70-120m/s -A beta (touch and pressure): 30-70 m/s -A delta (pain, temp and touch): 5-30m/s -C (pain): 0,5-2,5 m/s CODING OF INFORMATION: There are three ways of coding information in the nervous system: -A LABELLED LINE: is a set of neuron fibers dedicated to a given function, for example the fibers carrying the information for vision. An AP is stimulated anywhere along that line (not necessarily only from the receptor) will be interpreted by the CNS as something assocoiated with that function. Ex: A person will see something if you electrically stimulate their optic nerve. -A SPATIAL MAP: describes the information encoded by the nervous system by an array of neurons that are spatially related. Ex: if 2 neighbouring points on the skin receive cutanous innervation that projects to a region of the cortex where two points will again also be close. Applies to retinotopic maps for vision and tonotopic maps for the auditory system -A TEMPORAL PATTERN or timing of action potential/ n impulses via synaptic transmission Synapses between the neurons may occur between the dendrites, the cell body or the axon. Neurons receive numerous input synapses of both EPSP and IPSP, that are summed. If EPSP signals are stronger, then the membrane is depolarized and an AP i conveyed. Talk about summation like in previous topics. Then talk about EPSP and IPSP like in prev topics NB! What is important to mention is that NMDA is responsible for long-term potentiation (LTP) where NMDA receptors make certain neurons more strongly excitable, which is a major basis of memory formation. There are two important phenomena's important to mention here: -Presynaptic inhibition in which an inhib (GABA) inhibits the release of an excitatory NT, creating a smaller AP in the post-syn neuron and provides a selective inhibition of a given excitatory input. -The other is retrograde signalling that occurs with the CB1 receptors and (2-AG). The result is that a post-synaptic neuron is stimulated with glu to inhibit glu release of the presyn neuron. The cascade is this on postsyn n: mGluR5--> Gq --> PLC --> IP3 + DAG --> DAG lipase --> 2-AG diffuses across syn cleft to presyn glu neuron --> binds to CB1 rec --> Inhibits glu release. NB! Ap frequency in neurons is directly proportional to the summed postsynaptic potential amplitude. If there is a small summated EPSP, there will be a low frequency of AP's, and vice versa. SYNAPTIC PLASTICITY: Synaptic plasticity refers to how a synapse may be more or less sensitive, depending on its previous activity. Synaptic strength is the mean amplitude of the postsyn response, which is variable. LTP is an example of this where, in the hippocampus, synaptic strength is increased for hours- days. Via the cascade: high frquency stim --> increased AMPA-R activity --> stronger depol --> NMDA-R activation --> increased ca2+ --> CAM-Kinase II activation which phosphorylates AMPA-R to increase it's activity. GLIAL cells: Are the supportive cells on the nervous system, constitute half of the V of the brain. Can be divided into macroglia, oligodendrocytes and microglia cells. Astrocytes contain elaborate processes that link neurons and blood vessels, so their function often deals with transporting substances between the neurons and the blood. Types of astrocytes: -fibrous (white matter) -protoplasmic (grey matter) -radial glial cells (guide neurons during development) -Müller cells (int the retina) -Bergmann glia (cerebellum) Astrocyte functions (should probably draw to show my thoughts): -Provide fuel to neurons in the form of lactate: Astrocytes store glycogen, but this cannot be released as glucose like in the liver. Instead, the astrocyte glycogen undergoes glycolysis to become LACTATE, which is exported out of the cell via MCT1 transporters, then it enters the neuron via MCT2 transporters and is used to be converted to pyruvate and fuel in the citric acid cycle. -Astrocytes regulate the extracellular K+ and pH: Due to the frequent depolarizations of neurons, there is a high extracellular K+, and low Na+. Astrocytes regulates this via their Na/K ATPase Na/K/2Cl-cotransporter and K+-channels. The last ones allow INFLUX of K+, due to the very negative membrane potential of astrocytes which drive + charged K+ into the cell. This is called spatial buffering. -Astrocytes take up the glutamate released at synapses and release glutamine into the ECF, or else the high conc of glu would be toxic for the brain! Astrocytes contain glutamate transporters that take it into the cell, then glutamine synthase converts it into glutamine which is released to ECF and taken up by neurons. Then glutamine is converted to glutamate by glutaminase., which is then packaged in a vesicle and used as a NT again. ( draw) -Astrocytes secrete trophic factors that promote neuron survival like Brain-Derived-Neurotrophic-Factor (BDNF) and Glial-derived --´´-- (GDNF) -Modulate cerebral blood flow by causing vasodilation near active neurons which needs more blood flow. This occurs because some of the glu will activate metabotropic glu R (mGluR1 or 5) which are Gq coupled and releases Ca2+. This leads to the release of PGE2 and NO which causes the vasodil. Oligodendrocytes create the myeling sheath of CNS neurons. Microglia are the macrophages of the CNS and represent about 20% of all glial cells. Capable of AG-representation, phagocytosis, release of cytokines, free radicals and NO. Ependymal cells: simple columnar cells that line the walls of CSF filled ventricles. They are a form of glial cell, that produce, regulate, reabsorb and circulate the CSF using their cilia. (CSF production per day: 500 mL/day. 0,35mL/min)

6.3. Blood coagulation. Fibrinolysis. Physiological anticoagulant mechanisms.

BLOOD CLOT FORMATION: -A blood clot begins to form within 15-20 seconds of a severe trauma, and 1 - 2 minutes for a minor trauma -Within 3-6 minutes, the entire rupture is usually closed by the clot, if the damage wasn't too severe. -Blood coagulation occurs primarily because of the conversion of fibrinogen to fibrin via the enzymatic actions of thrombin. Thrombin itself must first be activated and have the necessary cofactors to perform this function, and THROMBIN ACTIVATION OCCURS VIA 2 DIFFERENT PATHWAYS: EXTRINSIC AND INTRINSIC!!! (i will include a picture of it all in the graph section) EXTRINSIC PATHWAY: -Called the extrinsic pathway since it is activated when something this isn't normally present in blood is exposed to blood and thus leads to the activation cascade. So, when there is an injury to the blood vessel, factor VIIa in blood is exposed to TISSUE FACTOR that is present on the surface of all cells that do not normally interact with blood. This interaction causes them to form a complex called the "EXTRINSIC TENASE COMPLEX" (VIIa-X-TF-ca2+) which converts X into Xa. Xa forms a complex with Va = "PROTHROMBINASE COMPLEX" (XA-II(prothrombin)-VA-PL-CA2+) used to activate prothrombin (II) into thrombin. Thrombin has many functions (expl later), but is the most important in converting fibrinogen into fibrin. Fibrin forms a mesh network that is the basis of blood clotting INTRINSIC PATHWAY: -The name, intrinsic is misleading, since they thought that when blood started coagulating in a glass tube it was doing it on it's own, but it was actually THE NEGATIVE CHARGES ON THE GLASS TUBE that was initiating the coagulation cascade. -Factor XII is activated by endothel damage, collagen exposure, negative charges, kellikrein/HMW kinogen. -Factor XIIa then converts factor IX, and factor IXa forms the "INTRINSIC TENASE COMPLEX" (IXA-X-VIIIA-PL-CA2+) with VIIIa which is what converts X into Xa and then the prothrombinase complex is formed as explained previously. NB!: -The extrinsic tenase complex can actually activate IX and thus activating the intrinsic pathway -thrombin also activates factor IX, which is a positive feedback mechanism where the stimulatory effect of thrombin on IX aids it's own production. FIBRIN FORMATION: -This happens when thrombin converts fibrinogen dimer to fibrin monomers which spontaneously polymerize, HOWEVER, they are not stable and only bound by H-bonds. -This is why thrombin activates factor XIII (TRANSGLUTAMINASE) which converts the fibrin bonds to stronger COVALENT bonds. -The fibrin network is now stable and insoluble FIBRINOLYSIS: -Actually occurs alongside fibrin formation to limit the size of the fibrin mesh. (I HAVE A DRAWING ON THIS, draw that one) PHYSIOLOGICAL ANTICOAGULANTS: -Protein C (when activated by thrombin+ thrombomodulin complex) will inactive Va and VIIIa cofactors. This is a way of negative feedback of thrombin, and it also shows the minor anti-coagulatory actions of thrombin -Anti-thrombin: directly inactivates thrombin. This effect is further potentiated by HEPARAN SULFATE or heparin, which is present on the surface of endothelial cells. -Tissue factor pathway inhibitor (TFPI): SECRETED BY ENDOTHEL CELLS and inactivates the complex formed between TF and VIIa. It is activated by factor Xa as a neg feedback mechanism -A high physiological ca2+ conc is needed for coagulation and ir may be inhibited by EDTA which chelates Ca2+ ions -Vitamin K deficiency/block = WARFARIN/COUMADIN: is used to block coagulation as many of the cofactors need to produce Gla domains --> II --> VII --> IX --> X 6 IMPORTANT FUNCTIONS OF THROMBIN: -PROCOAGULANT EFFECTS: --converts firbinogen to fibrin --activates factor XIII --activates platelets --activates TAFI (fibrinolysis inhibitor) --activates V, VIII, IX via pos feedback -ANTICOAG EFFECTS: --activates protein C via the thrombin-thrombomodulin complex FACTORS PRODUCED BY ENDOTHELIAL CELLS: -PGi2 - vasodilator and inhibits platelet aggregation -NO - vasodilator, inhibits platelet aggregation -Collagen - platelet activation in the subendothelium -vWF - platelet adhesion + activation of the subendothelim -Thrombomodulin - termination of clotting process by activation of protein C -Plasminogen activators - activate fibrinolysis -Plasminogen activator inhibitors - restrict fibrinolysis ROLE OF PLATELETS: -provides a surface for coagulation -Release of plasminogenactivator-inhibitors -release of local vasodilators --> activated by: ADP, Seretonin, epinephrine etc

2.12. Coronary circulation. Circulation of the brain. Cerebrospinal fluid. Blood-brain barrier.

CORONARY CIRCULATION: -Coronary blood flow: 250mL blood/min (5% of the CO) -AVDO2: really high oxygen extraction! 120mL o2/L blood, since the mass of the heart is about 300g --> The heart is an obliagte AEROBIC ORGAN meaning it must have constant oxygen supply to function. It's extremely susceptible to limits in the blood supply, ISCHEMIA RAPIDLY DEVELOPS, since there is not enough colleterals to help save the tissue when there is an occlusion REGULATION OF CORONARY BLOOD FLOW: -can be regulated by physical, neural and metabolic controls --> METABOLIC REGULATION: During exercise, blood flow can increase to max 5x and this is due to the increased heart work and need for O2. -Metabolic factors that cause vasodilation: --> o2 decrease (hypoxia) --> increased adenosine (this is a reaction to the low O2 levels, since adenosine is released into the myocardial interstitium to relax the coronary resistance vessels. --> incr K+ conc --> incr CO2 -->incr lactate --> decreased pH --> AUTOREGULATION is very important to change the BP to maintain the blood flow within narrow ranges. Can regulate from 40-220mmHg BP values. --> PHYSICAL REGULATION: -Remember that the coronary arteries gets their blood supply from the aorta DURING EARLY DIASTOLE -->NEUROHUMORAL REG: -SY innervates the blood vessels directly through the alpha1 (constrict) and beta2 (dilate) receptors and indirectly by increasing HR and contractability which overall increases metabolism, dilation and flow. -PSY; the vagus DOES NOT INNERVATE THE BLOOD VESSELS, however, the endothelial cells express M3 ach receptors so if these are stimulated, then dilation through the NO/cGMP pathway CEREBRAL CIRCULATION: -Q: 750-850ml/min (80% goes to grey matter, 20% to white, since less synapse= smaller blood flow. Basal ganglia and choroid receive huge amount of blood flow because these areas have an extremely high metabolism due to the activity. -15% of CO -weight: 1400g, BUT the CSF makes it feel like it weighs 50g! -CSF: 150mL -Intracranial pressure remains between 5-14mmHg The cerebral circulation is controlled ALMOST ENTIRELY BY LOCAL METABOLITES and exhibits autoregulation and both active and reactive hypermia. The most important local vasodilator is CO2 (or incr acidity, H+), which is sensed by the central chemoreceptors. The increased pCO2 causes vasodilation of cerebral arteries which results in an increase in blood flow to assist in removal of excess CO2. When hyperventilating, there are low pCO2 levels and thus cerebral arteries vasoconstrict and this can lead to loss of consciousness. N.B!: MANY VASOACTIVE SUBSTANCES DOES NOT AFFECT CEREBRAL CIRCULATION AS THEY ARE TOO LARGE TO CROSS THE BBB! -The brain gets its blood supply from the 2 internal carotid arteries and the 2 vertebral arteries. --> What is special about the brain is that the vessels are located on the surface of it, so increasing intracranial pressure will be able to decrease the blood flow (centrically vessels are not affected by ICP -The brain has a very high rate of metabolism --> AND IT IS ALSO AN OBLIGATE AEROBIC ORGAN, which primarly metabolizes glucose with oxidative phosphorlytaion, but can adjust to using ketone bodies during starvation --> If there is a closure/occlusion of the arteries for 5 seconds then there is a loss of consciousness. After 3-5 min without O2, the damage is still reversible, but >5 min then IRREVERSIBLE DAMAGE --> which is a major reason for poor outcomes even after succesfull resuscitation from cardiac arrest INTRACRANIAL COMPARTMENTS: -Remember that the brain is inside the skull which is rigid and mostly closed off from the rest of the body. If you increase the pressure in one of the intracranial compartments, then the other intracranial compartments will also increase CEREBRAL BLOOD FLOW DEPENDS ON PERFUSION PRESSURE AND RESISTANCE: -Usually, perfusion pressure is just the arterial pressure- venous pressure, but in the brain, the intracranial pressure also has an effect on the constriction of the arteries and thus, THIS HAS TO BE TAKEN INTO ACCOUNT. PERFUSION P= ARTERIAL P -INTRACRANIAL P 90-10 = 80mmHg -->Meaning that if ICP increases, then perfusion pressure decreases, which leads to decreased flow. This is part of why increased ICP is so deadly! -metabolic control --> pCO2 should be 40-50mmHg (can range from 20-80mmhg -->pO2= 50-160mmHg -autoreg is able to successfully moderate blood flow between 50-140 mmHg arteriolar control BLOOD-BRAIN BARRIER: Created by: -endothelial cells -end-feet of astrocytes -basement membrane -pericytes BBB allows transport of small molecules (h20,O2, CO2) lipophilic molecules passive transport of glucose, active transport of aa's, NT precursor. (like for ex L-DORA) --> It prevents passage of larger molecules NE, E, proteins, charged molecules ABC TRANSPORTERS like Multi Drug Resistant/MDR proteins punp out xenobiotics from the brain--> blood Certain parts of brain doesn't have BB as they are sensing organs, to sense osmolarity, concentraion, volume, toxic substances etc. Such organs are called CIRCUMVENTRICULAR ORGANS and include: -area postrema, subfornical organ (sensory) -neurohypophysis, pineal body (secretory) CSF: -CSF produced daily: 550ml/day -rate of formation: 0,35mL/min --> 70% produced in the choroid plexus -->30% produced on the ependymal surface of ventricles Function of CSF: acts like a sink for different solutes and waste products -it substitutes lymph in the brain -buoyancy: weight of brain is 1400g, but feels like 50g cuz of CSF -Protects from trauma by preventing brain from hitting sides of skull during movement Composition of CSF: compared to blood it has low K+, since there is an active Na+/K+ pump that removes K+ from i.c and higher chloride + low proteins due to the BBB The choroid plexus has 3 layers: -capillaries with fenestrated endothelium without tight junctions -ECM -ependymal cells which is what provides the tight junctions Resorption of CSF: absorption of CSF is done passively by the arachnoid villi, goes to the sinuses (which have their own rigid layers so is not affected by ICF. The sinuses also have lower pressures than CSF) DRAW THE GRAPH!!1 --> remember that formation of CSF is at a steady state, always -> however, the absorption is affected by pressure in a linear manner. PATHOLOGY: --So, if there is an obstruction of the lateral ventricles, formation of CSF which is independent on pCSF is still being produced even when the pressure increases, thus the volume of the lateral ventricles expand, which puts abnormal pressures on the brain and this causes HYDROCEPHALUS (VANNHODE) --> another example can be when the absorption is damaged by having a problem with the arachnoid villi like in meningitis.

1.3. Signal transduction: receptors, G proteins, second messengers.

Cells release signalling molecules (mediators) which are received and responded by target cells SIGNAL TRANSDUCTION: -Stimulus --> transducers --> amplifyers --> messengers --> sensors --> effectors --> cellular response MECHANISMS OF INTRACELLULAR COMMUNICATION: -GAP JUNCTIONS: proteins in gap junctions called CONNEXINS open/close to allow transport of small ions, and can transmit electrical signals especially important in cardiac muscle -AUTOCRINE: cells secrete mediator detected by its own receptor -PARACRINE: 1st cell sends out local hormone to nearby cells -CONTACT-DEP-COMMUNICATION: membrane-bound signal molecule on cell A, with it's receptor being on cell B must be in contact for signal to occur -SYNAPTIC COMMUNCIATION: mediator is NT released in NMJ, synaptic cleft -ENDOCRINE: mediator hormone released into blood which goes to distant target cell which has a receptor to recognize mediator RECEPTORS: -They are bifunctional as they both recognize the ligand as well as produce a biological response in the target cell -They have a high affinity and reversible binding to their mediators -Rec-ligand binding can be saturated -rec-ligand binding can be specific (-kd= lignad conc at 50% max binding and tells us about the receptors affinity. -- full agonist = will have 100% efficacy so it produces the response --neutral antagonist = 0% efficacy but occupies the ligand site and blocks the receptor in this way --inv receptor = binds to the receptor and produces an opposite effect than the desired one) LOTS OF GRAPHS FOR THIS ONE We have both intracellular (signalling molecule must be hydrophobic/lipid soluble) receptors and plasma membrane receptors PLASMA MEMBRANE RECEPTORS: -G-protein coupled receptors: -->The receptor have 7TM domains -->heterotrimeric structure, where the abd + GDP is inactive, but when the alpha binds GTP and dissociates from the bd = ACTIVE! Gs, Gi, Gq, G12/13 which reg GEF's and activates rho --> smooth muscle contraction -Ion channels: --> the receptor binds the ligand then allows for ions to pass through --> uses paracrine signalling --> works more quickly than GcPR --> examples include nicotinic receptors and muscarinic receptors -Receptors with enzyme activity: --> tyrosine kinase receptor which leads to DNA transcription and cell growth. They dimerize and autophosphorlyates. SH2 recognizes activation --> GRB2 --> SOS --> ras-GEF --> MAPK cascade --> nuclear transcription reg --> guanylyl cyclase receptor --> GTP --> cGMP --> vasodil effect --> ser/thre kinases -Enz activity linked receptors: the receptor itself have no intrinsic tyr k activity, but their signal pathway JAK does!!! (Janus-kinase (JAK) --> STAT --> reg gene expr --> ex: cytokines, Growth hormone, prolactin 2 TYPES OF INTRACELLULAR SIGNALLING MOLECULES CAN ACT AS MOLECULAR SWITCHES: -ATP: phosphorlytes signalling molecules tp activate them -GTP: binds to G-coupled proteins to activate them. This is done by the GEF which activates G-coupled proteins in this way. They are inhibited by GAP, which stimulates the intrinsic GTPase activity to cleave GTP--> GDP, thus inactivating the G-coupled protein

7.6. Calcium metabolism. The physiology of bone and growth

FORMS FOUND IN BLOOD: There is 10 000 x more calcium outside the cell than outside: Ca2+ i.c : 100nM Ca2+ e.c: 1-1,3mM free and 2,2- 2,6mM total -45% of calcium is found in it's free, ionized form -45% are bound to proteins such as albumin -10% are in complexes with anions such as citrate, phosphate and sulphate. The forms of calcium can be altered if there is an increase in blood proteins for example, or if the anion conc of pH increases, then more of ca2+ will be bound, so there will be less, free, active ca2+ in the blood. --> In acidosis: we have an increased level of H+ in the blood, which will bind to albumin and replace ca2+, thus increasing the free calcium levels --> in alkalosis, it is the opposite, and the free calcium levels decrease -->CALCIUM REGULATION CONSISTS OF THE REGULATION OF THE FREE, IONIC STATE OF CALCIUM THROUGH ABSOPRTION, REAB AND EXCRETION PARATHYROID HORMONE: is synthetized by chief cells in the 4 parathyroid glands located behind the thyroid gland and their role is to INCREASE THE FREE CALCIUM! -When PTH secretion increases, so does the free calcium levels, however, there is always some basal amount of PTH secreted (graph) PTH secretion is regulated by the calcium-sensing receptors (CaSR) present in the chief cells in the parathyroid, but these receptors are also present in the proximal tubule, osteoblast, osteclasts and enterocytes. A mutation in the CaSR causes familial hypercalcemic hypocalciuria. There are 2 CaSR receptors: -->Gq-coupled with a low affinity for ca2+, thus it detects high ca2+ values. Since it is Gq-coupled it will cause an incr i.c calcium signal which INHIBITS EXOCYTOSIS OF PTH IN CHIEF CELLS or: -->Gi-coupled, in which cAMP levels are decreased and this inhibits it's gene expression since it inhibits the cAMP responsive element-dependent stimulation of PTH expression THE REGULATION OF PTH (must draw): -Increased phosphate will increase PTH expression (because it binds calcium and causes a decrease in fee ca2+ which increases PTH secretion) -Vit D decreases it's expression by INCREASING CaSR EXPRESSION AND BY DIRECT PTH GENE INHIBITION!!!! ACTIONS OF PTH: --> In summary, the actions of PTH causes ca2+ reabsorption in the kidney and ca2+ mobilization from bones to increase the net plasma values. Also, since phosphate binds calcium, PTH causes decreased plasma levels of phosphate by decreasing it'a reabsorption in the kidney. The actions of PTH are carried through by it's two receptors: -PTH1R: which is the most important one and has both Gq and Gi-coupled functions -PTH1R IN THE PROX TUBULE: -PTH increases the activity of 1-alpha-hydroxylase which helps to synth vit D which increases ca2+ reab -PTH inhibits the pi reabsorption by inhibiting the Na+/Pi cotransporter IN THE DIST CONVOLUTED TUBULE: -PTH activates ENac channels to transport Ca2+ from the apical membrane to inside the cell, and then it increases the gene expression of NCX1 (ca2+ out and 3Na+ in) and PMCA (calcium channel out) IN BONES: -Initially, PTH receptors on osteblasts will cause bone formation, but long term, the osteblasts will produce RANK ligand to stimulate the osteclasts increasing bone resoprtion and increasing calcium levels and pi levels. VITAMIN D/calcitriol SYNTHESIS AND TRANSPORT: Draw the synthesis. Involves several organs; skin --> liver --> kidney. -The active form of vit D is then transported in the blood via the Vit-D binding protein since it is hydrophobic and when it reaches its target, it will bind to the i.c vit D receptor --> forming a heterodimer with the RXR to modify gene expression. THE ACTIONS OF VIT D INCLUDES: -incr ca2+ and pi absorption in the GI -increased ca2+ and pi abs in kidney -increased bone resorption and mobilization of ca2+ and pi maintaining the immune system --> in long term vitamin D deficiency, the disease Rickets or hypophosshpahtemia occurs which is a deformity of the long bones. It can result in cardiac and respiratory issues due to deformeties in the the thoracic cage. Used to be a problem with people who worked in dark factories since we need UV light to hit our skin for the first reaction to produce it! CALCITONIN: -WANTS TO DECREASE CALCIUM LEVELS -it is a peptide hormone secreted by the C cells in parafollicular cells of the thyroid in response to too high ca2+ levels. -It does so by INHIBITING osteclasts (thus inhib bone resoprtion and ca2+ mobilization) --> it will be secreted if calcium levels are ABOVE 1,3mM (exact opposite of PTH) HYPOCALCEMIA: -significant decreased free ionized ca2+ and can be caused by a lack of PTH, decreased vit D, alkalosis --> symptoms: -nerves become much more easily depolarizable as the increased ca2+ moves the Em to a much more positive level, causing spaasm, tingling, burning HYPERCALCEMIA: -Incr free calcium -Rarely caused by an increase in PTH, but rather an increase in PTH-RELATED PEPTIDE which can also use the PTH1R causing the same actions as PTH -symptoms include formation of calcium phosphate stones in various tissues TYPES OF BONES: -DENSE/COMPACT BONE: include 80% of long bones and have a functional unit called the osteon -TRABECULAR BONE/SPONGY BONE: includes 20% of all bones. It has a high surface area so it is important in bone formation and resorption of bone and is located in: -- vertebral body --neck of long bones --w/in the bone cavity FORMATION OF BONES --> 2 phases 1) OSTEOID FORMATION: osteoid is the protein matrix of the bone and takes 10-14 days to produce. The osteoid is important as it gives structure and elasticity to the bone, but also because it is the site of nucleation and precipitation of hydroxyapetite. 2)MINERALIZATION: takes longer -It involves the activity of alkaline phosphatase. Pi is released from hydroxyapatite which will precipitate and trap osteblasts making them inactive --> ostecytes RESORPTION OF BONE: This process is dependant on osteoclasts (derived from hematopoetic cell lineage) and the osteclasts gets activated by M-CSF, RANK-ligand, IL-6. 1) osteoclasts attach to the bone surface polarizing the cell and creating a RESORPTION CAVITY 2)osteoclasts have V-TYPE PROTON PUMPS to secrete H+ into this cavity + secrete TRAP (acid phosphatase enzyme) 3)this causes the release of pi and calcium, degradation of protein to release stored proteins and catabolic enzymes which have a POSITIVE FEEDBACK ON THE OSTECLASTS to continue downgrading the bones! REGULATION OF BONE FORMATION: -->PTH and VIT D: acts on osteoblasts only, inducing the secretion of RANK ligand and OPG(decrease) which have opposite effects: -Rank ligand is produced from the osteoblasts and interacts with the receptor on the osteoclasts to upregulate their activity (since osteoclasts does NOT have PTH or vit D receptors) -->calcitonin directly acts on osteoclasts to inhibit them. OPG binds to the RANK ligand, preventing it to bind to the receptor. (USED TO TREAT PAGET DISEASE WHICH IS OVERACTIVITY OF OSTEOCLASTS) --> cortisol: acts on osteoblasts increasing the Rank-L --> estrogens: decrease rank-l --> decr activity of osteoclasts ( so when estrogen levels decrease, osteoporosis can occur since the osteoclasts are inhibited by estrogen anymore) -->tumors can secrete rank-L to act on the receptors on osteoclasts and increase resoprtion of bones. This is a way in which tumours can cuase hypercalcemia!

2.5. Organization of the circulatory system. Hemodynamic functions of different vessel segments in the systemic circulation. Biophysical basis of blood flow. Relationship of pressure and flow.

FUNCTIONS OF THE CIRCULATORY SYSTEM: -Nutrient and waste transport -Thermoregulation -hormone transport -immune function (ATTACHED) is a schematic drawing of the organization of the circulatory system. It shows how the cardiac output ejects out oxygenated blood of the heart on the left side into the systemic circulation. The blood is then distributed in a PARALELL arrangement to various organ systems! The blood is then transported back to the heart through the vena cava system and ALL OF THE BLOOD GOES THROUGH THE LUNGS TO BECOME OXYGENATED. Repeat! HEMODYNAMICS: are the factors that govern the flow of blood through the cardiovascular system; which includes parameters such as flow, pressure, resistance and capacitance. CHARACTERISTICS FOR THE DIFFERENT VESSELS: (There is a table I should draw I believe) -AORTA: 25mm diameter, 2mm wall thickness. Lots of elasticity -Arterioles: 20mikrom diameter, 2mikrometer wall thickness with LOTS of smooth muscle. TOTAL VESSELS 10^6. Cross sectional area: 40cm^2 -capillaries: 5-7mikro m diameter, with a 0,5mikrom thickness. 10^10 in number and the LARGEST CROSS SECTIONAL AREA of all the vessels 2500cm^2 -Veins has smaller diameter and thickness of walls and mostly store large portions of the CO = 64%! ! Some IMPORTANT NOTES when talking about hemodynamics: ! --> the smooth muscles in arterioles are extensively innervated with A LOT of alpha1 receptors (to cause contraction and increase the pressure), but also some beta2 receptors in vita organs to increase their blood flow and supply if needed. --> HOWEVER, it is important to remember that alha1 receptors doesn't bind catecholamines very well unless their concentration is REALLY HIGH (which is why the arterioles only vasoconstrict when levels are very high like in SY stimulation, NOT when the adrenal medulla is producing the epi and NE!!!! -->not all capillaries are perfused with blood all the time, there is a selective perfusion of the capillaries depending on the needs of the tissue. This is determined by the PRE-CAPILLARY SPHINCTERS (remember that pre-cap sphincter DOESN'T GET INNERVATED BY SY, only local control) --> thus, the diameter of the capillaries are controlled by active and reactive regulation! -->venules and veins are said to be compliant, because they are distensible/expandable to hold a much higher V of blood than the arteries. They contain the largest % of blood in the entire cardiovascular system. Alpha1 receptors cause vasoconstriction, thus reducing the V of blood that they store. (64% storage capacity) VARIOUS EQUATIONS GOVERNING BLOOD FLOW: -FLOW=VELOCITY * CROSS SECTIONAL AREA 1)Velocity of flow is inversely propertional to the cross-sectional area. This means that the vessels with the largest cross sectional area (in the body this is the capillaries with 2500cm^2), so the velocity of flow here is the largest. --> It can be explained by the CONTINUITY EQUATION = A1*v1 = A2v2 --> v2=(A1*v1)/A2 (showing the inverse relationship of velocity and area!!!! (There's two graphs to explain this. First is A plotted against vessels of the circ system --> shows a normal bell curve. The other shows velocity vs vessels of systemic circ which is an inverse bell curve. Both graphs show that the capillaries has the highest cross-sectional area, and thus the lowest velocity!!!) 2)An increase in the speed of a fluid occurs simultaneously with a decrease in pressure. When talking about blood vessels this is a decrease in side pressure (Ps). EXPLAINED BY BERNOULLI'S LAW: Ps= Pt - 1/2d(ensity)*v^2 This is physiologically important in atherosclerosis when a plaque builds in the arteries, increasing the side pressure by decreasing the volume. Thus the flow increases in the middle, but not at the sides, so the the branching arteries of for example the abdominal aorta will experience decreased flow to the organs (for ex kidney's). 3) Blood flow is determined mostly by two factors: the pressure difference between two ends of the vessel and the resistance of the vessel to blood flow. Both of which are expressed in the HAGEN-POISEUILLE LAW: Q= (pi*r^4* pressure difference)/ 8* l * viscosity) Can be rearranged to the resistance equation: R= (8*l * viscosity) /pi * r^4 Which: both shows how resistance is inversely proportional to vessel radius to the 4th power which is an important tool of physiological vasodilators and vasoconstrictors. It also shows how flow is directly prop to the pressure difference (it's driving force). 4) SERIAL/PARALELL RESISTANCE Series is used to describe the resistance of blood flow through vessels, because the total flow through each system is the same (cerebral artery-> capillaries -> veins Q is the same). However, arteriolar resistance contributes the most to the total resistance. --> Rt= Rarteries + Rarterioles + Rcapillaries + Rveins etc Parallel is used to describe the R of the flow of blood through different organ systems --> 1/Rt = 1/RGI + 1/Rcoronary etc This aids us in finding the TOTAL PERIPHERAL RESISTANCE that must be overcome to push blood through the circulatory system and create flow. TPR is an important det of BP and highly modifiable via vessel radius --> Parterial = TPR * CO N.B!: Since circulations of various organs are connected in parallel, excluding any part of the circulation from the total DECREASES THE RECIPROCAL OF TPR and thus INCREASES THE TOTAL PERIPHERAL PRESSURE! 5) Determining if the flow is laminar or turbulent is done via determining the Reynold's number. Determines the tendency of flow to be laminar or turbulent. <2000 prob laminar >3000 prob turbulent 2000<Nr<3000 - varies N.B!: High diameter, velocity or low viscosity (means decreased hematocrit in blood) can cause turbulence Examples: anemia (decreases hematocrit) causes increased turbulent flow Blood clots will increase turbulent flow by narrowing lumen of vessels 6) The wall tension is determined using Laplace's law which is important regarding rupture of vessels T = (P*r)/(2* x (thickness wall)) --> Physiological examples are aneurysms which cause an increase radius and decreased wall thickness leading to greatly increased wall tension and eventual rupture. 7) Distensability and compliance of vessels (graphs, complience is the slope of a volume/ pressure graph) Distensibility: ability if vessel to distend under pressure or the amount of volume it can hold. Dveins is 8 x greater than Da D = diff V /(V0 * diff P) UNIT: ml/mmHg Compliance (elasticity --> returning to it's original shape) in the veins are 25x greater than c in arteries. The compliance of the pulmonary system is also greater than the systemic. If compliance of the veins decreases then blood is pushing from the veins to the arteries. With aging, compliance goes down as vessel wall gets stiffer-> increases BP 8) Shear of the vessels: near the vessel walls as there is a layer of unmoving blood with v = 0 and next to it blood is moving. The velocity difference is the shear. Shear is highest near the wall of the vessels and lowest in the center (as here the blood is moving at the same velocity). RELATIONSHIP BETWEEN PRESSURE AND FLOW (PRESSURE PROFILES OF THE VESSELS) : N.B!: draw the pressure profile of the vessels to describe this! -The pressure starts of high 120/80 (sys/dia), and towards the end it decreases to about 4mmHg in the veins. This is because of the energy consumed by overcoming the increasing resistance. -In the aorta, the pressure is high due to elasticity of the aorta, thus it can store quite large volumes of blood (up to half of the SV), so the resistance isn't huge here. The pressures are also pulsatile in the aorta and larger + smaller arteries, but is contineous everywhere else due to the elasticity of the aorta, which can store blood during diastole which is called the WINDKESSEL EFFECT! -In the arteries, there is a huge pressure drop, as can be seen on the graph, and it is also why arterioles are called RESISTANCE VESSELS, because p and R is inv related. -The pressure decreases even further in the capillaries due to the resistance and also to be able to have time for filtration of fluids and diffusion of gases. -In the veins, the pressure decreases further until the blood gets to the right atrium which has a pressure of 2-0mmHg!

2.6. Measurement of arterial blood pressure. Factors influencing arterial blood pressure.

Mean arterial pressure (Pa) is the driving force for blood flow and it must be maintained at a high, constant level of 93mmHg (around 100mmHg). Because of the parallel arrangement of the circulatory system, the pressure of the major artery serving each organ is equal to Pa. (MAKE GRAPH) --> We have systolic 120 and diastolic pressures 80, in which the pulse pressure is psys-pdia = 40mmHg usually. To calculate the mean arterial pressure, which is NOT an average considering how Psys is SHORTER than Pdia, we need to divide it into 3 equal parts. Therefore: Pmean = (Psys + (2* Pdia))/ 3 = 93mmHg Blood pressure is also related to CO and TPR --> MABP = CO* TPR, so if either one of the parameters increase, then BP increases too. HOW TO MEASURE BLOOD PRESSURE: -Directly through the "bloody method", iNVASIVE: --> Invasive arterial pressure measurement with intravascular cannulae involves direct measurement of arterial pressure by placing a cannula needle in an artery (usually radial, femoral, dorsalis pedis or brachial). The cannula is inserted either via palpation or with the use of ultrasound guidance The cannula must be connected to a sterile, fluid-filled system, which is connected to an electronic pressure transducer. The advantage of this system is that pressure is constantly monitored beat-by-beat. This invasive technique is regularly employed in human and veterinary intensive care medicine, anesthesiology, and for research purposes. INDIRECT: via: By the sphygomanometer, which is done by a stethoscope + sphygomanometer + cuff. FACTORS INFLUENCING IT: Physical parameters: blood volume and compliance Physiological: -cardiac output (results in overall pressure increase but a larger psys than pdias so pulse pressure also changes) -TRP changes both psys and pdias equally, so no change in ppulse -compliance (when we get older elasticity (returning to original shape) decreases and psys is increased while pdias decrease causing high ppulse increase -viscosity (increases TRP so effects are same as with TRP) -gravitation (pressures, when standing are higher in lower limbs, however both arteries and veins are affected so pressure diff between them is unchanged) -gender (estrogen is a vasodilator and thus decreases TPR) -climate (warmth -> vasodil -> decrease TPR) -sleep -emotion -PE

2.10. Neurohormonal and reflex control of circulation: baroreceptor and chemoreceptor reflexes. Cardiovascular centers.

NEUROHORMONAL CONTROL OF CIRCULATION: SYSTEMIC MEAN ARTERIAL BLOOD PRESSURE (MAP): Is the principal variable of the cardiovascular system which is controlled by reflex regulation. -Normally, it should be 93mmHg --> If there is NO sy nerve activity, then MAP drops to 50mmHg --> If there is a lot of SY nerve activity then it increases to 150mmHg SY nerves innervates: -Resistance vessels such as arteries, arterioles, metaarterioles that all contribute to the total peripheral resistance -Capacictance vessels such as veins and venules which stores a large portion of the CO blood. Decreased SY activity decreases their compliance -Heart, SA, AV and myocytes REFLEX CONTROL OF CIRCULATION: There is a negative feedback regulation that promotes stability/equilibirum by detecting small changes in the blood pressure, and then activates mechanisms that restores blood pressure back to it's set point. A decrease in BP is sensed by the baroreceptors, which activate mechanisms to increase it. As BP is no longer off, there is no signal sensed by the baroreceptors and thus no signal to restore it back either. CARDIOVASCULAR CENTERS: The cardiovascular centers are loctaed in the reticular formations of the medulla and in the lower third of the pons. These centers function in coordinated fashion, receiving infor about BP from the baroreceptors and then directing changes in output of the SY and PSY nervous system to correct these changes. Afferent info about BP is carried up the the medulla via the glossopharyngeal and vagus nerves. The cardiovascular centers are as follows: -The VASOCONSTRICTOR CENTER (C1): send out efferent fibers via the sympathetic nervous system, which produce VASOCONSTRICTION OF ARTERIOLES AND VENULES -The CARDIAC ACCELERATOR CENTER: efferent fibers are also here carried by the SY nervous system to the heart where it increases the firing rate of the SA node, increase the contractability and incr the conduction velocity. -the CARDIAC DECELERATOR CENTER: efferent fibers are carried by the PSY system to the heart where it travels down the vagus nerve and synapse on the SA node to decrease heart rate BARORECEPTORS: are mechanoreceptors which sense stretch resulting in a change in their membrane potential and thus incr/decreased AP fired from the afferent nerves that travel from the baroreceptor to the brainstem! HIGH PRESSURE BARORECEPTORS: FAST-ACTING BARORECEPTORS: (In hypertension, they are desensitixed and do not perform a reflex arc) -Located in the: -->carotid sinus: contain elastic fibers, so when they distend due to increased pressure it activates the baroreceptors. They are sensitive to BP ranging from 50-200mmHg, so it can detect both high and low BP's -->the aortic arch: 100-200mmHg detection range The reflex arc goes as follows: The baroreceptors send their information via their afferent fibers, which goes into the cardiovascular centers in the medulla, which decypher the information and sends down efferent fibers, on either the SY part or PSY part of the nervous system to respond to the changes. -->PSY: M2 receptors on SA and AV node will lowering the frequency and conductivity of the heart --> SY: -beta1 receptors will increase the chronotropy, dromotropy and ionotropy of the heart -alpha 1 receptors on the arterioles will cause vasoconstriction --> incr TPR --> incr venous return --> increasing CO (RESPONSE TO LOW BP) SLOW-ACTING BARORECEPTORS: Consists of the renin-angiotensin system (RAS) -The RAS system detects drops of pressure in the renal artery via mechanoreceptors in the AFFERENT arteriole of the kidney. This causes a release of renin, which converts angiotensinogen --> AT1 (in the lungs), and then ACE converts AT1--> AT2 in the kidney Angiotensin II causes: -an increase in blood volume as it upregulates aldosterone + Na+/H+ exchanger --> Na+ reabsorption --> increased blood volume -It also acts on the hypothalamus to increase thirst and thus increasing blood volume -ATII also acts DIRECTLY ON THE ARTERIOLES, actvating Gq-coupled receptors which cause vasoconstriction to increase BP! LOW PRESSURE BARORECEPTORS: These are located in the venous system, and they sense an increase in blood volume or "fullness" of the vascular system. Located: -SVC and IVC -Sinus venarum cavarum -An increase in BP--> increase right atrial pressure --> stimulates the receptors --> incr HR + hormone regulation to increase excretion of Na+ in effort to decrease the blood volume and thus BP Done by: -incr secretion of ANP, which causes vasodil of arterioles. In the kidney it increases Na+ and h20 excretion -renal vasodil (inhibition of SY vasoconstrictor of renal arterioles) leading to increased GFR thus incr Na+ and h20 excretion -decreased secretion of ADH as ADH increases water uptake and blood volume which we do not want -THEY INCREASE THE HR --> CALLED THE BAINBRIDGE REFLEX: occurs when mechanoreceptors embedded within the right atrial myocardium respond to an increase in pressure and stretch (distention of the right atrium). stimulates the vasomotor centers of the medulla and results in increased sympathetic input and heart rate. reflex can also influence a decrease in heart rate when heart is beating too fast. Also leads to increased GFR of Na and water THE INTEGRITY OF THE BARORECEPTORS CAN BE TESTED BY THE VALSALVA MANEUVER: forceful exhalation against a closed glottis, which increases intrathoracic pressure and thus decreases venous blood return to the heart which stimulates baroreceptors to increase heart rate to Get more blood back to the heart. CHEMORECEPTORS: regulate respiration, stimulate respiratory centers and increase the ventilatory drive, but also changes blood pressure through changes in SY and PSY output. Operates mostly against the dramatically low blood pressures but via detecting low O2, high CO2 and or metabolites that build up during poor perfusion. CENTRAL CHEMORECEPTORS: -Are most sensitive to the partial pressures of CO2, and pH. -If there is a decreased rate of cerebral blood flow, there is an immeiate increase of pCO2 and decreased pH due to the H+ formation which increases SY outflow --> causing an intense arteriolar vasoconstriction throughout the body to incr TPR to REDIRECT THE BLOOD FLOW TO THE BRAIN THE CUSHING'S REFLEX ILLUSTRATES HOW THE CENTRAL CHEMORECEPTORS WORK: The combination of a slowing pulse, due to PSY activation, rising blood pressure due to activation of SY to overcome the increased intracranial pressure, and erratic respiratory patterns; a grave sign for patients with head trauma or cerebrovascular accident. --> basically, when people hit their heads and the intracranial pressure is increased, firstly the central chemoreceptors are activated to increase blood pressure and redirect the blood flow to the brain, but the arterial baroreceptors detect this high BP and thus slows the HR down to compensate PERIPHERAL CHEMORECEPTORS: Located: -Near the bifurcation of the common carotid arteries -aortic arch -Sense changes to pO2, but also increase pCO2 and pH changes. --> When the pO2 decreases, there is an increased firing rate of sensory nerves from the carotid bifurcation and aortic arch to activate the SY which will cause vasoconstriction of the arteries in the skeletal muscle, renal and splanchnic vascular systems (to redirect to brain), and vasodil in cerebral circ.

3.3. Oxygen and carbon dioxide transport. Hemoglobin. Types of hypoxia.

OXYGEN TRANSPORT: -Body needs 250ml of O2 per min -Only 2% of O2 is free, so we need the bound portion (bound to Hbg) -O2 is usually bound to hbg (2alpha2beta), 4 molecules of O2 binds, and which each molecule that binds, the affinity for O2 increases. (fetal has 2alpha2gamma) -Binding of O2 to Hbg is NOT linear, but sigmoidal -Hbg releases O2 when there are high CO2 levels, decr temp, inhibitor (2,3BPG), low pH, incr lactate etc CO2 TRANSPORT: -Free CO2 accounts for 5% of the total Co2 content in blood -It can also be bound to Hbg and proteins such as albumin -It can also be chemically modified into bicarb= 90% of the co2 content in blood -CO2 binds in an allosteric site of Hbg to inhibit o2 binding CHLORIDE SHIFT: -CO2 is produced in high concentrations in the tissue due to metabolism -The co2 then leaves the cells and goes into RBC via simple diffusion -RBC has carbonic anhydrase which converts it to bicarb + H+ -The H+ stays in the RBC where it is buffered by deox hbg, and bicarb is transported out of the cell via the chloride/bicarb transporter -This is the chloride shift and it is done to maintain a change balance --> ALL OF THESE REACTIONS HAPPENS IN REVERSE IN THE LUNGS TO REGEN CO2 AND H20 TO BE EXPIRED BY THE LUNGS HALDANE EFFECT: -is a property of Hbg -oxygenation of blood in the lungs displaces co2 from hb which increases the removal of co2! HYPOXIA: (KNOW THE TABLE!!) -4 types of hypoxia: -->HYPOXIC HYPOXIA: lack of o2 due to high altitude or just low o2 levels. Every value decreases and thus there is no change in the AVDO2 value -->anemic hypoxia: lack of o2 due to low Hbg levels. There is no change to paCO2, and no change to the saturation of o2 (even though there is less hbg) -->stagnant (circ) hypoxia: low o2 due to bad blood supply in the tissues (no change in the total o2 content, but just low o2 levels in the venous part, however the AVDO2 is higher as blood has more time in the capillaries so more o2 is extracted) -->histotoxic hypoxia: low o2 because the tissue cannot take up or utilize oxygen. AVDO2 is lower since the tissues cannot take up the o2

4.4. Control of body fluid volumes and extracellular fluid osmolality

REMEMBER: 60 - 40- 20! 60% h20, 40% ECF and 20% ICF! -ECF and ICF should be kept at 290mOsm OSMORECEPTORS: in the hypothalamus detect changes in osmotic status when they swell or shrink depending on the hyper/hypoosmtic nature of their surrounding ECF. --> these receptors then stimulate/inhibit thirst receptors + ADH production to incr/decr water intake + conservation in relation to the detected osmolarity -Because drinking water won't immediately change the osmotic environment around the hypothalamic osmoreceptors, we have GI OSMORECEPTORS IN THE MOUTH, STOMACH, INTESTINE + LIVER which can signal the hypothalamus to "turn off" thirst upon detection of ingested fluid. This prevents overcorrection Remember that RAS also stimulates thirst centers + adh prod via renin. BLOOD VOLUME IS DETECTED BY SEVERAL RECEPTORS: -Stretch: --low p: atria, large veins --high p : carotid sinus, aortic arch, juxtaglomerular apparatus -chemoreceptors for Nacl in macula dense of the JGA indir detects the blood volume via Na+ V BODYFLUID CONDITIONS: -Hypoosmotic hypervolemia (fluid V goes up, so fluid osmolarity goes down -Hyperosmotic hypovolemia - opposite WHEN WE DRINK, IT IS CORRECTED BY: -Hypothalamic osmoreceptors --> swell --> ADH secretion goes down --> kidney h20 reab decr --> urination increases -Automatic renal response in which the plasma oncotic p decreases, increasing GFR, thus h20 reab decr --> slightly increased BP in increases filtration out of the vasa recta to decrease the osmotic force driving collecting duct h20 reab WHEN WE SWEAT, IT IS CORRECTED BY: -Hypothalamic osmoreceptors --> shrink --> ADH secretion increases and the oppostie of above occurs -stretch/volume receptors also play a role in stim ADH secretion at low volumes WHEN WE EAT SALT, A SPECIAL CONDITION CALLED HYPEROSMOTIC ISOVOLEMIA OCCURS, since: with salt intake, osmolarity increases with a constant V, resulting in a redistribution of fluid volume ratios, favouring high ECF volume --> correction occurs by incr thirs/drinking + ADH secreton which results in isoosmotic hypervolemia (because now we have higher overall V to balance out the ingested salt, thus ANP will be released to incr excretion of NA+ from the urine

1.5. The development of the resting membrane potential. The development and properties of the electrotonic potential.

Resting membrane potential (Em): is the potential difference between the intra- and extracellular space when a cell is at rest (when the cell isn't performing a specific function or firing an AP). Important parameters for this topic: Em for skeletal muscle is -90mV Em for neuron is -70mV Diffusion potential: is any potential difference generated across a membrane when an ion diffuses down its conc gradient its concentration gradient. Its magnitude depends on the size of the conc gradient and it's sign dep on the charge of the diffusing ion. Can be generated ONLY when the membrane is permeable to that ion. The conc gradient is the driving force Equilibrium potential is an extension of the concept of diffusion potential. Eq of a particular ion is the transmembrane potential difference (U) at which the influences of concentration gradient and electrical gradient on ion's movement exactly balance each other out. In other words, when there is NO NET MOVEMENT of the ion across the membrane. The equilibrium potential is created, as permeant ions diffuse across the membrane down their concentration gradients, which have been established by primary and secondary transport mechanisms. As each ion wants to get to its equilibrium potential. At rest, the membrane is most permeable to K+ and Cl- (so Em is closest to their equilibrium potentials, usually between -60 to -80 mV). Eq of K+= -90mV and Cl- = -70mV Na+/K+-ATPase contributes to Em in two ways: 1. Electrogenic: results in net loss of 1+ charge (3Na+ out and 2K+ in) 2. Indirect: establish K+ gradient (wants to go ICF to ECF bc K+ concentration gradient lower there, however it won't bc ICF is more negative making K+ stick around) We can calculate the Eq for one ion using the NERNST EQ. If we want to take into account the permeability of the membrane for the different ions then we use the GHK equation (Goldman- Hodgekin- Katz)

8.7. Motor functions of the spinal cord. Cord reflexes. Spinal cord transection and spinal shock

SPINAL CHORD AND MOTOR FUNCTION: -Motor unit is defined as A SINGLE MOTOR NEURON AND THE MUSCLE FIBERS THAT IT INNERVATES. -Motor neurons can innervate just a few fibers to many thousand depending on how precise the innervation needs to be (ocular muscle is for ex highly innervated for precise movement) ALPHA MOTOR NEURONS: -Can be either alpha or gamma --> an alpha motor neuron innervates EXTRAFUSAL muscle fibers or regular skeletal muscle that is used to generate force -->A gamme motor neuron innervates INTRAFUSAL MUSCLE FIBERS = muscle spindles. These are very small and run paralell to the extrafusal fibers and are common in muscles for fine, precise movements THE MUSCLE SPINDLE: -The m spindle is innervated by both an afferent and an efferent n fib and can be different in shape. -Their basic FUNCTION is to correct for any change in muscle fiber length after a contraction or stretch via stimulation of alpha motor neurons to oppose the change. -The two shapes may be: --> NUCLEAR CHAIN, where the nuclei are arranged in a row. They get sensory information from Group Ia (fast) and group IIa (slow) nerve fibers. Their efferent fibers are received by STATIC gamma motor neurons which have a large surface area end-plate --> NUCLEAR BAG, where the nuclei are all centrically located is the most common shape of the muscle spindle. The afferent innervation of tje nuclear bag is only from group Ia fibers, and the efferent is received by DYNAMIC gamma motor neurons which have a small plate ending SPINAL CHORD REFLEXES: -There are several spinal chord reflex arces which are purely controlled at the level of the spinal cord with an afferent sensory fiber, efferent motor fiber and in some cases interneurons in the ventral horn of the cord. --> STRETCH REFLEX: -!Monosynaptic! -Initiated by strecthing of the muscle and results in effector muscle being contracted -Sensory/afferent neuron: Type Ia fiber -Interneurons: NO, it is monosynaptic -Effector neuron: alpha motor neuron -Effector organ: motor end plate in the same muscle as afferent fibers are coming from -EX: PATELLAR REFLEX! --> GOLGI TENDON REFLEX: -Uses 1 interneuron, is triggered by muscle contraction and results in muscle relaxation to prevent overstretching! -Afferent neuron: Ia nerve fiber -Interneuron: yes, the Ia nerve fiber will synapse on a Ib nerve fiber which inhibits the alpha motor neuron of the contracted muscle --> this causes muscle to relax -Effector organ: muscle -->FLEXOR-WITHDRAWEL REFLEX: -Sensory receptor: Sensory receptor free nerve endings in the skin - nocireceptors Sensory fiber: Sensory neuron neurons with fine myelinated (Aδ) or unmyelinated (C) branches (pseudounipolar neurons) -Interneurons: Interneurons at least one or several in the dorsal horn and intermediate zone -Effector neuron: Aα motoneuron -Effector organ: motor end plate in striated muscle SPINAL CHORD TRANSECTION AND SPINAL CHORD SHOCK: -Refers to the partial of complete tear of the spinal cord which leads to the LOSS OF ALL NEUROLOGICAL ACTIVITY below the level of injury (spinal shock). This is due to the discontinuation of the tracts and thus, INABILITY to cause depolarization of the alpha motor neurons. Effects: --> The blood pressure can decrease to as low levels as 40mmHg due to the loss of SY regulation --> ANS loss, lack of thermoregulation -->flaccid paralysis - loss of skeletal muscle function N.B! Eventually some functions can recover and this is due to the occurance of neuronal hypersensitivity. The hypersensitivity is in part due to the increased dendritic size -Mass reflex --> in which spasm can occur below the level of the lesion due to stimulation -Fictive locomotion in which the spinal cord activates neurons to walk, but ofc these functions aren't carried to the effectors (muscles) as these are severed

1.9. Neuromuscular junction and physiology of the skeletal muscle.

STRUCTURE OF THE SKELETAL MUSCLE: MOTOR UNIT: 1 motor neuron + innervated muscle fibers. Each skeletal muscle fiber behaves as a single unit and consist of multinucleated cells (created from fusion of embryonic myoblasts) Myofibrils are surrounded by sarcoplasmic reticulum and invaginated by transverse tubules which are contineous with the sarcolemma membrane. The myofibrils are divided into repeating units called sarcomeres which are what creates the striation characteristic for sk and cardiac muscle. The sarcomere consists of thick and thin filaments. -Thick filaments contain myosin which has 1 pair of heavy chains and 2 pairs of light chains. Together, they form 2 heads which bond to actin and these heads contain ATPase activity. -Thin filaments consists of 3 proteins: --Actin: the long base that interacts with myosin for contraction --tropomyosin: covers the myosin head binding sites --troponin: a complex of 3 proteins: --> Troponin C: if i.c ca2+ levels are high, then ca2+ binds to troponin C --> Troponin T: attaches the troponin complex to tropomyosin --> Troponin I: inhibits the cross-bridge cycle by blocking the binding site of myosin DRAW THE SARCOMERE: -spans between two Z discs. -Each sarcomere has a full A (anisotropic) band and a half I (isotropic band) -The I band consists mostly of actin and titin (holds the thick filaments to the Z disc) -The A band consits of both myosin and actin and is the dark band. -The H band is encompassed into the A band and is a lighter band before the M band which is in the midline. DURING CONTRACTION: -A BANDS ARE THE SAME LENGTH -I BANDS BECOME SHORTER -H-BANDS SHORTER -THE WHOLE SARCOMERE ITSELF BECOMES SHORTER!!! TRANSVERSE TUBULE (continuation of the sarcolemma, responsible for carrying depol from muscle surface to the interior of the fiber): make contact with two longitudional terminal cisternae of the SR, which is where the release of Ca2+ from the SR occurs. There is an extra high density of SERCA here, because it is critical for reaccumulation of Ca2+ into the SR, causing muscle relaxation (these two terminal cisternae and the T tubule forms a TRIAD --> the gap between the T tubule and the terminal cisternae is 15nm) SARCOPLASMIC RETICULUM: is the site of storage and release of Ca2+ used for contraction (since skeletal muscle is HIGHLY and oNLY dependant on i.c ca2+ levels). THE CROSS-BRIDGE CYCLE: When no ATP is bound, myosin is tightly attached to actin in "rigor" position. If the muscle is severely lacking ATP, as in the case of recent death, this causes the stiff muscles in RIGOR MORTIS. ELECTROCHEMICAL COUPLING: 1 AP --> 1 twitch There is no contraction without motor neuron action potential (unless you artificially stimulate the muscle with electricity) -AP is explained in topic 1,6!!! -AP lasts 2ms, but the contraction lasts 180ms After an AP triggers a twitch, there should be enough time for the SR to be reabsorb the ca2+. If the muscle is stimulated repeatedly with insufficient time for the reacc of ca2+, then the cytosolic ca2+ conc remains high and the cycle continues which is called a TETANUS (MUST BE DRAWN) LENGTH-TENSION RELATIONSHIP = the forrce of the contraction depends on the length of the sarcomere -refers to the amount of tension that can be developed from various lengths of a muscle -There is an OPTIMAL LENGTH a muscle should be for the max amount of tension it can generate, but the muscle is weaker if it is longer or shorter. --if too short, the filaments are mushed together and can't function --if too far apart, they can't interact due to the distance -The voluntary action of the muscle creates ACTIVE TENSION, but PASSIVE TENSION is also created when the muscle is strecthed too long (due to the elasticity, like a rubber band) --THE ACTIVE AND PASSIVE TENSION GIVES U THE TOTAL TENSION ISOMETRIC (same length so holding a weight up or pushing against a wall) ISOTONIC (same force, so biceps curl where the length changes, but the weight of the dumbbell and therefore the F needed to lift it is the same) (DRAW) (For isometric (holding an object at the same length) contraction, contractile force increases as muscle length increases up to a certain point (l0). As the muscle is strecthed beyond this point, contractile force is decreased. ) FORCE-VELOCITY RELATIONSHIP: (THERE IS A GRAPH for this) Force=Afterload, which represents load the muscle works against -The F, not the length is fixed and therefore, it is called an ISOTONIC contraction. -The velocity of shortening reflects the speed of cross-bridge -Vmax will ofc be when the Force/afterload is 0. -As the afterload increases, the velocity will be decreased as the cross-bridge cycle can cycle less rapidly against the higher resistance. SKELETAL MUSCLE FIBER TYPES: GRAPH -Type I muscle fibers can be remember by the mneumonic: (they aerobic) Oxidative Network - blood, so they are red Endurance - they are slow, with low glycogen and high mitochondria -Type IIa and IIb fibers are anaerobic IIa: red, oxidative and resistant -IIb: white, glycolytic and fatiguable ( Type I and Type IIa have higher resistance to fatigue than Type IIb because in the case of Type IIb, the main pathway for ATP production is anaerobic glycosis which cannot be sustained for as long a period of time as aerobic cellular respiration (the main pathway for ATP production in Type I and Type IIa). MUSCLE FATIGUE: -Fatigue is NOT THE RESULT OF DEPLETION OF E STORES, but it occurs due to the depletion of: -glycogen -creatine phosphate -and due to the accumulation of lactic acid It is important to understand that fatigue occurs when ATP levels only decreases a bit as we do not want to go into rigor! During INTENSE WORKOUT, accumulation of inorganic phosphate + lactic acid accounts for muscle fatigue. The increased lactate levels causes the pH to drop to 6,2 and thus decreases the binding of Ca2+ to tropinin C. The high phosphate levels decreases the release of calcium from SR. OXYGEN DEBT: (Graphs) There is an increased o2 consumption after completing exercise (increasing the respiratory rate) to restore the ATP + creatine phosphate. O2 is also needed to metabolize the lactate generated by anaerobic glycolysis. NEUROMUSCULAR JUNCTION: -Also called the motor end plate, is a chemical synpase in which Ach (ALWAYS) is released by an alpha-motor neuron into a synaptic clect between the axon terminal and the skeletal muscle membrane, the sarcolemma. Steps: 1) An AP traveling down the axon of the alpha-motor neuron reaches the axon terminal, depolarizing it. 2)As a result of depol, voltage-dep Ca2+ channels open and Ca2+ flows into the cell 3)Increased ic ca2+ signals for exocytosis of the synaptic vesicles containing high levels of ach (150mM) -Ach is released to the synaptic cleft and bind to nicotinic receptors. These receptors change their confirmation, allowing Na+ influx and K+ efflux (Em goes from -90mV --> -50mV) THIS IS WHAT IS KNOWN AS THE END-PLATE POTENTIAL, no muscular contraction can occur without an EPP -Depol of the end plate spreads to adjacent parts of the muscle -Ach is then degraded by ACETYLCHOLINESTERASE into choline and acetate. Acetate diffuses away and chole re-enters the cell via Na+-choline symporter

2.3. The heart cycle. Changes in pressure and volume during the cardiac cycle. Heart sounds.

SYSTOLE: contraction of the ventricules = 0,3s DIASTOLE: relaxation of the ventricles. Atria contract at the end of diastole = 0,5s RULES/APPROX FOR THE CONSTRUCTION OF THE CARDIAC CYLE CURVES: 1) liquid is incomresseable 2)direction of flow is det by pressure gradient 3)opening/closing of valves is controlled by the direction of the flow --> passive process 4) no flow through closed valves EXPLAINING THE GRAPH: A) Atrial systole: P wave of ECG --> depol of atria, atria contract (S4, not heard) --> av/mitral valve open (S3, typically not heard) and letting blood being pushed from atria to the ventricles B)isovolumteric ventricular contraction -QRS complex --> depol of ventricles -ventricular pressure increases and as soon as the ventricular pressure exceeds the left atrial pressure, the mitral valve closes = 1ST HEART SOUND -The ventricular pressure increases, but volume stays constant as aortic valve and mitral valve are closed C)Rapid ventricular ejaculaton: -ventricles contract -ventricular pressure reaches it's max value -aortic valve opens as the ventricular pressure exceeds the aortic pressure -T wave = ventricular repol and relaxation -Ventricular volume reaches a minimum -aortic pressure begins to fall as blood runs off into the arteries D)Isovolumetric ventricular relaxation -begins after ventricles are fully repolarized marked by the end of T wave -ventricles relax -ventricular pressure decreases -but VOLUME IS CONSTANT as both valves are closed. The closure of the aortic valve is what CREATES THE 2ND HEART SOUND E) Rapid ventricular filling -ventricular pressure falls slightly below the aortic pressure and thus, the mitral valve opens -this leads to filling of the ventricles w blood from the atria -the ventricular pressure remains low and constant as they are relaxed F) Reduced ventricular filling / diastasis -atrial systole (P wave) marks the final portion of V filling -diastasis is the LONGEST PHASE in the cardiac cycle SUMMARY OF HEART SOUNDS: S1: the loudest one, occurs during isovolumetric contraction (the most forceful period) and the sound is a result of the recent closure of the mitral valve (aortic valve was already closed) S2: results from the closure of the aortic valve in the beginning of the isovolumteric relaxation S3: typically not heard, from mitral valve opening in atrial systole S4: also typically not heard, but occurs from atrial contraction LEFT VENTRICULAR PRESSURE-VOLUME LOOP 1)isovolumetric contraction, where the pressure goes from 10-90mmHg 2) aortic valve opens and pressure increases further while the volume decreases from 120ml to 50ml 3)the aortic valve closes and isovolumetric contracton occurs where the pressure goes down again to 10mmHg

8.12. Integration of autonomic responses. Regulation of behavioral mechanisms. Motivation. Emotion.

The autonomic responses of the PSY and SY are closesly integrated with both somatomotor and enodrcine responses PROCESSES CONROLLED BY ANS INTEGRATED - Talk about fight and flight response -reg of water uptake -pupil reflex: basal activity is mostly SY, meaning the pupils are dilated via info from T segment. PSY comes from light stim of the retina, which leads to pupilary constriction. -accomondation reflex: involves both pupillary constriction and somatomotor response to make the lens more convex -cardiovascular reflex EXAMPLES OF NON-COGNITIVE BEHAVIOUR: -conrol of alertness -mood -hunger, thirst -fear -sexuality -self-def LIMBIC SYSTEM: is made up of the paleocortex and is more ancient part of the brain shared with many mammals. It is responisble for feelings of rage, fear, panic, feelings of being lost and lonely, joy, sexuality, reward, punishment, regret. consists of the amgydala, fornix, nucleus accumbens,

8.6. Physiology of equilibrium. The senses of taste and smell.

The vestibular system is used to maintain equilibrium or balance by detecting angulat and linear accelerations of the head. The sensory information from the vestibular system is then used to provide a stable visual image for the retina (while the head moves) and to make the adjustments in posture necessary to maintain balance. The vestibular organ is located within the temporal bone and consists of a membranous labyrinth (contains endolymph) within the bony labyrinth (perilymph). The semicircular canals (sup, post, lat) are arranged perpendicular to each other and used to detect ROTATIONAL MOVEMENTS of the head. Each canal, filled with endolymph has an enlargement at the end called an ampulla. In this ampulla, the vestibular hair cells can be found. They are covered in a gel like substance called a cupula. During angular displacement of the head, the cupula is displaced (it has the same density as the endolymph) and causes depol or hyperpol of the vestibular hair cell. The vestibular hair cells differ from the cochlear hair cells in the fact that they have many stereocilia AND ONE LARGE KINOCILIUM. When a person's head rotates, endolymph moves through the semicirc canalsm causing the cupula to move and place mechanical stress on the hair cells. There is a 15second delay before the endolymph starts to move together with the head. If the head rotates left, this means that the stereocilia of the hair cells of the left horizontal semicircular duct bend towards the kinocilium and thus AP's from the left afferent n fibers increase. However, the opposite occurs in the right horizontal semicircular duct --> AP's are reduced. REMEMBER THAT WE HAVE TWO EARS SO 2X OF BOTH. Otholithic organs: The saccule and utricle are considered otholith organs due to the presence of small calcifications calles otholiths that rest on top of a gel that covers the hair cells. These otholiths consist of calcium carbonate crystals and are more dense than endolymph, thus they can detect linear movement, since the movement of the otholiths are based on gravity. The hair cells of the utricle and macula are located in a sensory epithelium region called the macula. The sacular macula is oriented vertically and the utricular macula is oriented horizontally. The hair cells of the mecula are oriented in such a way that they are related to a groove caøøes the striola which runs through the middle of each macula. The striola is useful because AP's will increase on one side and decrease on the other side of the striola. In the sacular macula, the kinocilia are oriented AWAY from the striola, while in the utricle they are oriented TOWARDS the striola. The changes in the discharge of the aff nerves from each macula creates a different pattern based on these hair cell orientation, which is analyzed and interpreted as head position and acceleration. (HMMM...... må gå over) VESTIBULAR PATHWAYS: Afferent nerves from the vestibular hair cells terminate in vestibular nuclei of the medulla. The superior, medial and lateral (collectively known as the Deiter's nuclei) and the inferior nuclei. The sup+med receive input from the semicirc canal and project to nerves innervating the extraocular muscles via the medial longitudional fasciculus. The lat vestibular nucleus receives inout from the utricles and projects to the spinal cord motorneurons via the lat vestibular tract. THIS TRACT PLAYS A ROLE IN MAINTAINING THE POSTURAL REFLEXES. The inferior vestibular nucleus receives its input from the all of the components and projects it to the brain stem and cerebellum via the medial long fasciculus. Vestibulo-oculo reflexes occurs when the patient is spinning on a chair (Barany test) in which the eyes initially move in the opposite way of the rotation, which is the slow component of the nystagmus. When the eyes reach their lateral rotation limit, there is a rapid eye movement in the same direction as the head is rotating. This is the fast component of nystagmus. If the rotation is stopped abruptly, the eyes will move in the direction opposite that of the original rotation which is called postrotationary nystagmus (during this time, the patient tends to fall in the direction of the original rotation). A patient with normal vestibular function, when rotated to the right, would experience a right nystagmus, a left postrotationary nystagmus, and the patient will fall to the right. This can be tested using the Barany test (rotating a patient on a chair 10 times) or with the caloric method in which warm or cold water is used to isolate the semicircular canals and excite/inhibit them. OLFACTION: The sense of smell involve detection of chemical stimuli and transduction of those stimuli into electrical energy that can be transmitted in the nervous system. The sensory receptors of olfaction are located in the olfactory mucosa in the post-sup part of tge nasal cavity. The bipolar olfactory receptor cells are themselves primary afferent neurons, having an apical process with cilia that extend into a layer of mucous in which dissolved chemicals elicit an olfactory response. THERE ARE SUPPORTING AND STEM CELLS THAT CONTINOUSLY REPLACE OLFACTORY CELLS. The sense of smell UNIQLY, DOES NOT PASS THROUGH THE THALAMUS, but the afferent side runs through the olfactory bulb and projects to the piriform cortex, olfactory tubercle, amygdala and entorhinal cortex. THE MECHANISM OF SMELL: -humans have about 400 types of smell receptors encoded by 800 genes, which is quite weak for a mammal. -Each odorant is recognized by a unique combination of receptors. Chemicals induce activation of a pattern of olfactory receptors, so each smell is really from many diff chemicals and creates a complex pattern of GCPR activation -a group of GCPR's are dedicated to one olfactory sensation. Each olfactory neuron has only one type of GCPR THE SIGNAL TRANSDUCTION CASCADE: odorant --> Golfaction (similar to Gs) activation --> adenylate cyclase activation --> camp incr--> activation of CNG CATION CHANNEL (CYCLIC NUCLEOTIDE GATED CATION CHANNEL)--> cation pass through membrane --> depol. TASTE/GUSTATION: Human taste uses taste bud receptors to detect chemical stimui and interpret them as sweet, salty, bitter or umami. Information collected by the taste buds is relayed by the facial, glossopharyngeal and vagus nerve, which have pseudounipolar neurons in their ganglia. The n fibers are then projected to the solitary nuclei, then to the VPM and then to the insula and post-central gyrus. THE TASTE PATHWAYS IS IPSILATERAL. The taste bud consists of about 50 gustatory receptor cells in association of supporting cells and basal cells. They are continously replaced by differentiation of basal and supporting cells. The taste pore come into contact with the chemicals in the saliva. One taste pore is specialized for only ONE taste. There are TWO FUNDAMENTAL MECHANISMS for the taste bud synapse, which both leads to a calcium signal. SWEET(T1R2, T1R3), UMAMI(T1R1,T1R3), BITTER(T2R) USES: -stimulation of the different receptors above in paranthasis stimulate GPCR activation--> phosholipase C --> IP# --> ca2+ released from ER --> calcium signal --> NT release --> synapse and AP fired from neuron SALTY (ENAC) AND SOUR(PROTON-SENSITIVE ENAC TO SENSE ACID CONTENT) USE: -stimulation of the receptors lead to opening of cation channels --> depol --> vd-ca2+ opens --> calcium influx --> calcium signal --> NT release --> synapse and AP fired.