OSSF 4

Identify key microanatomic and physiologic characteristics of capillary vessels that allow for the exchange of diffusible substances.

Capillaries contain ~5% of the circulating blood volume (small portion even though it has a large surface area). It also has the slowest velocity of blood flow to allow time for exchange processes to occur. The capillary wall is very thin (0.001 mm) made of a single layer of flat endothelial cells and a thin basal lamina. There is extensive branching of the capillary network (creates a large cross-sectional area) in order to make the distance between any cell and the nearest capillary very small. Capillary density correlates with the rate of metabolism of the tissue because the arteriole will regulate how much blood flows into the capillaries depending on the needs of the organ its connected to. When the metabolic rate rises, more capillaries are open ("capillary recruitment"). Capillaries receive blood from the arterioles, however, in some tissues (e.g., skin, hoof) there are arteriovenous anastomoses (shunts) that bypass the capillary networks. These shunts contain innervated, smooth muscle and can adjust blood flow under certain conditions. Pericytes have long processes that wrap around the capillaries and the smallest post-capillary venules & communicate with the endothelial cells. They secrete substances that stimulate endothelial cells to differentiate, multiply, and form vascular branches (angiogenesis). Angiogenesis is going on all the time in response to many things like inflammation. Pericytes also form the blood-brain barrier, regulate glomerular blood flow in the kidney, and store Vitamin A in the liver.

Describe the relationships between form and function for each type (arteries, arterioles, capillaries, venules and veins) of blood vessel.

Capillary exchange is the ultimate purpose of the circulatory system. The rest of the cardiovascular system functions to transport blood to/from the capillaries. Arteries are very muscular and elastic which allows them to transport blood away from the heart and change the size of their lumen to regulate blood supply for each organ (contract = increase resistance). Arterioles are a major point of control of resistance to blood flow especially blood entering capillaries. Veins have less muscle and larger lumens in order to transport blood back to the heart and serve as a blood reservoir (increase capacitance).

Review the importance of hydrostatic and osmotic pressures especially with regard to capillary exchange

Capillary hydrostatic pressure (fluid pressure within the capillary) --> The difference between the inside and the outside of the capillary is referred to as the transmural pressure. Hydrostatic pressure will always favor filtration out of the capillary (even as the pressure inside decreases down the capillary) as the pressure of the interstitial fluid is essentially zero. Capillary hydrostatic pressure is determined by arterial and venous pressures, and decreases along the length of the capillary (significant drop but still favors movement out). Capillary oncotic pressure --> A protein oncotic pressure is a type of osmotic pressure. It is specifically called oncotic pressure with an effective osmotic pressure of capillary blood due to the presence of large plasma proteins. Capillary oncotic pressure will oppose filtration because proteins cannot cross the endothelial cell wall of the capillary. Diffusion → refers to the movement of MOLECULES --> Type of transport used for nutrients, gasses, and waste products. Molecules move from a region of higher concentration to a lower concentration and occur independently of the diffusion of other substances. Diffusion depends on the permeability of the capillary wall to a substance and the difference in concentration between the blood & interstitial fluid. --> Bulk flow is a mass movement of water and dissolved substances governed by pressure differences --> straight through the membrane for O2, CO2, (gases rate of diffusion depends on the partial pressure difference for the gas and the surface area available for diffusion) and lipid-soluble molecules OR through the clefts for lipid-soluble substances, H2O, electrolytes, small molecules, and glucose --> larger molecules must cross the endothelium through transcytosis (vesicles for proteins and IgGs or transport for ions and small molecules) because they are too large to diffuse on their own Filtration & Osmosis → refers to the movement of FLUID A mass movement that transports water and dissolved, low molecular weight substances simultaneously. •Filtration = transport of a fluid through a porous membrane due to due to hydrostatic pressure •Osmosis = transport of a fluid through a porous membrane due to differences in the total concentration of dissolved substances (osmolarity) on the two sides of a membrane --> Capillaries have a semipermeable membrane with different concentrations on either side. H2O (solvent) will cross the membrane and try to even out the concentrations. The pressure for water to flow is called the osmotic pressure. Terms for Solute Concentrations Osmolarity → a description of the total concentration of solutes in a solution --> Hyper, Hypo, and Iso-osmotic are terms used to compare solutions of different osmolarity (compare solutions relative to one another) --> Normal plasma osmolarity in mammals is ~290 mOsm/L (tightly regulated!) Tonicity → describes both the relative solute concentrations and the permeability of the membrane between those solutions (the cell membrane) ***the tonicity of the fluid surrounding each cell is critically important for the health ofht the cell*** ~ Two solutions have the same osmotic pressure = isotonic --> often want to give a fluid that is isotonic to plasma ~ When two solutions have different osmotic pressures: --> The solution with the lower effective osmotic pressure is hypotonic (when a cell is placed in a hypotonic solution, causes water to move into the cells causing swelling and bursting of cells) --> The solution with the higher effective osmotic pressure is hypertonic (when the cell is placed in a hypertonic solution, water moves out of the cells to dilute the solution causing the cell to shrivel up)

Identify factors that regulate blood pressure with emphasis on regulation of the arteriolar diameter.

Arterial blood pressure can be affected by --> Cardiac Output (MAP= CO * TPR) --> Total Peripheral Resistance: resistance of the arterioles is large and subject to regulation (point of most regulation) -- well-regulated --> Elasticity of the blood vessels: Declines with age so arterial pressure and pulse pressure increase with age --> Blood Volume: Acute changes (often highly regulated by kidney) affects venous pressure (blood storage), end-diastolic volume, and stroke volume (and thus cardiac output) -- well regulated Regulation of the Arteriolar Diameter 1. Sympathetic innervation: endings of nerve fibers release norepinephrine → binds to α-adrenergic receptors in the membrane of the muscle cells → depolarization → Ca 2+ influx → vasoconstriction ~ There is always some resting sympathetic "tone" to arterioles, so arteriolar resistance can be reduced from a normal resting situation by reducing the frequency of impulses in the sympathetic nerve fibers to levels below the low basal level 2. Neurohormonal regulation: Hormonal regulation of arteriolar diameter occurs mainly via epinephrine and angiotensin II ~ Epinephrine constricts the arterioles in most organs through activation of α-adrenergic receptors, though in some organs (liver, skeletal muscle), it causes vasodilation via b2 receptors ~ Angiotensin II causes constriction of arterioles, except those in the brain and the heart 3. Autoregulation: a mechanism by which organs can alter their own arteriolar resistance; 2 forms: a) Metabolic autoregulation: metabolic by-products cause local vasodilation b) Pressure autoregulation: when arterial pressure falls, vascular smooth muscle cells in some organs relax and vice versa ( ↑ arterial pressure leads to vascular smooth muscle cells contracting) → only in select organs very sensitive to acute changes in blood flow (like the brain where you cannot afford for blood flow to be inhibited) *****The functions of autoregulation are to adjust the blood perfusion of each organ to match variations in metabolism and maintain a constant blood supply to organs when arterial blood pressure changes. Endothelial cells play a key role in autoregulation. When endothelial cells are affected by local changes, such as reduced pO2 or stretch, they release substances (Nitric Oxide (NO) & prostacyclin) that act upon the smooth muscle cells adjacent to the endothelial cells. The coronary and cerebral arterioles have sparse sympathetic innervation, but their autoregulation is efficient so that their blood supply is well-adjusted to the metabolic needs of those organs.*****

Contrast the compliance of the chest wall and lungs themselves at high and at low lung volumes

At high lung volumes, the chest wall is compliant with the elastic recoil becoming smaller, and the lung recoil increases. The diaphragm is the main muscle used for inspiration but the intercostals can also be recruited to aid inspiration. Expiration is mainly passive, but muscles can also be recruited to speed it up. Lung volume can also increase by raising the sternum thus, the accessory muscles of inspiration are those that tend to raise the sternum and facilitate inspiration. At low lung volumes, the chest wall is stiff with a strong tendency to recoil outward and the recoil of the lung is very small and directed inward. At total lung capacity, the chest wall is expanded even more to the point where it wants some inward recoil and the lung wants inward recoil as well. Both of these then favor a decrease in lung volume. At Functional residual capacity, the opposing recoil tendencies of chest wall vs. lungs are equal and opposite. Thus, the end of a normal tidal breath seems to come to an equilibrium point in humans. In humans and small ruminants, the end of a normal tidal breath (FRC) comes at the equilibrium point (VRX) where inward lung recoil is nearly equal to outward chest wall recoil. In large animals with a stiff chest wall (horse), the equilibrium point is at a higher lung volume, and the tidal breath will end below the equilibrium point. In very small animals or infants of most species, the chest wall is very compliant, the equilibrium point is therefore at a lower volume, and it is below the end of a normal tidal breath.

Outline the anatomical differences between the avian and mammalian respiratory systems. Explain the greater efficiency of the avian lung vs the mammalian alveolar lung with respect to gas exchange

Avian lungs are amazing! Ventilation is accomplished by the downward movement of the keel, which decreases pressure in the thoracoabdominal cavity and pulls air into the compliant air sacs. These air sacs are not involved in gas exchange, but ensure that only oxygenated blood enters the parabronchi. Gas exchange occurs in the air capillaries (thinnest air-blood barrier) of the parabronchi by cross-current flow of blood and air which allows for more efficient absorption of O2 from the air. The parabronchi are rigid and do not move during the respiratory cycle which means that they do not need additional support that could interrupt gas exchange. This diagram shows the flow of air through the avian respiratory system during inspiration and expiration. Air flows into the parabronchi and posterior air sac on inspiration and then the posterior air sac air is directed through the air capillaries of the rigid parabronchi where gas exchange occurs during expiration. This means that air flows through the parabronchi during both inspiration and expiration and there is a potential for gas exchange during the entire respiratory cycle.

Define BALT and explain where it is found. Describe the differences between type I and type II pneumocytes.

BALT (bronchus associated lymphoid tissue) and NALT (nasal associated lymphoid tissue) are types of MALT (mucosal associated lymphoid tissue). These are lymphoid tissues embedded in the walls of the large airways and nasal passage. They wait around until they encounter their antigen. NALT and BALT are made of lymphs, PCs, dendritic cells, and macrophages. They appear as little, roughly round, follicles with many little blue dots. BALT is often not readily visible in the healthy lung. Type I pneumocyte (T1P) - Squamous - Thin for gas exchange - 97% of alveolar surface --> they are small and long so they cover a lot of area w/ few cell numbers Capillary endothelium - Very metabolically active - Inactivates many circulating signaling molecules Type II pneumocyte (T2P) - Sit at "corners" of alveoli - Cuboidal (more type II but cover less area) - Help remove H2O - Progenitor for type I - Produce surfactant -->Surfactant is made by type II pneumocytes and packaged in lamellar bodies. They decrease surface tension (lipids, phospholipids, hydrophobic proteins) so that the alveoli do not collapse. They have an innate immunity by hydrophilic proteins allowing for direct microbial killing and opsonizing microbes (facilitate phagocytosis).

Identify some autonomic reflexes involved in modulating cardiovascular function. (think of the sensors in the cardiovascular system)

Baroreceptors are sensory nerve endings containing mechanoreceptors (sensitive to stretch) that are located in the carotid sinus (innervated by the carotid sinus nerve off the glossopharyngeal nerve) and the arch of the aorta (innervated by the aortic depressor nerve off the vagus nerve). Changes in arterial pressure will change the membrane potential (↑ in MAP will cause ↑ stretch will cause ↑ firing rate in afferent nerves) and there is always some basal activity in these nerves. The impulse frequency of the baroreceptors is higher if the pressure is increasing rather than decreasing meaning they are sensitive to the rate of change in pressure, as well as the pressure itself. The baroreceptor reflex allows dynamic, moment-to-moment regulation of arterial blood pressure. Signals from the carotid sinus nerve and the aortic depressor nerve are integrated into the cardiovascular center of the medulla. The cardiovascular center continuously analyzes information from the afferent nerves and compares it with an inherent reference value ("set point") Efferent nerve activity is adjusted accordingly: a)↑ MAP causes a decrease in sympathetic outflow (inhib. of cardiac accelerator and vasoconstrictor centers) & increase in parasympathetic outflow (cardiac decelerator center) ⇢ vasodilation, slower HR, reduced cardiac contractility b)↓ MAP causes the opposite: an increase in sympathetic outflow & decrease in parasympathetic outflow **Remember that MAP = CO * TPR --> arterial pressure is constantly shifting as CO shifts (changes in EDV, ESV, SV, and HR) therefore the mechanisms for blood pressure regulation are in continuous operation. Volume sensors (low-pressure sensors) are mechanically sensitive nerve endings present in the large thoracic veins and atria that are stretch sensitive. Stimulation of these nerve endings results in: 1. Direct effect → release of Atrial Natriuretic Peptide (ANP*) from atrial myocytes → increased natriuresis (Na+ excretion so that water follows and pressure decreases) 2. Signal to the hypothalamus to decrease the production of Vasopressin (a.k.a., Antidiuretic Hormone, ADH) 3. Direct effect → renal vasodilation → increased diuresis **All cause a reduced blood volume Peripheral and Central Chemoreceptors are chemosensitive nerve endings that are activated by a ↓pH, ↓PO2, and/or ↑PCO2. The primary effect following stimulation of these receptors is to increase pulmonary activity (inhalation). For example, a fall in arterial PO2 (hypoxemia) or an increase in arterial PCO2 (hypercapnia) leads to an increase in the rate and depth of respiration through activation of the chemoreceptor reflex. Secondary effects include stimulation of CV activity (increase SNS) which would then increases MAP.

List the factors that determine regional blood flow in the lungs and be able to explain how their interaction produces (at rest in the sitting human) a zone of negligible flow, one of intermittent flow, and one of constant flow

Blood flow through vessels depends on the driving pressure from cardiac pumping (delta P) and the resistance to flow (R). If the same amount of blood flows through the systemic and the pulmonary circulation (Q) but the pressure generated in the right ventricle is less than in the left, then the resistance to flow in the pulmonary circulation must be much less than resistance in the systemic circulation. Resistance in pulmonary circulation is normally low due to low baseline tone in pulmonary vessels. When cardiac output increases, resistance in the pulmonary circulation is kept low by 2 mechanisms: 1) Recruitment of vessels that were previously not patent (open) and 2) Distension of vessels due to their compliance (distensibility). As the lung inflates, alveolar vessels (capillaries in the alveolar walls) become progressively compressed by air in the alveoli because they lie right next to it. The larger extra-alveolar vessel will be progressively pulled open by connective tissue "tethers" as the lung is inflated. Thus, resistance to flow changes with the inflation of the lungs, as small vessels are progressively compressed and larger vessels are pulled open. Because of these opposing effects, the overall resistance varies at different lung volumes. At first overall resistance to blood flow decreases as the extra-alveolar vessels are pulled open. At higher lung volumes, however, compression of smaller alveolar vessels is the predominant effect, and overall resistance increases. In a normal sitting human, there is an effect of gravity on the distribution of perfusion in the lung. In the most apical region of the lung, there is minimal blood flow at rest. In the mid-region, there is more flow, and in the basal portion of the lungs, the flow is greatest. The differences in flow are mainly due to the effect of gravity because the heart must pump blood "uphill" to the apical part of the human lungs. In the basal portion, the flow is aided by gravity pulling it downhill, which is partially why it is greatest there. If cardiac output increases (as with exercise) pulmonary blood flow becomes more homogeneous. Experimental data in quadrupeds indicate that gravity is not the major determinant of blood flow, and in fact, the flow appears to be greatest in the dorsal portion of the lungs.

Explain how pulmonary artery pressure is measured

Blood pressure is most often measured by placing a catheter with a pressure transducer into the bloodstream. Catheters can be introduced into systemic blood vessels to measure pressure, but it is impossible to place a catheter to directly measure blood pressure in pulmonary veins and the left atrium. Thus to estimate the pressure, doctors use a Swan-Ganz catheter. It is long to allow threading from a systemic vein, through the right atrium and ventricle, and out into the pulmonary artery. A balloon is inflated when the catheter is threaded into a pulmonary arteriole, occluding the arteriole (referred to as "wedging" the catheter tip). Flow in the smaller arterioles, capillaries, and veins downstream from the occluded arteriole cease. This "wedge pressure" then measures blood pressure in the downstream pulmonary veinule and provides a good estimate of the pulmonary vein pressure. This pulmonary capillary wedge pressure is a good estimate of left atrial pressure as well because from pulmonary veins to the left atrium, there is very little change in pressure. Note that in the pulmonary veins, the pressure normally drops to only a few mmHg.

Identify parabronchi, atria, and air capillaries in a histologic section of avian lung.

A birds larynx lacks vocal folds, they have complete tracheal rings, and their sound is from the syrinx at the tracheal bifurcation. Their conducting portion includes airways and air sacs (which change volume with respiration, are thin, transparent structures, and lined by simple squamous/cuboidal). Airsacs act like bellows to move oxygenated air through gas exchange regions. Gas exchange occurs in parallel parabronchi which only receive oxygenated blood. Parabronchi appear as an opening surrounded by numerous air capillaries (very small with walls like alveolar septa). Gas exchange region is rigid with continuous flow and no blind endings. Inhalation pulls air into the posterior air sacs and some into the parabronchi for gas exchange. The deoxygenated air from the parabronchi then fills the anterior air sacs. Exhalation pulls the air from the posterior air sac to the parabronchi for gas exchange. It also moves the deoxygenated air from the anterior air sacs out trachea. Gas exchange occurs in air capillaries (equivalent to alveolar septa) that extend from parabronchi (function to move air around). There is also a thinner barrier b/w air & blood which aids in the efficiency of their respiratory tract. There is also cross-current exchange which makes it more efficient. In the avian lung it goes from primary to secondary to tertiary (parabronchi) bronchi. Then it goes to the atrium to infundibulum and then air capillaries.

Explain the meaning and significance of pressure volume loops

A pressure-volume loop is a way to graphically visualize cardiac function. You follow the loop in a counterclockwise fashion to follow the progression of the cardiac cycle. The loop begins with ESV. a. Ventricular filling (passive + active) b. Isovolumetric contraction c. Ventricular ejection d. Isovolumetric relaxation These loops are very helpful because they allow you to analyze different changes of the heart. --> Increased Preload (refers to EDV or the end-diastolic fiber length) results from increased venous return. This means that there is an increased EDV and thus an increased SV. This change follows Starling's Law of the Heart (more blood in = more blood out). ESV remains unchanged because this is not affecting heart contractility (only intrinsic modulation). --> Increased Contractility of the Heart (+inotropy) results from increased ventricular pressure which increases how much blood is pumped out of the heart (decreased ESV means more efficient emptying of the heart). This causes an increase in SV and in the ejection fraction. --> Increased Afterload (the "load" against which the heart must contract to eject blood) results from increased TPR (total peripheral resistance) which increases aortic pressure. This causes the left ventricular pressure to increases (b/c must overcome aortic pressure to open the aortic valve). The higher aortic pressure also causes an increase in ESV (and thus a decrease in SV) because relaxation happens faster from the ventricle pressure dropping below the aortic pressure faster.

Explain how alveolar ventilation influences measured PCO2

Alveolar ventilation must be adequate for removal of CO2 produced by tissue metabolism, or arterial PCO2 will increase. The partial pressure of carbon dioxide in alveolar gas (P_ACO2) depends on the rate of CO2 production by peripheral tissues (V_CO2) over the rate of CO2 removal by ventilation (V_A). Since the rate of CO2 production by tissues is constant, the alveolar CO2 is a good index of how adequate alveolar ventilation is for CO2 removal. Alveolar CO2 is impossible to directly measure, but arterial CO2 is equivalent and easily measured. Thus, arterial CO2 is used clinically to assess alveolar ventilation. When alveolar ventilation decreases, the PCO2 begins to rise dramatically.

Discuss the clinical utility of troponin I in assessing damage to the heart. Discuss cardiac glycosides.

Cardiac Glycosides **Digitalis increases the force of cardiac contraction by slowing the removal of Ca2+ from the cytosol. --> Digoxin is a compound isolated from the Foxglove plant (Digitalis purpurea), and is the basis for drugs called cardiac glycosides which have a pronounced stimulatory effect on the contractility of the heart --> Mechanism of action: 1. Inhibition of Na+/K+ ATPase 2. Less Na+ is pumped out of the cell, increasing intracellular Na+ 3. Ca2+/Na+ exchanger decreases activity because there is a decreased Na+ gradient to power it 4. Less Ca2+ is pumped out of the cell by the Ca2+/Na+ exchanger, so Ca2+ builds up inside the cell 5. More Ca2+ = positive inotropic effect (increase contractility) Troponin I and T as Biomarker of Cardiac Injury ***I=inhibitory subunit, T=tropomyosin binding subunit, C=Ca2+ binding subunit*** The troponin complex functions as the "molecular switch" for cardiomyocyte contraction. I and T have tissue-specific isoforms, but C is completely homologous with skeletal muscle troponin C so measuring troponin C is useless for isolating a problem specific to the heart. Troponins are purely intracellular proteins, so their presence in the blood indicates intracellular content release from cardiomyocytes. After a cardiac insult, a rise in troponin levels in the blood is observed within 2-3 hours, and peaks at ~18-24 hours. Troponins as biomarkers are TISSUE SPECIFIC but not DISEASE SPECIFIC. Cardiac troponins have many characteristics of an ideal biomarker to aid in a diagnostic work-up: 1. Tissue specificity 2. High sensitivity for injury (never present in circulation without cell damage) 3. Correlation with severity of injury 4. Assays readily available and validated; normal and disease values established

List one positive and one negative result of a highly developed collateral ventilation system. Describe species differences in vascular smooth muscle (added by me).

Collateral ventilation pathways exist at the level of bronchi, bronchioles, and alveoli. All provide alternative pathways to supply ventilation if airways are blocked or obstructed. More collateral ventilation has more connecting pathways (appear as holes on an scanning electron micrograph) between airways to ensure that there are many ways to get fresh air to the areas of the lung with an obstruction. However, these connections mean that an infectious agent can spread through the lungs more easily through these collateral pathways. Dogs, cats, and subhuman primates have good collateral ventilation. Cattle, sheep, and swine do not have collateral ventilation. Horses have partial collateral ventilation. Cattle and swine have larger amounts of smooth muscle surrounding pulmonary arterial vasculature than other species. These same species have a greater pulmonary hypoxic vasoconstriction response. In general, if there is an increase in vascular smooth muscle, they have a greater capacity to change pressure.

Be able to draw a compliance curve (w/ axes labeled) for a fibrotic and an emphysematous lung and explain what kind of changes in lung parenchyma would be responsible for the differences in the curves

Compliance= how stretchy the lungs are Compliance in the lungs is technically the amount of volume change for a given pressure change. Pressure in this graph is shown as negative pressure in the interpleural space. As the pressure becomes more negative, air rushes into the lungs, and the volume increases. Compliance depends upon the elastic fibers within the lungs, and a useful synonym would be "stretchiness". As the lungs get stretched out (higher lung volumes), it's harder to stretch it out further (shallower slope) whereas the slope of the curve is steeper at low lung volumes. Compliance is measured in cooperative humans by having them swallow a balloon with a pressure transducer into the thoracic esophagus. After the patient inhales up to TLC, a bolus of gas is exhaled and measured while the pressure is recorded (measuring resistance). Pulmonary fibrosis causes excess collagen in the pulmonary interstitium causing the lung to become stiff. This means that the compliance has decreased (curve shifts down and to the right) the lung is more difficult to stretch and thus more work needs to be done to inflate the lungs. **Increased fluid in the pulmonary interstitium from pulmonary edema can also cause stiff lungs** Emphysema results from a net loss of pulmonary collagen and elastin in alveolar septae which causes a loss of this structural tissue. The most common cause of this process is cigarette smoking. Emphysema causes compliance to increase (curve shifts up and to the left) because there is not as much elastin for the recoil of the lung.

Compare and contrast the structural and functional differences between the conducting portion and gas exchange portions of the respiratory tract. Explain how the structure relates to the function.

Conducting Regions ◼ 1˚ Role: Conduit for transport of gas from environment to lungs ◼ Other roles: Air filtration, olfaction, phonation, temperature regulation, immunity, metabolism of some xenobiotics ◼ Nose/Sinuses, Pharynx, Larynx, Trachea, Bronchi, Bronchioles and (+/- Respiratory bronchioles) Gas Exchange Portion ◼ 1˚ Role: Diffusion of gases to provide oxygen to cells of the body and eliminate carbon dioxide produced by tissue metabolism ◼ Other roles: Metabolism of hormones & xenobiotics, acid-base regulation ◼ (+/- Respiratory bronchioles), Alveolar ducts and alveoli Pleura/Pleural Space ◼ Smooth surface for lung and thoracic movement ◼ Elastic properties of visceral pleura contribute to ventilation Thoracic Wall/Diaphragm

Compare different types of capillary vessels.

Continuous: most common type; endothelial cells form a continuous wall connected by tight junctions with clefts in between. Lipid-soluble substances dissolve through the cells while water-soluble substances diffuse through the clefts. Fenestrated (a bit more leaky): endothelial cells contain 60-80 nm "holes" (fenestrations) through which water-soluble substances can diffuse; occur in organs whose functions depend on extensive movement of material across capillary walls (intestines [lots of absorption], kidney, exocrine glands [lots of secretions that need to be released]) Discontinuous (sinusoids): Large diameter capillaries with fenestrae large enough for cells and large proteins to pass through (liver, bone marrow [WBCs are too large and need big holes to enter circulation], spleen, lymph nodes) ***Proteins are generally too large to cross the capillary walls via the clefts between endothelial cells and are retained in the vascular compartment (stay in the capillary lumen) ***Fenestrated and discontinuous are strategically located where there are larger particles that need to enter circulation

List the mechanoreceptors stimulated by maximal inspiration

Control of respiratory activity originates in loosely organized groups of cells in the pons and medulla. The most discrete areas are the apneustic center in the pons that initiates a sustained inspiratory discharge and the pneumotaxic center in the pons that mediates inspiratory cutoff. H+ and HCO3- ions do not cross the blood-brain barrier, but CO2 can. CO2 that diffuses into the cerebrospinal fluid causes the [H+] to increase, stimulating chemoreceptors. Chemoreceptors located in the aortic bodies and carotid bifurcation respond to increased PaCO2 and stimulate ventilation. This diagram shows mechanoreceptors, including stretch receptors in lung parenchyma that help terminate the inspiratory response, irritant receptors in the airway lining that promote rapid shallow breathing, J receptors in the interstitium that promote rapid shallow breathing, and proprioceptors in ribs and intercostal muscles that promote increased inspiratory muscle activity if ventilation is impeded. If airway irritant receptors are stimulated, the airway smooth muscle will constrict as a protection mechanism in order to limit the penetration of the irritant further into the airway.

Explain the most likely fate of an inspired particle of 5 micrometer diameter; of 0.2 micrometer diameter

Deposition of particles in the respiratory tract depends upon particle size. Large (>5um) particles collide with walls of upper airways and become stuck in mucus. Medium sized particles (1-5um) particles settle out of the air stream as flow slows down in smaller airways. The decreased velocity of flow allows for these particles to settle out. Smaller (<0.1um) particles are carried down to alveoli and alveolar ducts. They may move by diffusion and may contact the alveolar wall and become trapped. Bacteria and fungal spores are in the size range that can be carried deep into the lung parenchyma. Here we see that the alveolar septa are thin which is good for gas exchange but leaves them vulnerable to these infectious agents. Thus they need some sort of protection. The same principles are important in quadrupeds, where deposition of particles depends on size and the airway branching pattern.

Define the following important concepts pertaining to heart function (systole, diastole, isovolumetric contraction and relaxation, cardiac output, stroke volume, heart rate, end systolic volume and end diastolic volume)

Diastole: starts when the ventricular pressures become lower than the atrial pressures → AV valves open → ventricles fill --> Diastole is divided into thirds: First 1/3 = rapid filling with blood that has accumulated in the atria Middle 1/3 = filling with blood that is flowing straight in from the venous return Final 1/3 = filling with blood from atrial contraction (only 20-30% of the total amount of blood in the ventricle) Systole: starts when the ventricles contract and the ventricular pressure almost immediately causes the AV valves to close --> For a brief moment, the pressure in the aorta is higher than in the ventricle, so the aortic (and pulmonic) valves are closed and the ventricles contract against a fixed volume (because both sets of valves are closed) = isovolumetric contraction --> The ventricular pressure exceeds the artery, opening the valve --> Once the ventricle starts to relax and the pressure falls below the aorta/pulmonary artery, the aortic/pulmonic valves close, and once again, for a brief period both sets of valves are closed = isovolumetric relaxation Cardiac Output: the amount of blood pumped by each of the ventricles per minute --> Cardiac Output (CO) ml/min = Heart Rate (HR) X Stroke Volume (SV) --> can be regulated by changing HR, SV, or both (they may not change in the same direction) HR is the number of heartbeats per minute (beats/min) --> at rest, the influence of the parasympathetic system (PNS) predominates, and the heart rate is normally lower than the inherent rate of impulse generation in the SA node (↓ PNS, ↑ SNS = ↑HR) --> Increased activity in vagus fibers (PNS) prolongs the delay of the AP at the AV node which is part of the reason that differences in resting heart rates between individuals is often due to differences in resting vagal "tone" (parasympathetic-mediated control of the heart rate) -- higher vagal tone = lower resting HR SV is the volume of blood pumped out by each ventricle during each heartbeat (ml/beat) At rest, CO is approximately equal to total blood volume (7-8% of body weight). A healthy heart can adjust CO according to the needs of the body (exercise, digesting a meal, pregnancy, etc.)

Explain how a compliant chest wall is adaptive for mammals at parturition and for diving mammals. Discuss the pleural space in the elephant and how cats purr (added by me).

Diving mammals need a mechanism to minimize the amount of nitrogen they absorb as they dive deeper. They are able to minimize nitrogen absorption through their flexible chest wall and increased cartilage in their distal airways. The flexible chest wall results in the collapse of the alveoli as they dive deeper and pressure increases. The alveoli collapse results in less gas exchange occurring when they are deeper in the water and thus less nitrogen is absorbed. The air that was in the alveoli is pushed into the non-gas exchange airways for storage while they are deep. Myoglobin in their muscle proteins can also act as an O2 storage when they dive. There is increased cartilage around the distal airways and this external support allows movement of air in the alveolar region into the distal airways as the lungs are compressed during a dive, limiting N2 absorption. **Neonates of all species have a very flexible chest wall to facilitate passage through the birth canal. When elephants cross a river, they walk along the bottom and put their trunk out of the water like a snorkel. Their body under the water would be compressed, causing an increased pressure (pressure in tissues and the blood vessels at this depth would be 150 mmHg, and the transmural pressure in pleural microvessels would be >150 mmHg). The elephant has dense connective tissue in the pleural space which protects the small vessels from rupture due to these high pressures. This increased CT also means that they do not have a vacuum in their pleural space like humans. Panting (dogs and cats): rapid, shallow breathing used for thermoregulation because it causes lots of potential heat loss through membranes --> dead space ventilation so does not affect CO2 or O2 ventilation in tissues (not a lot of CO2 loss or acid-base abnormalities) Purring: alternating activation of diaphragmatic and laryngeal muscles causing epiglottal vibration turbulent flow --> some increased minute ventilation but tidal volume does not change, just dead space

Identify the physiological basis for each wave, segment and interval of the electrocardiogram (ECG).

Electrocardiography is the measurement of tiny potential differences on the surface of the body that reflect the electrical activity of the heart. The amplitude & direction of each component of the electrocardiogram is a result of all the cardiac cells undergoing depolarization & repolarization at a given time, recorded extracellularly. The last part of the heart to depolarize is the base of the left ventricle. An electrode is a device that registers voltage differences between 2 points. A vector indicates the strength (size) and direction of a voltage difference. The arrowhead points in the positive direction and the depolarization wave follows the arrow direction. When measuring heart electrical activity, we are measuring resultant vectors (summation of main depolarization and repolarization vectors of individual cardiomyocytes). The size and direction of the resultant vector are continually changing during the depolarization and repolarization of the heart. The individual vectors on the left side of the heart are larger because the muscle mass is larger. The voltage difference recorded depends on where the electrodes are placed in relation to the resultant vector (the difference will be greatest when the electrodes are placed parallel to the vector). A lead is the position of the electrode on the body anatomically. the direction of negative to positive across that lead is called the axis of the lead. A bipolar recording is the voltage difference between 2 surface electrodes recorded over time. In a standard bipolar recording of an ECG, the leads are placed according to "Einthoven's Triangle", an imaginary triangle with 3 equal sides in the frontal plane, with the corners being the left foreleg, right foreleg, and left inguinal region. The net depolarization moving through the ventricles is the left hind leg. Recordings will be positive if the exploring electrode (2nd electrode, positive electrode) is positive relative to the reference electrode (1st electrode, negative electrode). There is an upward deflection if the depolarization is towards the positive electrode or the repolarization is toward the negative electrode. The opposite is true for a negative deflection. The shape of the ECG waveform depends on the overall direction of depolarization/repolarization AND the attachment sites of the electrodes. The ECG waveform is going to look different for the different leads and no one individual lead is perfectly positioned across the vector generated by depolarization. PQ interval = Time it takes an AP to go from SA node to the ventricle (sometimes referred to as PR interval because Q deflection often missing) ➔ conduction time through the AV node! QT interval = Time from the onset of ventricular depolarization to end of ventricular repolarization ST segment = Plateau of ventricular AP (Ca2+ influx, phase 2) R-R interval = One cardiac cycle P wave: depolarization of the atria QRS complex: depolarization of the ventricles Q wave: septum is the first part of the ventricle to depolarize S wave: base of the left ventricle is the last part of the ventricles to depolarize T wave: repolarization of the ventricles **Heart rate can be automatically calculated by an ECG recording system by counting the # of R waves per unit of time Repolarization of the atria and depolarization/repolarization of the conduction system cells are not visible on the ECG. Atria have a relatively small muscle mass and slow repolarization, and the conduction system cells are too small to contribute to any deflections.

Identify the excitation-contraction coupling in cardiomyocytes (added by me), the cardiac refractory periods, as well as the supranormal period.

Excitation-Contraction Coupling ① Cardiac AP ② Calcium enters the cell but is not enough to generate maximum contractile force ③ Cytosolic calcium induces release of much larger amounts of calcium from the sarcoplasmic reticulum --> Calcium release from the SR is induced by increased calcium in the cytosol, not directly due to the AP = calcium induced calcium release ④ Calcium binds to troponin C induces a conformational change that allows actin and myosin to bind ⑤ Formation of cross-bridges between actin and myosin filaments. ⑥ Voltage gated Ca2+ channels close, Ca2+ is pumped out of the cell and back into the SR, Ca2+ dissociates from troponin Absolute Refractory: The long depolarization leads to an absolute refractory period that lasts for almost as long as the contraction. This allows for the cyclical nature of cardiac contractions and avoiding tetanic contractions which are incompatible with the pumping function of the heart. Supranormal Period: following the refractory period, the cardiomyocyte is more excitable than normal (could stimulate with a subthreshold stimulus) during this period because the Na+ channels have fully recovered to their "inactivated state" but the membrane potential is not at max. polarization yet

Describe extrasystole and some basic examples of ECGs for diagnostic use (added by me).

Extrasystole is a single action potential generated outside the SA node (in an ectopic focus ➔ usually the conduction system cells) that can lead to an extra cardiac contraction outside the usual sinus rhythm. No blood is pumped from this because the ventricles have just been emptied. The next action potential in the SA node does not result in a contraction, because the cardiac muscle cells are then refractory. **Note that the first contraction after the extrasystole is particularly strong because the ventricles have had more time to fill so that the amount of blood in the heart at the start of the contraction is more significant than normal. Diagnostic Uses **Deflections are compared with normal values for a given species which can vary between species** P wave: enlargement of the atria leads to a prolonged P wave with greater amplitude PR interval: prolongation of the PR interval arises when the normally slow conduction speed of the action potentials through the AV node is further reduced (this is called first-degree heart block; common & normal in some species) QRS complex: In lead I, the R wave is normally positive during most of the depolarization of the ventricles; left ventricular hypertrophy causes abnormally high amplitude, and right ventricular hypertrophy causes the QRS complex to flip to negative in Lead I QRS complex: Increased duration of QRS complex occurs when ventricles are dilated (impulse has a longer distance to propagate) Overall ECG wave: abnormally small waves observed with fluid accumulation in the pericardial sac due to reduced conduction of current to the surface electrodes

Identify the major ion channels involved in cardiac membrane potentials and discuss their functional roles.

For the cardiac AP, Na+. K+ and Ca2+ are the important ions in AP generation. Resting membrane potential in cardiac cells is determined primarily by K+ ions going down their concentration gradient through their leaky channels pulling positive ions outside the cell and leaving the inside of the cell more negative. The AP in contractile cardiomyocytes has a different shape because of the CA2+ channels creating a plateau phase. This makes the cardiomyocyte stay depolarized for longer than normal so that it does not become excitable again and interrupt the wave of contraction (allow for a coordinated contraction). ① Stable resting membrane potential, close to equilibrium potential for K+ (note high K+ permeability) ② AP initiated when conduction cardiomyocyte depolarizes contractile cell to threshold ➔ explosive increase in membrane permeability to Na+ ③ The plateau phase of the cardiomyocyte action potential is due to the opening of voltage gated Ca2+ channels, which slow repolarization because calcium is flowing inward (higher conc. outside the cell) --> Permeability to K+ is also low during this phase, which keeps the cell depolarized --> This is a slow inward Ca2+ current, through L-type Ca2+ channels ④ The K+ channels open back up, so now the cell can rapidly become polarized again. The return to negative resting membrane potential (i.e., repolarization) is primarily due to the high permeability to K+, but also due to the low permeability to Ca2+ ⑤ The high K+ permeability maintains the resting membrane potential

Contrast the differences between O2 and CO2 at the air-blood barrier with respect to molecular weight and solubility. Understand what factors would slow diffusion of either gas through this barrier.

Gas exchange is the second major function of the respiratory system. It takes place via diffusion at the air-blood barrier in the lungs. Mammalian lungs are divided into many alveoli, which vastly increases the surface available for diffusion of gases at the air-blood barrier. The Type I epithelial cell in the alveoli is very thin and provides minimal barrier to gas diffusion. The next cell visible is the capillary endothelial cell--again a very thin minimal diffusion barrier. Between these 2 cells is a small amount of epithelial basal lamina and no real connective tissue. The diffusion distance from the alveolar air space to the erythrocyte is approximately 1 micron. The Fick equation (Vgas = (A/T) * D * (P1-P2) where D= Sol/ sqrt_MW) describes gas diffusion through tissue. The volume of gas transferred across the air-blood barrier per unit time (V̇) depends upon the surface area (A) and is inversely proportional to the thickness of the barrier (T). The next parameter is diffusivity (D) for the specific gas, and this depends upon the solubility of the gas in tissue fluid and the square root of the molecular weight. When comparing oxygen and carbon dioxide, carbon dioxide is much more soluble (20x) than oxygen. The final parameter that influences diffusion is the partial pressure gradient (P1-P2). In this case, oxygen has a much greater partial pressure gradient than carbon dioxide at the air-blood barrier. The partial pressure gradients for oxygen and carbon dioxide at the air-blood barrier are 60 mmHg (40 in venous to 100 in arterial) for oxygen and 6 mmHg (46 in venous, 40 in arterial) for carbon dioxide. The difference in driving pressure across the diffusion barrier between the two gases is offset by the difference in their solubility, and they require about the same time to diffuse across the barrier. Both O2 and CO2 can diffuse with plenty of time to spare before the RBC leaves the capillary. During exercise, the transit time for red cells through the pulmonary capillaries is faster, but complete gas equilibration still occurs.

Explain the ionic basis of ACh and NE effects on the pacemaker potential.

Heart rate (chronotropy) -SNS (NE release) ➔ b1 receptors in SA node ➔ increase f-channel current (increase slope of current so reach threshold quicker) ➔ threshold potential decreases ➔ SA node is depolarized to threshold more frequently (increased HR) -PNS (ACh release) ➔ M2 receptors in SA node ➔ decrease f-channel current (decrease slope of current so reach threshold quicker) ➔ slower rate of phase 4 depolarization ➔ SA node depolarizes to threshold less frequently (decreased HR) -PNS (ACh release) ➔ increases conductance of K+ out of the cell through K+Ach channels ➔ hyperpolarizes the cell ➔ SA node depolarizes to threshold less frequently (decreased HR) Contractility (inotropy) **The magnitude of the tension developed by myocardial cells directly correlates with intracellular calcium concentration** -SNS (NE release) ➔ bind to b1 adrenergic receptors in the cell membrane ➔ increased cAMP formation ➔ phosphorylation of Ca2+ channels ➔ prolongs their opening time ➔ more calcium entering the cytosol from outside the cell and the SR ➔ more calcium = more forceful contraction --> The increased Ca2+ movement also applies to putting it back into the SR (takes it out just as fast as it was released), which leads to a shorter contraction time

Explain the relationship that exists between blood flow, cross-sectional area, and velocity of blood flow through a blood vessel.

Hemodynamics refers to the physical principles that govern blood flow in the cardiovascular system. These basic principles of physics are the same as those applied to the movement of fluids in general. Flow through a tube (blood vessel) is driven by a difference in the fluid pressure (hydrostatic pressure). There is always a certain resistance to fluid flow through a tube due to friction between the moving fluid and the stationary tube wall. For a certain pressure difference, fluid flow decreases as the resistance increases. Resistance to flow causes the fluid pressure to gradually decline as the fluid flows through the tube. If part of a tube is narrowed, the flow speed in this section increases, but the fluid pressure decreases (fluid pressure is converted into kinetic pressure in the narrow segment). ***↑ Pressure difference ⇢ Increased flow ↑ Resistance ⇢ Decreased flow*** As blood vessels repeatedly branch into smaller and smaller vessels, the overall cross-sectional area gets larger due to the large # of capillaries. At a given Mean Arterial Pressure, the larger total cross-sectional area will result in a slower velocity of blood flow in the capillaries. The low speed of flow in the capillaries allows time for gas/nutrient exchange. The pressure in the large arteries and the aorta is the arterial pressure (pulsatile). The mean arterial pressure (MAP) is the pressure driving blood through the tissues (pressure difference) and can be measured. The resistance to blood flow exerted by the entire systemic circulation is called the total peripheral resistance (TPR) which can be changed. The general equation for the relationships between flow, pressure difference, and vascular resistance (Q = ∆P/R → Ohm's law) applies to the entire systemic circulation in the following way: ***Cardiac output (CO) = MAP/TPR*** According to this equation, all changes in arterial blood pressure are due to changes in cardiac output or in the resistance of the blood vessels. Forces that drive blood through vessels are the resistance in the vessel and the pressure difference. The pressure difference depends on the contractions of the heart. Resistance itself is affected by the length of the vessel (L), the radius of the vessel (r), and the viscosity of the blood (n). The radius of the blood vessel is the only thing that can be regulated to influence vascular resistance (the length of the vessel can't be changed and the viscosity can change but that change cannot be controlled). You can visualize these variables by using Poiseuille's Equation R=(8Ln)/pi*r^4). This equation says that a small increase in radius results in a large drop in resistance and thus a large increase in blood flow.

List the causes of hypoxemia. Discuss capnography (added by me)

Hypoxemic = PCO2 < 85 mmHg (if %O2 saturation is below 90, they are most likely hypoxemic) 1. Hypoventilation: not breathing enough or not receiving enough tidal volume causes decreased PO2 and increased PCO2 2. Shunt: the blood travels from venous straight to the arterial without a chance of gas exchange so it creates a venous admixture 3. Ventilation/perfusion mismatch: most common cause from a good ventilation alveoli being placed with low perfusion or bad ventilation being placed with high perfusion 4. Diffusion impairment: thickening of the air-blood barrier Hypercarbia, or elevated levels of carbon dioxide in blood. The most common cause is inadequate alveolar ventilation because then CO2 is not being taken up. An elevated PaCO2 level is the best indication of hypoventilation. Capnography measures CO2 in exhaled gas. The measured value varies with the respiratory cycle and is affected by cellular metabolism, cardiac output and ventilation. Increases or decreases in end tidal CO2 can help assess respiration in ventilated patients. End tidal CO2 is where we are most concerned about when looking at lung function. An increased end tidal CO2 would suggest hypoventilation. Decreased end tidal CO2 would suggest hyperventilation.

Discuss how and why mean blood pressure changes throughout the systemic circulation.

If the body wants to alter the proportion of cardiac output going to a specific organ, it must alter the resistance of the blood vessels to that organ. Because the perfusion pressure is identical for all organs, changes in the distribution of cardiac output between organs can only be achieved by alterations in their relative resistances to flow. The walls of the arterioles (point of regulation of blood vessel resistance) are muscular & richly innervated w/ sympathetic nerve fibers (↑ activity of sympathetic nerves --> reduction in diameter of arterioles --> ↑ resistance to flow). It is possible to alter the blood flow to a tissue dramatically by only moderate changes in the diameters of the supplying arterioles (due to the Poiseuille Equation). Since increased resistance decreases blood flow, vascular resistance must be low in organs receiving large amounts of blood (low resistance in individual arterioles or many parallel arterioles to one organ). During exercise, the needed organs would see an opening of their supplying arterioles.

Recognize the tunics of blood vessels and describe their compositions (see Histo Lab LOs)

In blood vessels, there is the tunica intima (like the tunica mucosa + tunica submucosa), the tunica media (like the tunica muscularis), and the tunica adventitia. The tunica intima has endothelium, with a basal lamina, and an underlying subendothelial CT cushion. The endothelium runs down the length of the vessel, is very heterochromatic and its nuclei follow the flow of the vessel. Between the endothelial cells are tight junctions to control permeability. The endothelial cells themselves produce various active compounds (anticoagulants, vasoconstrictors, and growth factors). There may or may not be internal elastic lamina at the bottom b/w the tunica intima and the tunica media (present in arteries and arterioles). The tunica media is made of helically arranged layers of smooth muscle with an extracellular matrix of elastic fibers, collagen, and proteoglycans. The number of elastic fibers and the contractile state of the smooth muscle regulates vessel compliance (regulates blood flow). This muscle cuffs the vessel. This layer has external elastic lamina (present in arteries but may be less obvious). The tunica adventitia (external) has longitudinally arranged CT elements like blood vessels (needed b/c layer is far from the lumen where blood supply is) and nerves. This CT is important for cushioning (adipocytes) and protection. It is also the avenue for neural regulation of the vessel wall. This layer merges with the surrounding loose CT.

Contrast gas exchange with the environment in a fish and a mammal (added by me)

In fish, gas exchange takes place in the gills. They bring fresh water across the gills with the delivery of fresh gas accomplished by swimming or by buccal pumping of water across the gill surface. Gas exchange occurs at the epithelium covering the gill lamellae. There is a countercurrent flow of blood vs. water which means that the flow of the water and the flow of the blood is running in opposite directions. This proves to be a very efficient gas exchange. On the circulation side, they have a two-chambered heart with one atrium and one ventricle. They also only have a single circulation system with blood leaving the heart towards the gill capillaries to receive O2 and then traveling to tissue capillaries for delivery. The deoxygenated blood then returns to the heart.

Be able to draw the relationship (with axes) b/w ventilation or perfusion and height in the chest in the human.

In human lungs, the change in perfusion from top to bottom of the lungs is greater than the change in ventilation. Thus, the ratio V/Q is not equal to 1 except in the mid-region of the lungs. We can see how the V/Q (ventilation/perfusion) ratio changes as we move through the lungs by looking at the red line. At the top, ventilation exceeds perfusion, and at the bottom (the diaphragmatic portion of the lungs) perfusion exceeds ventilation. In dogs, ventilation and perfusion would be more perfectly matched because they are both uniform across the lungs.

List the cell types present in the conducting airways and gas exchange region. (added by me).

In the conducting airways we start with the large airways (nose --> bronchi) whose epithelium are too tall for exchange. There is mucus and cilia with goblet cells and subepithelial glands (exceptions are the SE and TE in the nose and portions of the larynx). These have thick walls with support of bone and cartilage (nose) or just cartilage (larynx, trachea, bronchi). The trachea and bronchi have respiratory epithelium and goblet cells, subepithelial glands, and cartilage (U-shaped in trachea [trachealis muscle spreads gap] and plates in bronchi). The bronchi has circular smooth muscle. Next, is the bronchioles whose epithelium are shorter (become non-ciliated cuboidal) but still too tall for exchange. There are fewer ciliated cells and no goblet cells/glands. The bronchioles lack rigid support and just have smooth muscle. The muscle contraction is regulated by the ANS and controls the diameter and resistance of the airway. Bronchioles are the only place where you will find club cells which are non-ciliated cuboidal (almost dome shaped) cells. These have numerous mitochondria, a well developed ER and Golgi (cytochrome p-450 enzymes to detoxify inhaled toxins), progenitor (can replace ciliated and non-ciliated cells) and many secretory granules (surfactant-like product and anti-inflammatory proteins). There are terminal bronchioles (last pure conducting airways) and then respiratory bronchioles (cuboidal epithelium [club cells] w/ some alveoli in walls making them not "purely" conducting). The respiratory bronchioles give rise to alveolar ducts whose wall consists of mostly alveolar sacs with small knobs of smooth muscle covered by cilia free simple cuboidal cells. Alveolar ducts give rise to alveoli. Now we reach the gas exchange region (O2 in, CO2 out) made of the alveoli. The epithelium is thin enough, there is no mucus or cilia and scant CT (small amount of collagen and elastin) making them good for diffusion. The gas-exchange requires fresh air, thin epithelium, thin interstitium and fresh blood. The alveolar septa (walls) are made of two layers of simple squamous epithelial cells, interstitium (elastic fibers, CT cells, capillaries) and alveolar pores (equalize pressure and passage of macrophages).

Identify factors that could lead to a change in laminar blood flow to turbulent blood flow.

Laminar flow = the friction between a flowing fluid and the wall of the tube --> causes the fluid molecules closest to the wall to move relatively slowly --> the highest speed of flow is in the center of the tube Above a certain flow speed of a fluid or below a certain viscosity, turbulence arises (image b). Turbulent flow has a disorganized pattern with crosscurrents and eddies. This can be caused by valvular insufficiency, anemia ( ↓ viscosity), etc. The Reynolds number is a dimensionless number that is used to predict whether blood flow will be laminar or turbulent. It considers a number of factors including diameter of the blood vessel, mean velocity of flow, and viscosity of the blood.

Identify relationships between pulse pressure and mean arterial pressure.

Large arteries are thick-walled with an increased proportion of elastic tissue. They store energy, function as a "secondary pump" to propel blood through the vasculature and maintain flow during the diastolic phase. Arterial blood pressure varies during the cardiac cycle --> Systolic pressure is the highest pressure --> Diastolic is the lowest The mean arterial pressure (MAP) is the pressure driving blood through the tissues (pressure difference). At rest, the mean arterial pressure (MAP) is closest to the diastolic pressure because the diastolic period lasts longer than the systolic period. At high heart rates, MAP is closest to the systolic pressure because the diastolic phase is shortened more than the systolic phase. The difference between the systolic and diastolic pressures is called the pulse pressure. The amplitude of the pulse pressure depends on heart rate and stroke volume, the elasticity of the arteries, and the total peripheral resistance. Measuring Arterial Blood Pressure Direct → fluid-filled catheter inserted into an artery and connected to a pressure transducer (gold standard) Indirect → blood flow occluded by cuff which is slowly deflated --> Cuff pressure at which flow resumes is equal to systolic pressure --> Cuff pressure at which detection disappears is equal to diastolic pressure --> Done by auscultation (auscultation not possible in animals!), or cuff + balloon placed over artery using ultrasound or oscillometer to detect pressures

Identify paracrine factors that can control blood flow locally.

Local paracrine factor regulation occurs at the arterioles and inflammation will cause the release of a lot of local mediators in order to increases local blood volume (increase nutrients to injured site to aid in healing). Some of the mediators include: •Histamine → Arteriolar dilation (H1), ↑ capillary permeability, venous constriction (H2). •Bradykinin → Arteriolar dilation and ↑NO production •PGI2 and PGE2 → Vasodilation. •TXA2 and LTs → Vasoconstriction Autoregulation mediated by NO is also an important mechanism for local control of blood flow. NO is produced by endothelial cells from arginine using nitric oxide synthase. It is very soluble so it can then diffuse across the membrane of smooth muscle cells where it will cause vasodilation. NO donors (nitroglycerin, nitroprussides) have clinical relevance for improving blood flow or treating left-sided heart failure. Exercise stimulates numerous physiologic changes to meet the metabolic demands of working muscles: ✓Skeletal muscle blood flow increases ✓Ventilation increases ✓Glucose and fatty acids released into the circulation ✓Extensive circulatory changes to redirect blood flow to the muscles while maintaining vital organ perfusion ***Cardiac output will increase 4-6 fold during exercise from increased cardiac contractility and increased HR (both from increased sympathetic stimulation through increased CNS stimulation) and increased venous return (from increased skeletal muscle pumping). The distribution of the CO goes to the increased metabolism in the working muscles (causes local vasodilation via autoregulation), increased blood flow to the cardiac muscles (via autoregulation), and increased blood flow to the skin to facilitate the dissipation of heat (mediated by the thermoregulatory center in the hypothalamus). Blood flow to the heart, brain, and working muscles is prioritized during exercise!

Describe the anatomical sequence the cardiac action potential follows

Membrane potentials in cells are determined primarily by three factors: 1. The concentration of ions on the inside and outside of the cell 2. The permeability of the cell membrane to those ions (i.e., ion conductance) through specific ion channels --> when conductance and permeability are both high then you have a higher probability for the pump/channels to be open 3. The activity of pumps that maintain the ion concentrations across the membrane (Na-K pump is the most important) Sequence 1. This spontaneous, slow depolarization of the non-contractile cardiomyocytes is fastest in a small cluster of cells located in the right atrium, the sinoatrial node (SA node normally functions as the pacemaker of the heart). 2. Impulses from the SA node travel across the atria and reach the AV node, but the ONLY way they can reach the ventricle is through the AV node & the Bundle of His! --> The annulus fibrosus acts as an "electrical insulator" ➔ does not transmit the electrical impulses, ENFORCES the passage of the signals through the AV node which slows them down --> Allows adequate ventricular filling time 3. From the AV node, the signal travels through the bundle of His which then branches into the Purkinje fibers (have a large diameter and therefore conduct AP at high speed [10X faster than contractile cardiomyocytes]) 4. From the Purkinje fibers, the APs are propagated from muscle cell to muscle cell via gap junctions. 5. Then, nearly simultaneous contraction of the entire ventricle ➔ actually, the apex contracts a little before the base, which allows for efficient emptying of the ventricles.

List 2 functions of surfactant and explain how its presence helps maintain stable alveoli of unequal diameter

Normally, there is a liquid layer on the inside of the alveolar surface, but this is lost during tissue processing. The force of surface tension is created by the aqueous layer normally on the surface of the alveolus because it creates an air-liquid interface. Surface tension a this air-liquid interface arises due to the polar nature of water molecules. Cohesive attraction is stronger between molecules at the surface and causes water droplets to "round up", creating a curved surface that has less overall surface area. This cohesive, or attractive, forces between water molecules at the surface of an air-liquid interface are responsible for the force of surface tension. Surface tension (T) acts to minimize the surface area of the alveolar air-liquid interface, or to collapse the alveoli. An inflation pressure (P) is required to resist surface tension to keep the alveolus open. If we fill the lung with saline, we remove this air-liquid interface and there is no surface tension force. The compliance is now high, and there is less tendency to recoil back after inflation. The pressure required to keep small alveoli open is much greater than that required to keep larger ones open. When two alveoli have a common airway and thus a common pressure, the smaller one will tend to collapse and send its air into the larger one. Surfactant is a phospholipid produced by type II epithelial cells. It is released out into the alveolar lining fluid where it floats on the surface of the aqueous layer and reduces surface tension. Surfactant functions to stabilize alveoli septa in order to decrease their tendency to collapse and allows the surface tension in an alveolus to vary with different radii (stabilize alveoli of different sizes so that smaller ones stay open). *** Issues with type II cell maturation late in gestation could cause issues producing surfactant so when a baby is born, their alveoli collapse and they cannot breath. IF the infant is given surfactant right as they are born, they can avoid alveoli collapse and allow the type II cells to develop later.

Contrast the airways and alveoli with respect to the predominant mechanisms of particle clearance and of immunologic defense

Once particles are deposited in the respiratory tract, there are 2 main mechanisms for removal, or clearance. The first is the mucociliary escalator, which operates throughout the ciliated airways, down to the level of terminal bronchioles. The mucus blanket and deposited particles are carried upward toward the pharynx by coordinated sweeping action of the airway epithelial cilia. Remember that microtubules in cilia are arranged as 9 outer doublets and a central pair. The dynein arms projecting out from the microtubules can make reversible connections between adjacent microtubule pairs, allowing the pairs to move relative to one another (sliding filament model). Microtubule sliding allows cilia to move in a coordinated fashion so that the mucus blanket is swept from the distal airways to the laryngeal region. Once mucus and particles reach the pharynx, they are swallowed and removed via the GI tract. At the junction between terminal airways and the alveolar ducts, particles clearance changes from the mucociliary escalator to alveolar macrophage phagocytic activity. Phagocytic alveolar macrophages move about on the alveolar surface and engulf particles that are deposited there. Alveolar macrophages, when stimulated by engulfing bacteria, can recruit neutrophils from the circulation to assist in fighting infection in the alveolar region. Neutrophils respond to chemotactic signals, adhere to the capillary endothelium, and migrate between endothelial cells (diapedesis). Once alveolar macrophages have engulfed particles, they can carry them away by moving to the mucociliary escalator and being carried to the pharyngeal region, or by moving between alveolar epithelial cells and into pulmonary lymphatic vessels. Bronchus-associated lymphoid tissue (BALT) can be seen as nodules of lymphocytes often near airway bifurcations. This is where we begin the development of an immune response to the inhaled pathogen. IgA consists of a dimer connected by a J-chain and a secretory piece. The secretory piece (contributed by the airway epithelial cell) allows the binding and transport of the particle/pathogen through the epithelial cell.

Be able to use the alveolar gas equation to calculate the PAO2, given an arterial blood gas determination, and be sure you understand under what circumstances PIO2 would change

PAO2 = Partial pressure of oxygen in alveolar gas The relationship between PO2 and ventilation is not as simple as PCO2, and the arterial and alveolar PO2 are not equivalent. In fact, they may be quite different. The equation shown here is an effective way to estimate the average alveolar PO2, since this cannot be directly measured. Note that the formula takes into account the arterial CO2 and also uses a constant, 0.8, as the ratio between CO2 production and oxygen consumption by tissues. Based on the normal numbers, the alveolar oxygen partial pressure is 100 mmHG.

Be able to explain how PCO2 influences ventilation and how this response is affected by hypoxia

PICO2 is the most important stimulus to change rate and depth of ventilation. When there is an increasing PICO2, chemoreceptors are stimulated which send a signal to the CNS creating a very brisk response of increasing alveolar ventilation rate and depth. The fresh gas then goes to functioning parts of the lung which will blow off CO2. As the alveolar (and subsequently arterial) PCO2 rises up to 100 mmHg (normal is 40), ventilation increases. PaCO2 greater than 100 mmHg actually depresses ventilation (CO2 narcosis). Hypoxia does stimulate receptors near the carotid body, and severe hypoxia will mediate increased ventilation. Hypoxia accentuates the ventilatory response to rising PaCO2. Sleep, anesthesia, and some drugs depress the ventilatory response to increased PaCO2. Note that the rate of alveolar ventilation does not increase until the PaO2 has dropped down well into the hypoxic range.

Be able to calculate PIO2 for gas mixtures with different fractions of inspired oxygen.

PIO2 = Partial pressure of oxygen in inspired gas As air is inspired, it is humidified in the nasal passages. Thus, the inspired oxygen partial pressure can be calculated by subtracting the partial pressure of saturated water vapor from the total barometric pressure (760 mmHG) and multiplying by 21% (the fraction of air that is composed of oxygen). ** P_IO2 = (P_total - P_H2O) * F_O2 ** The partial pressure of oxygen in inspired air is 150 mmHg (PIO2). The inspired oxygen partial pressure will change when a patient is given supplemental oxygen to breathe, and the FIO2 (fraction of inspired oxygen) is increased.

Discuss pericytes, arteriovenous shunt and portal system (added by me).

Pericytes are contractile cells that wrap their endothelial cell arms around capillaries and venules. They are located b/w endothelial cells (make physical and chemical contacts - gap and tight junctions) & basal lamina and are capable of differentiating into other cell types. They can regulate microvascular blood flow and permeability as their contraction may resist high systolic pressure. They are important for angiogenesis and maintenance of blood vessels. They appear to facilitate the movement of inflammatory cells out of vessels. Arteriovenous Shunt: Artery delivers blood directly to a vein, bypassing capillaries (shunts away from the capillary bed) Portal system: Made of two capillary beds interposed by a vein or artery (directly connect two capillary beds) -->bypass the long distance -->using two capillaries because the slow flow through them facilitates the absorption/leaving of molecules --> ex hypothalamus blood supply to anterior pituitary or portal blood taking venous blood from GI tract to liver

Explain how interlobular septa and collateral ventilation differ between species

Pleura (CT surrounding lung) is made of mesothelium (often very flat), collagen and elastin and blood and lymphatic vessels Interlobular septa is continuous with pleura and subdivides lungs into lobes --> Cattle & pigs = thick pleura and robust interlobular septa so its easier to confine disease to a lobule but susceptible to interstitial emphysema secondary to respiratory disease --> Horses & humans = intermittent --> Absent in dogs, cats, & rodents

List the mediators inactivated or metabolized by pulmonary endothelial cells

Pulmonary endothelial cells metabolic activity are an important control point for inactivation of circulating potent inflammatory mediators because the entire cardiac output moves through the lungs. Inflammatory mediators (like bradykinin, PGE, PGF2alpha, Histamine) are inactivated by pulmonary endothelial cell metabolism during circulation through the lungs. Potent inflammatory mediators can be synthesized and released by many cells in the airway epithelial layer. Mediators such as histamine can have a profound effect on nearby airway smooth muscle and vascular endothelial cells and can affect pulmonary function. Angiotensin I is an example of an enzyme that is activated during circulation through the lungs.

Contrast gas exchange with the environment in an amphibian and a mammal

Respiration in mammals has developed to make maximal use of internalized, compartmentalized lungs. In other species, the gas exchange region may depend on the exchange between water and circulation. Adult amphibians, reptiles, mammals, and birds have internal lungs. In general, the goal of respiration is to deliver O2 to tissues and remove produced CO2. There is bulk flow of air or water in the environment bringing oxygen to the gas exchange region. Then there is a diffusion of oxygen into the circulation, where bulk flow again takes it to the peripheral tissues. Diffusion accomplishes the final delivery of oxygen to the cells. When comparing systems we want to look at the efficiency of the ventilation to bring the O2 from the environment to the gas exchange system. We consider the oxygen partial pressure in the atmospheric gas or the aqueous environment as the optimal value to try to achieve in circulation. So, how close is the PO2 at the gas exchange region to the PO2 of the environment? Amphibians exchange gas through gills as larvae, and through lungs or the skin as adults. As larvae, the need to swim in order to bring in fresh water through their gills (external lung system) or they can pump water across the gills. There is no efficient lung system, so they can't manage ventilation or dead space in the body. This is part of the reason that amphibians do not have a trachea (which limits the head's range of motion) in order to avoid that dead space. Gills and the branchial circulation are resorbed during metamorphosis and an internal lung system is developed. With the development of the ribs, it allows efficient ventilation movement, an aspiration type of ventilation is possible, rather than buccal pumping. The development of divisions within the lungs, rather than a single chamber with folds (septation) to increase surface area (like in the amphibian lung), allows much more efficient gas exchange and supports a higher metabolic rate in mammals. On the circulation side, amphibians and reptiles have a three-chamber heart with two atria and one ventricle. There is a more developed pulmonary circulation with mixed circulation at the level of the common ventricle (a mix of deoxygenated blood from tissues and oxygenated blood from lungs). Mammals with two separate circulations separated by the 4 chambers of the heart prevent this mix of oxygenated and deoxygenated blood.

Identify factors both intrinsic and extrinsic that regulate stroke volume.

SV=EDV - ESV End diastolic volume (EDV) = volume of blood in the ventricles at the end of diastole. --> Determines the length of muscle fibers prior to contraction. End systolic volume (ESV) = volume of the ventricle at the end of systole ***Changes in stroke volume can result from changes in EDV or ESV. Up to a certain limit, an increase in EDV automatically results in a proportional increase in SV. A change in EDV is a function of filling time or amount of venous return. Intrinsic Regulation (increase EDV) Cardiac muscle fibers (like skeletal muscle fibers) have an optimal resting length (amount of overlap) regarding the development of force during contraction. At rest, venous return to the heart provides a degree of stretch of the muscle fibers that is less than optimal meaning that the muscle fibers do not contract with maximal force. EDV and stroke volume increase in fit individuals because a lower heart (↑ vagal "tone" from increased parasympathetic influence on the SA node) allows more time for diastolic filling of the heart. So, if blood flow into the heart during diastole is increased, the muscle cells will approach their optimum length. The contractions will then become stronger meaning stroke volume increases. This intrinsic regulatory mechanism enables the two ventricles to continuously adjust their stroke volumes to match each other (Starling's Law of the Heart = "more in → more out"). It is critically important that the Left & Right sides of the heart pump the same volume of blood, otherwise fluid will back up in one circulation or the other. Venous return affected by: •Increased use of the skeletal muscle pump → contracting skeletal muscles compress veins between them (squeeze blood between them to push it towards the heart); one-way valves in veins increase venous return toward the heart •Increased respiratory activity (respiratory pump) → decreased pressure in the thoracic cavity during inspiration •Increased blood volume ( ↑ blood volume = ↑ venous pressure) •Increased activity in the sympathetic nervous system → walls of the veins contain smooth muscle innervated by sympathetic nerve fibers •Cardiac suction → during ventricular contraction, the papillary muscles (which help prevent "inversion" of the AV valves) contract and help keep the AV valve closed, which increases atrial filling Extrinsic Regulation (decrease ESV) Stroke volume is also affected by the contractile force of the heart (inotropy) because more blood will be pushed out with greater contractions. So an increase in cardiac contractility due to SNS activity will increase stroke volume. This is also referred to as "extrinsic regulation of End Systolic Volume" (i.e., the heart empties more efficiently).

Compare skeletal muscle cell contraction with cardiac muscle cell contraction

Similar to skeletal muscle fibers -Striated like skeletal fibers -Both have T tubules which communicate with extracellular fluid -Ultrastructural elements are the same as skeletal muscle --> Actin (thin) filaments and myosin (thick) filaments form sarcomeres. Differences from skeletal muscle -Cardiac muscle fibers make a syncytium as they link end to end at structures called intercalated disks (histology term for the dark line, not a true structure), which contain gap junctions (made of connexin proteins) which cross both adjacent cells' membranes. --> Ions and small molecules can move through, from cell to cell allowing AP to move from cell to cell --> Cardiac muscle cells can depolarize and contract without innervation b/c signal spreads on own -Shorter and branched (have bifurcations to spread signal throughout entire heart) -Action potentials can be propagated from cell-to-cell within atria BUT NOT from atria to ventricles --> instead all signals get accumulated and funneled through AV node

List those mechanical properties of human lung function that can be assessed through spirometry. Discuss flow-volume loops (added by me).

Spirometry can be used to directly measure tidal volume and vital capacity, which can be exhaled and collected. In other words, you can only measure exhaled volumes. Determination of functional residual capacity and residual volume requires special techniques. Spirometry can also be used to measure forced expiratory volume in 1 second (FEV1) by collecting the gas exhaled during a forceful exhalation. The volume collected during the first second is the FEV1. This parameter is very sensitive to changes in airway radius, which can increase resistance and decrease flow. Patients with airway disease that limits flow are said to have an obstructive disease. The FEV1 is a very sensitive parameter to show obstructive airway changes which result in a decreased FEV1 (not able to exhale nearly as much air). Restrictive diseases (ie from stiff lungs causing difficulty inflating the lungs) on the other hand, do not involve the airways, there is less resistance to flow, and FEV1 is less affected but still generally decreased. A graph of volume vs time will give you a slope that equals flow (Change in volume/change in time). As a patient exhales rapidly from Total lung capacity (left-most point on the graph) down to residual volume (rightmost point on the graph), the flow will be greatest at the beginning of exhalation and then taper off. A flow-volume loop or a plot of flow determined from the slope of the volume-time plot begins on the left side at TLC. By convention, expiratory flow is in the positive direction on the graph. The patient exhales down to residual volume (at the far right b/c horizontal axis of lung volume decreases to the right) and then inhales (negative on the flow axis) back to TLC. Changes in the shape of the flow-volume loop are a sensitive way to demonstrate airway disease, and we can make these measurements in veterinary patients. Although we cannot measure FEV1 in veterinary patients, it is possible to create flow-volume loops, which help differentiate between obstructive and restrictive diseases. Obstructive diseases would decrease the max expiratory airflow and shift the loop to the left (higher TLC and RV). Constricted lungs would still decrease the max respiratory airflow but the loop would shift to the right (lower TLC and RV). ***Note that forced expiration creates some positive pressure in the lungs, thus pressing in on the alveoli and airways. Small airways without cartilage support can be compressed during forced expiration.

Define tachypnea, apnea and dyspnea. Be able to demonstrate Cheyne-Stokes and Kussmaul breathing patterns

Terms for breathing patterns Eupnea = indicates normal breathing Tachypnea = increased respiratory rate Dyspnea = the sensation of breathlessness Apnea = no breathing Cheyne-Stokes respiration is an abnormal pattern characterized by changing tidal volume and periodic apnea (changing tidal volume frequency in a rhythmic pattern). Kussmaul breathing is rapid rate with large tidal volume and is associated with metabolic acidosis (rapid deep breaths)

Be able to define and calculate the A-a gradient for oxygen when provided arterial blood gas values. Explain how you would use the value obtained in evaluation of a patient's lung function

The A-a gradient can be determined by subtracting the partial pressure of arterial oxygen from the partial pressure of alveolar oxygen (PAO2-PaO2). You estimate this gradient for the lung as a whole and it is a sensitive indicator of V/Q mismatch. An A-a gradient of 4-6 mmHg is normal and takes out V/Q mismatching as the cause of hypoxemia, and over 10 mmHg indicates that gas exchange is compromised. The A-a gradient calculation is used to help distinguish the cause of hypoxemia in a clinical case. If the A-a gradient is elevated, it is likely that VQ mismatching is a significant cause of hypoxemia (the most common cause) and thus you should try to give supplemental oxygen. There is no direct way to measure PAO2, so it must be calculated. The alveolar oxygen partial pressure depends upon the inspired oxygen partial pressure, the alveolar ventilation (which can be evaluated by the arterial carbon dioxide partial pressure), and the constant representing the ratio of oxygen consumption vs. carbon dioxide production by tissues (0.8). You must first make an estimate of the alveolar ventilation (find PIO2 and then calculate PAO2) then subtract the alveolar oxygen partial pressure.

Describe and explain the effects of sympathetic and parasympathetic stimulation on cardiovascular function.

The MAP must remain within relatively narrow ranges to preserve blood supply to vital organs and prevent damage to the heart and blood vessels. The core objective of the cardiovascular system is to monitor and regulate blood pressure both in the short term through neural reflexes and local control and in the long term through hormonal regulation (from kidenys or heart stretch receptors) of blood volume. In general, sympathetic stimulation increases blood pressure and parasympathetic stimulation decreases blood pressure. ANS effects on the heart are an important component of their overall effect on blood pressure (see table in image). Effector side (efferent nerve fibers) Sympathetic Nervous System: ✓Increased heart rate through effects on the SA node and the conduction velocity through the conduction system ✓Increased cardiac contractility mediated by b1 receptors ✓Vasoconstriction in blood vessels via a1 receptors ✓Vasodilation in some specific vascular beds (skel. muscle) via b2 receptors Parasympathetic Nervous System: ✓Decreased heart rate through effects on the SA node and conduction velocity in the conduction system mediated by M2 receptors ✓Vasodilation in some specific vascular beds mediated via M3 receptors & local mediator release

Explain how "Starling's Forces" influence filtration and reabsorption of fluid out of and into systemic capillaries.

The Starling Equation describes how the net movement of fluid across capillary walls depends on the hydrostatic pressure difference, the oncotic pressure difference, and the water permeability of the capillary wall. If the net pressure is negative, then there will be more pressure into the cell and thus a net absorption. If the net pressure is positive, then there will be more pressure out of the cell and thus a net filtration. Jv = Kf [{Pc - Pi) - (pi_c - pi_i)] J_v = fluid movement (mL/min) K_f = Hydraulic conductance (mL/min/mm Hg) --> water permeability of the capillary wall *constant* P_c = capillary hydrostatic pressure (mm Hg) P_i = interstitial hydrostatic pressure pi_c = capillary oncotic pressure (mm Hg) pi_i = interstitial oncotic pressure (mm Hg) Under normal circumstances, in most tissues, filtration exceeds absorption because the hydrostatic pressure drop across the length of the capillary. In most cases, the protein-osmotic pressure difference stays the same and the hydrostatic pressure difference decreases down the length of the capillary. Towards the end of the capillary, the hydrostatic pressure drops below the protein-osmotic pressure and there is some capillary reabsorprotion. The interstitial fluid hydrostatic and oncotic pressures remain constant. About ~90% of the filtered fluid is reabsorbed and 5-10% is picked up by the lymphatics (edema can occur if lymphatic drainage is impaired). The lymphatics pick up and transport the excess filtered fluid. Some capillary beds with specialized functions are different under normal conditions (the digestive system has more absorption and the glomerulus of the kidney has filtration across the entire capillary). Dilation of the arterioles or reduction in plasma proteins can increase filtration (increase hydrostatic pressure or decreases osmotic pressure). The excess fluid which accumulates in the tissues results in edema. Constriction of the arterioles or reductions in arterial pressure results in a temporary dominance of absorption (decrease hydrostatic pressure).

Explain how anatomical features of arteries, arterioles, capillaries, venules and veins dictate their function

The capillaries are where everything happens as nutrients are delivered and waste is picked up in these vessels. -Arteries: carry blood away from the heart to the tissues --> because they are under pressure, they must have thick muscular walls & be elastic -Arterioles: smaller branches of arteries, extensive innervation, and smooth muscle but a bit less elastic, the major site of regulation through vasoconstriction and vasorelaxation -Capillaries: smallest of vessels across which exchanges are made with surrounding cells, thin-walled (single layer of epithelial cells, no muscle) for efficient gas exchange, overall volume is low so that blood moves very slowly through them (for gas exchange), have the smallest cross-sectional diameter per vessel BUT the largest overall cross sectional area when combined -- lipid-soluble substances can diffuse across membranes, water-soluble substances can pass through clefts and pores -Venules: formed when capillaries rejoin, return blood to the heart -Veins: formed when venules merge, return blood to the heart, largest thin-walled vessel, serve as a blood reservoir (~65% blood volume and second largest cross-sectional area), also have some innervation Typically, blood passes through one set of capillaries before returning to the heart via veins, but there are exceptions called portal systems (when blood passes through 2 successive capillary networks) --> Hepatic blood supply (all the venous blood coming from the intestines then goes through the liver to metabolize toxins -- 75% of liver blood supply is from GI tract through the hepatic portal vein and only 25% is from the hepatic artery) --> Kidneys (1st one (afferent and efferent arteries on either side of the glomerular capillaries) makes urine, 2nd one (peritubular capillaries) brings O2/nutrients to the kidney itself) --> Anterior pituitary (Hypothalamus ➔ release of hormones from pituitary gland uses two capillary systems)

Describe the major functions of the cardiovascular system AND define the overall circuitry of the cardiovascular system including both the systemic and pulmonary circulations. (combined two learning objectives)

The cardiovascular system regulates arterial pressure and blood volume. Its overall purpose is to maintain a stable environment in the body (homeostasis). In order to regulate blood volume the heart acts as two separate, efficient muscular pumps that pump blood through the pulmonary and systemic circulation in series (so that blood flowing to tissues is always rich in O2). The right side of the heart (pulmonary circulation) is at low pressure (needed for successful gas exchange) and moves deoxygenated blood from the right ventricle to the lungs and then oxygenated blood from the lungs to the left atrium. The left side of the heart (systemic circulation) is at high pressure and it delivers O2 and nutrients from the left ventricle to the tissues and then takes CO2 and waste products from the tissues into the right atrium. Cardiac output is the amount of blood that leaves the heart each minute. Total blood volume is usually 7-8% of our body weight with about 85% of that in the systemic circulation, 10% in the pulmonary circulation, and 5% remaining in the heart. Since mammals have a closed circulatory system, this has to be distributed to different organs according to their needs and functions. Arteries in systemic circulation go to different organs in parallel so that adjustments of blood supply (through diameter changes) to different organs are based on the organ's needs (NOT based on organ mass at rest). Under baseline conditions, organs that use the blood to transport things like oxygen, nutrients, heat, and waste tend to get larger proportions of the cardiac output than those that receive blood for their own metabolic needs. The kidney is a great example of this because its role in making urine and regulating blood volume allows it to get 20% of cardiac output even though it is less than 1% of the body's mass. These baseline conditions may change in different scenarios like after a meal (blood supply to the intestines increases), during exercise (blood supply to the skeletal muscles increases), and in mammary tissue (during lactation, uterus during late pregnancy etc).

Explain the difference between FRC and relaxation volume (Vrx). Which is the higher volume in a kitten? In a horse? Explain why there is an energy-requiring portion of exhalation in the horse

The chest wall is stiff causing the ribs to be constricted and pushed in by the muscles. This creates a tendency of outward recoil in the chest wall. The lungs have an inward recoil tendency. This opposite recoil tendency of the lungs and chest wall allows for the negative pressure for respiration. These recoil tendencies can change at different lung volumes (ie the outward chest wall recoil decreases and the inward lung recoil increases at larger lung volumes). In humans, the elastic recoils of the lung and the chest wall are equal but opposite at functional residual capacity (end of tidal breath). Since the stiffness of the chest wall affects its outward recoil tendency, different species may have this equilibrium point (V_RX) in recoils occur at different lung volumes above or below the functional residual capacity (FRC). In humans and small ruminants, FRC comes at VRX. In large animals with a stiff chest wall (horse), the equilibrium point is at a higher lung volume, and the tidal breath will end below the equilibrium point. The bigger the mammal, the stiffer the chest wall, and thus the equilibrium point is at a higher lung volume. In a very small animal or infant of most species, the chest wall is very compliant, the equilibrium point is therefore at a lower volume, and it is below the end of a normal tidal breath.

Describe the location, composition, and function of the mucociliary escalator, including cilia ultrastructure.

The cilia and glands create the mucociliary escalator (MCE). This is the major innate defense of the respiratory tract. It is made of H2O, glycoproteins, immunoglobulins (esp. IgA), lipids and salt. On top of the epithelium with cilia is a serous secretion layer and then a mucus secretion layer. The cilia will move the serous layer which will then move the mucus layer with trapped particles. **Remember that cilia are made of 9 microtubule doublets and 2 central microtubule singlets. There are radial spokes from the doubles to the central singles and Nexin links the doubles. Cilia also contains Dynein (dynein is ATPase) whose arms link adjacent doublets. The dynein protein "walks along" the microtubules to bend the cilium. You can disrupt the MCE with primary ciliary dyskinesis (very rare), viruses, bacteria (common esp. Mycoplasma and Bordetella spp), gases/smoke ad environmental factors (temp/humidity).

Identify and describe the different vessel types within the body, including lymphatics (see Histo Lab LOs).

The circulatory system is a system of circuits running in a continuous loop. This is made of the pulmonary circuit (to the lungs), and the systemic circuit (to the body). General blood circulation through these two circuits goes through arteries (conductance and distribution of blood), capillaries (diffusion and gas exchange) and then veins (conductance and collection, 60% capacity). As the blood moves through these vessels, there are pressure gradients made by the pumping action of the heart, movement of the muscles and gravity. In general, the pressure decreases as you move from arteries to capillaries to veins. The l. ventricle has highly variable pressures (filled or unfilled, contracted or relaxed), the aorta has high pressure and the vena cava & r. atrium have low pressure. The lymphatic vascular system collects extracellular tissue fluid and returns it to the cardiovascular system through the thoracic duct and the right lymphatic trunk. It runs close to the arteries and veins of the cardiovascular system but is not a continuous loop. The lymphatic system picks up proteins and lipids from the GI tract and also plays a role in immune function. Lymphatic capillaries begin as blind-ended tubes (don't connect to anything) held open by anchoring filaments (prevent collapse) --> more permeable than blood capillaries (thin-walled) and carry protein-rich fluids, lipids, and lymphocytes --> lined with endothelium with NO tight junctions and an incomplete basal lamina (added to its higher permeability) --> very wide, distorted lumen containing no red cells but may see lymphocytes --> contain an amorphous material (lymph) that precipitates during the preparation of the sample --> similar to venules but are thinner, floppier, and have wider lumens than venules. --> no muscle in their walls and thus rely on things moving through them by the movement of surrounding muscles --> Fluid build-up outside will cause pressure which can then push fluid through gaps into the lymphatic lumen. The pressure will then close these gaps so that the fluid remains in the lymphatics. Lymphatic vessels are progressively larger and will drain into large veins (internal jugular, subclavian) --> largest = thoracic duct --> larger lymphatic vessels contain a tunica media with smooth muscle, however, lymph still flows on account of intrinsic contractions of surrounding muscles --> hard to differentiate from veins but shouldn't see RBCs in them --> punctuated by lymph nodes which is important for immune function --> have valves and a weird-looking lumen (not a circle nor an oval)

Recognize the phases of the cardiac cycle and list the major events that occur during each phase.

The events on the right and left sides of the heart are basically the same and happen in parallel. The only difference is that the pressures on the left side are much higher during ventricular contraction. The cardiac cycle can be divided into two main phases: diastole (ventricular relaxation) and systole (ventricular contraction). The events in the atria are opposite the respective ventricular events. **one cardiac cycle = one systole + one diastole** RA, RV and PA pressures are always lower than their left heart counterparts (LA, LV, A). Phase 1: Passive Ventricular Filing ▪Initially rapid because the atria have been filling during systole (passive) ▪Ventricular filling slows as blood passes from veins through atria and into ventricles (passive) ▪AV Valves Open ▪Aortic and Pulmonary Valves Remain Closed ▪Ventricular pressures are lower than atrial pressures so AV valves are open. ▪Majority of ventricular filling occurs here Phase 2: Atria Contract ▪20-30% of left ventricular filling ▪AV valves open ▪P wave (atrial depolarization) ▪Volume of ventricles at end of diastole is referred to as the end-diastolic volume (EDV). ▪At the end of Phase 2, the ventricular volume is maximal, but the pressure is still low Phase 3: Isovolumetric Ventricular Contraction ▪QRS initiates. ▪AV valves close. ▪Ventricular pressures rise rapidly without a change in volume (before the aortic valve opens). ▪Isovolumetric corresponds to an isometric contraction (no shortening) of skeletal muscle. ▪As left ventricular pressure exceeds aortic pressure the aortic valve opens. ▪Small increase in atrial pressure as atria fill while the AV valve is closed ▪The first heart sounds are associated with the closure of the AV valves Phase 4: Ventricular Ejection Part 1: Rapid Ventricular Ejection •Pressures within the ventricles are high, and volumes are reduced. •Aortic valve is open, AV valves remain closed •Maximal systolic aortic and pulmonary arterial pressures are achieved. •S-T segment (the period between ventricular depolarization and repolarization) Part 2: Reduced Ventricular Ejection •Aortic valve still open, AV valve still closed •Ventricular Repolarization (T wave) •Ventricular pressure decreases •Aortic pressure falls due to blood running off into the arterial tree (blood has moved past the aorta) •Atrial pressures slowly going up due to venous return Phase 5: Isovolumetric Ventricular Relaxation •Aortic valve closes and the AV valve has not opened yet because ventricular pressure is slightly above atrial •All valves are closed → isovolumetric relaxation •Ventricles fully repolarized •Ventricular pressures fall •Dicrotic notch in aortic pressure tracings --> kind of an artifact from when the blood slams back against the valve as it closes (elastic recoil) •End systolic volume (ESV) remains steady •The second heart sound is associated with the closure of the aortic & pulmonic valves

Contrast the fetal vs adult pulmonary circulation and describe the circulatory changes that take place at birth

The fetal pulmonary circulation is high resistance and low flow in comparison to the adult pulmonary circulation. Pulmonary hypoxic vasoconstriction in response to the low oxygen environment in fetal tissue is responsible for high resistance to pulmonary flow. Blood that would have passed through the pulmonary circulation is preferentially directed through the Foramen Ovale (blood moves directly from RA to LA) and Ductus Arteriosus (blood moves from the pulmonary artery to the aorta towards systemic circulation) during fetal life. The blood in the fetus is being oxygenated by the placenta. At parturition, the Foramen Ovale closes, the Ductus begins to close, and the first breath initiates active pulmonary vasodilation. A rapid decrease in resistance allows initiation of pulmonary flow in the neonate within minutes—a very impressive circulatory change!

Name and describe the layers of the heart, heart valves and associated support tissue

The heart is a tubular organ that arises during development as a primary tube that folds. It is made up of chamber walls (cardiac musculature) made of three layers. **have layers, like all tubular organs, whose sizes are relative to their function, genetics and environment** --> Endocardium is like the tunica mucosa + tunica submucosa with endothelium a nd endothelial cells next to the lumen, then underlying subendothelial CT. This layer creates integrity and impulse conduction (contains conducting system). --> Myocardium is like the tunica muscularis with the bulk of the heart having these interlacing bundles of cardiac muscle (striated, tubular, branched, and uninucleated fibers with intercalated disks b/w fibers [adhering junctions of fascia adherens and desmosomes and gap junctions for cardiac AP propagation]). This layer has continuous, non-fenestrated capillaries in the endomysium b/w muscle fibers. The thickness of the wall reflects local forces with the l. ventricle having the thickest myocardium and the r. atrium having a thin myocardium (consistent with the lower pressure generated in atrial chambers relative to ventricles). This includes septae and is important for contraction (involuntary). --> Epicardium is the outer layer and is like the tunica serosa with dense CT and outer mesothelium (visceral pericardium with simple squamous to cuboidal cells and flat, round nucleus, pink cytoplasm mesothelial cells [hyperplastic/basophilic in response to pathologic processes]). It can have variable thickness and adipose tissue. The inner layer also has blood vessels and nerves. This layer reflects back and around to form the parietal pericardium. This forms the serous pericardium (double layer of mesothelial cells separated by pericardial space). The serous pericardium is important for free movement and lubrication as well as the production of pericardial fluid. The fibrous pericardium is dense CT attached to the diaphragm in order to anchor the heart and provide protection. It contains the coronary vessels. The heart has a fibrous skeleton that surrounds and supports valves as an electric insulator and attachment site for muscle. Some species (like cows) have os cordis (cartilage or osseous bone replaces fibrous CT). There is a set of two three-pointed stars that join the fibrous rings. The heart is also made of valves (a CT ring around an opening to create a one-way flow) that attach to the fibrous/cartilaginous/osseous supports at the heart base. The fibrous skeleton extends into the valve. These valves are typically avascular (except their base) because they are surrounded by blood on both sides. Histologically, they are lined with endothelium on both sides with a CT core. There may also be some ground substance to make the valves squishy so they can resist pressure. The atrioventricular valves (mitral and tricuspid) are anchored to papillary muscles with chordae tendinae (fibrous tissue surrounded by endothelium).

Identify and describe the structure and general function of the conduction system of the heart

The heart is an impulse conduction system with autorhythmicity. Some heart cells can rhythmically contract and the intrinsic rhythmicity generates a pacemaker potential. The heart does not require nerve/hormone input to beat. The cells that can rhythmically contract are -->SA (sinoatrial) node is the pacemaker who generates the base signal. It surrounds the sinoatrial artery nodal artery and is made of modified cardiac myocytes (smaller than surrounding atrial muscle cells, few myofibrils and lack intercalated disks). The myocytes appear thinner, squiggly and stain less intensely than normal cardiac myocytes. The base signal can be modulated by the ANS (may see these nerves near it). -->AV (atrioventricular) node -->Bundle of His -->Bundle branches - have fibrous tissue on either side to prevent sideways movement of signal -->Purkinje fibers are found in the myocardium on both sides of the heart. They are really big, have few myofilaments, lots of glycogen (so pale staining) and they conduct impulses ~4 times faster than muscle cells. There is a nucleus but the cross section may miss it.

Review the basic anatomy of the adult mammalian heart, including the names of venous and arterial vessels entering and leaving the heart, cardiac chambers and heart valves and trace the flow of blood through the heart.

The heart is divided into two parts to prevent the mixing of oxygen-rich blood from the lungs and oxygen-depleted blood returning from tissues. These make up two separate pumps that are stuck together but operate at different pressures (the right side is at low pressure). The left and right sides are then split into two chambers (atrium and ventricle) which creates 4 chambers total in the heart. Leaving the left ventricle is the aorta (oxygen-rich blood to tissues), leaving the right ventricle is the pulmonary artereris (oxygen-depleted blood to lungs), entering the left atrium is the pulmonary veins (oxygen-rich blood from lungs) and entering the right atrium is cranial and caudal vena cava (oxygen-deleted blood from tissues). There are valves in the heart that open/close due to pressure differences and ensure unidirectional flow by preventing retrograde flow. Cardiac valves are located at the entrance to and exit from the ventricles: --> Left side of the heart (systemic circulation) - mitral valve (or bicuspid, b/w the atrium and the ventricle) at the entrance and the aortic valve at the exit --> Right side of the heart (pulmonary circulation) - tricuspid valve (or right AV valve, b/w the atrium and the ventricle) at the entrance and the pulmonic valve at the exit. The AV valves will never be opened at the same time as the ventricle exit valves (and vice versa) but they can both be closed at the same time. Cardiac Cycle Deoxygenated blood from tissues comes towards the heart through the vena cava, enters the r. atrium, flows into the r. ventricle and then leaves for the lungs through the pulmonary artery. The now oxygenated blood then heads toward the heart through pulmonary veins, enters the L. atrium, flows into the L. ventricle, and then leaves for the tissues through the aorta. ***It is important to note that during one cycle, there is blood coming into EACH atrium (left and right), moving to the ventricle on its same side and then leaving the heart so that blood is always flowing into both circulations*** 1. Once blood enters the heart into the atriums, it pools because the AV valves are closed. 2. Once the ventricle relaxes, the ventricular pressure becomes lower than the arterial pressure and the AV valve opens which allows blood to flow into the ventricle. 3. The atria then contract and force more blood into the ventricles. 4. The ventricles start to contract, causing ventricular pressures to increase and the AV valves to close (the atrium can then fill with new incoming blood) 5. The pressure within the ventricles increases further and exceeds the pressure within the outgoing arteries. This pressure increase will then open the valves leading to the arteries (ventricle exit valves) and blood flows into the aorta or pulmonary arteries. 6. The ventricle relaxes and the pressure within them becomes lower than the pressure of the outgoing arteries. This causes the valves of the arteries to close. Ventricle relaxation continues until step 2 can occur causing a new cardiac cycle to occur.

Recognize that the renin-angiotensin-aldosterone system, atrial natriuretic peptide and anti-diuretic hormone have direct and indirect effects on cardiovascular function.

The long-term regulation of blood pressure is based primarily on adjustment of the blood volume and is mediated via the kidneys (requires normal kidney function). Increased arterial pressure equals increased urine volume as part of the regulation of blood volume. Hormonal pathways involved in the regulation of blood volume •Renin-Angiotensin-Aldosterone: Involves many organs, decreased arterial blood pressure causes a decrease of renal perfusion pressure which causes the release of renin (a protein from juxtaglomerular cells). Renin will convert angiotensinogen to angiotensin 1 in the kidneys. The lungs and kidneys will then use angiotensin converting enzyme (ACE) to make angiotensin II which then acts to restore blood volume (increased Na+ retention and thus H2O retention). •ADH (anti-diuretic hormone or vasopressin): Vasopressin is released from the pituitary gland and causes vasoconstriction and water reabsorption in the kidney. ADH is stimulated by angiotensin II, low-pressure baroreceptors (i.e., volume receptors) in the atria, increase in osmolarity (increase water reabsorption to try and keep osmolarity constant), and an increase in SNS. •Natriuretic peptides Circulatory adjustments post hemorrhage can illustrate the regulatory mechanisms interacting to maintain normal arterial pressure. A drop in blood volume, venous return, and EDV leads to a drop in arterial pressure 1. Initial responses are aimed at maintaining perfusion to vital organs and normalizing arterial pressure (reflexes here happen very quickly) 2. Long term goal will be to restore normal blood pressure Another important compensatory mechanism following hemorrhage is the mobilization of interstitial fluid into the vessels (acts as a volume buffer). Increased contraction of the arterioles due to increased sympathetic activity will reduce hydrostatic pressure in the capillaries. This then favors the absorption of interstitial fluid into the capillaries. The liver synthesizes plasma proteins aimed at restoring blood volume. Finally, a reduced urinary output occurs due to reduced renal blood flow and increased tubular reabsorption. These final steps are slow mechanisms that are occurring.

Describe the normal distribution of ventilation and perfusion in the lungs of a human sitting at rest. Understand how the existing ventilation and perfusion distribution data for quadrupeds differs from the observations in the human

The lungs are composed of hundreds of millions of alveolar-capillary units, and in each of these, ventilation and perfusion may not be perfectly matched. This will cause incomplete gas exchange, and the arterial oxygen partial pressure will not equal that in alveolar gas. In upright bipeds, incoming fresh gas is distributed preferentially, due to gravity, to the more ventral alveoli, because they are initially less distended and therefore more compliant. Apical alveoli are more stretched out and less compliant. They receive less of the incoming ventilation. In the human, ventilation is greater in the more ventral portion of the lungs. This means that there is a non-homogenous distribution of ventilation in humans. Perfusion is not homogeneously distributed throughout the lungs. Because of gravity effects, there are zones of flow with perfusion being greater in the ventral portion of the lungs in upright humans. Exercise will make the flow more homogenous as there is more energy to move the blood against gravity. Experimental data in quadrupeds indicate that gravity is not the major determinant of blood flow, and in fact flow appears to be greatest in the dorsal portion of the lungs. Perfusion and ventilation are almost uniform in dogs.

Recognize important physiological functions of the lymphatic system

The lymphatic capillaries (little, blind-end, single cell wide tubes) lie in the interstitial fluid, close to the vascular capillaries. They possess one-way flap valves (valve to the interstitial fluid), which permit interstitial fluid and macromolecules (lg. proteins, glycosylated proteins, etc.) to enter, but not leave, the capillaries. These clefts between the endothelial cells are large enough for macromolecules to pass through. They also have internal valves to ensure unidirectional flow of lymph fluid. Capillaries merge into larger lymphatic vessels and eventually into the thoracic duct, which empties lymph into the large veins (usually the internal jugular vein). The overall function of the lymphatics is filtration/absorption and to regulate the distribution of the extracellular fluid. The interstitial fluid is essentially a blood volume buffer that helps to stabilize blood volume. The lymphatics are preventing the accumulation of protein in the interstitial fluid (picks up protein and recirculates it). Lymphatic fluid flow (slow) is due to: •Skeletal muscle contraction --> a lot is done by these muscles squishing the lymphatics and thus squeezing the fluid along •Smooth muscle contraction of large-bore lymph vessels (little bit) •Valves to maintain unidirectional transport •The suction effect of high velocity blood flow in the veins in which the lymphatics drain (faster velocity in veins compared to lymphatics) Lymphatic Fluid Composition Lymph is a clear-to-milky white liquid with a composition similar to blood plasma (except that lymph is acellular). White opacity of lymph correlates with lipid composition. Large proteins from the extracellular matrix are picked up by the lymphatics as they are repaired/recycled because they are too large to enter circulation on their own. This is why many large therapeutic proteins administered subcutaneously are picked up by the lymphatics before entering the circulation. The lymphatics facilitate absorption of lipid products (fatty acids, monoglycerides, and cholesterol) in the small intestine by transporting chylomicrons & fat-soluble vitamins from the intestinal cells into the general circulation. The lymphatics also play a role in inflammatory processes through their transport of white blood cells.

Discuss the pacemaker and AP in the SA node (added by me)

The membrane potential in the non-contractile cardiomyocytes is not stable, but depolarizes slowly (drift of membrane potential = pacemaker potential) until reaching the threshold value (-40 mV) for generating another AP. The cells of the SA node continuously repeat the following sequence throughout life, without interruption. ① When the membrane potential is at -65 mV, the f-channels, which are permeable to both Na+ and K+, open ➔ Na+ flows into the cell --> The electrochemical gradient is much greater for Na+ than K+ ② The membrane slowly depolarizes, the f-channels close, the voltage gated Ca2+ channels open, and Ca2+ flows into the cell ➔ cell depolarizes further, and threshold is reached ③ Another type of Ca2+ channels open, and Ca2+ flows into the cell causing the steep phase of depolarization --> Major difference between cardiac cells and other excitable cells! The steep phase of depolarization is due to Ca2+ influx, NOT voltage gated Na+ channels ④ Ca2+ channels close, and slow K+ channels open K+ current from the inside to the outside of the cell repolarizes the cell to -65mV ⑤ Slow K+ channels close at -65mV and the f-channels open

List the cell types present of the epithelium in the nasal cavity and larynx.

The nasal cavity is a high surface area which makes it good for filtration (impaction), warming/humidification and olfaction. There are 4 regions to the nasal cavity Cutaneous (SE): continuation of nasal skin with stratified squamous epithelium (cornified/keratinized rostrally and then transitions to non-keratinized) supported by bone or cartilage Transitional (TE): this is a relatively short region between the SE and RE region made of stratified cuboidal (non-ciliated) Respiratory (RE): made of pseudostratified columnar ciliated epithelium (wasn't present in previous two zones) and goblet cells --> these cells also line the guttural pouch and sinuses **there may also be non-ciliated "brush cells" w/ short apical microvilli, non-ciliated serous cells, basal cells and neuroendocrine cells (In solitary or small clusters with granules of biogenic amines. Used for oxygen sensing and contribute to regulation of airway and vessel tone) Olfactory (OE): the olfactory epithelium is made of sustentacular cells, olfactory sensory neurons (bipolar neurons, stereocilia w/ chemoreceptors, axons from basal poles form CN 1) and basal cells (regenerate olfactory sensory neurons) -- there are also Bowman's glands that clean the chemoreceptors Next is the larynx made of non-keratinized stratified squamous on the vocal fold (supported by skeletal muscle) and then respiratory epithelium caudal to the vocal fold. The vocal folds are bulges responsible for sound production. There is laryngeal cartilage (hyaline and elastic cartilage) and then lymphocytes, plasma cells, and mast cells strategically placed in the CT of the lamina propria.

Be able to draw (with labeled axes) the Hb-O2 dissociation curve for a mouse and an elephant on the same graph

The respiratory system of mammals must adapt to provide adequate gas exchange for animals of widely varying size and metabolic rate. The smaller you are, the higher the metabolic rate per body mass. Hemoglobin affinity for oxygen varies among mammals of different size and metabolic rate (produce different hemoglobin molecules with varying O2 binding affinities). Smaller species have an oxygen-Hb dissociation curve that is right shifted relative to larger species. This means that there is a lower O2 binding affinity from hemoglobin which facilitates oxygen delivery to tissues in smaller species with greater oxygen demand. Larger species have a lower metabolic rate and thus they do not need to get O2 to tissues as quickly (Hb-O2 curve shifts left because there is a higher O2 binding affinity so hemoglobin holds onto the O2). There is essentially a linear relationship between body mass and lung volume. This means that one can make a relatively accurate estimate of lung volume in species for which you have no anesthesia experience.

Discuss the basics of how air gets into the lungs, the characteristics of airflow, and dynamic airway compression (added by me).

The space between the ribs and lungs (intra-pleural space) normally has negative pressure. This space creates a vacuum and allows the lungs and the chest wall to move together so that the lung movement is passive. When the diaphragm moves down and the ribs move up and out, the intra-pleural pressure becomes more negative and air flows into the airways. When the diaphragm relaxes and the ribs move down and in, the intra-pleural pressure is less negative, and air flows out of the lungs. In larger airways, there is bulk flow, but as the total cross-sectional area increases as the air bolus moves out into the peripheral airways, the air stream velocity decreases. In the alveolar region, air movement is by diffusion. When the lungs are auscultated, one can hear turbulent flow in the large airways, but diffusion into the alveoli is a silent process. Turbulence in the flow often occurs at large airway branch points. Turbulent flow generates more sound than laminar and contributes to what we hear during auscultation. Remember that the flow of air, in L/minute, through airways depends on the pressure change driving the air movement and is inversely proportional to the resistance to flow (V=P/R). Resistance is caused by friction of air molecules with the airway walls. Resistance to flow is inversely proportional to the 4th power of the airway radius. (R proportional to 1/r^4). This is a very powerful relationship, and it means that any factor that makes airways even a tiny bit narrower will vastly increase the resistance to flow and thus the work of breathing. In chronic bronchitis, there is smooth muscle contraction in the wall of the airway as well as filling of the wall with inflammatory mediators. This causes the radius of the airway to decrease causing resistance to increase. The air flow will then be decreased and a much larger pressure will be required to bring air in. As a patient exhales, pressures in the lung become positive. If the patient forces and exhalation, significant positive pressures may be achieved, and these tend to compress the airways. If the airways are supported by cartilage, they will remain patent. If, however, the pressure outside the airways exceeds airway pressure in small airways without cartilage support (as diagramed on the right), the airway may collapse. This is called dynamic airway compression. Once the patient inspires and pressures around the airway become negative, it will be pulled open.

Explain the basics of respiration (added by me). Explain what anatomical dead space is and be able to calculate what portion of the total ventilation is dead space ventilation

The two main respiratory system functions are ventilation (transport of gas from the environment to the gas exchange region in alveoli) and gas exchange (oxygen diffusion from the alveolar space to circulating blood for transport to body tissues). In the larger airways, the wall is thick and has cartilage, mucus glands, connective tissue, and a tall epithelial layer. In smaller airways, the epithelium is not as tall, the cartilage and mucus glands are no longer present, and the connective tissue layer is thinner. Both of these conducting airways have walls too thick for gas exchange to occur. In the alveolar region, there is only a thin basal lamina between the alveolar epithelial cells and capillary endothelial cells in the gas exchange region. In the alveolar region of the lungs there are few major cell types: Type I and II epithelial cells, capillary endothelial cells, and alveolar macrophages. Type I cells are flat and thin so they stay out of the way of gas exchange. Type II cells can divide and are more plump, so they get in the way of gas exchange. Capillary vessels in the lung parenchyma wrap around alveoli which allows for maximal surface area for gas exchange. Dead space is any part of the lungs where ventilation occurs without gas exchange. Anatomical dead space is the conducting airways (trachea, bronchi), where airway walls are too thick for gas exchange to occur. A giraffe has a lot of anatomical dead space because they have a very long trachea. Dead space also occurs when circulation has been lost to a part of the lung parenchyma. For example, this can occur due to a pulmonary embolism that occludes blood flow. In such an area there is ventilation but no blood flow and no gas exchange. Anesthesia equipment, for example an extra long tube, can contribute to dead space. In a patient being ventilated, the additional dead space must be accounted for when the anesthesiologist calculates the optimal tidal volume to deliver to the patient. ** Minute volume (VE ) is the amount of gas entering and leaving the respiratory system per minute. Minute ventilation includes both dead space ventilation (for example ventilation that remains in the conducting airways) and alveolar ventilation (the gas that actually participates in gas exchange) V_E = V_A + V_D Minute ventilation can be easily calculated as the resting tidal volume (V_T) * the respiratory frequency (breaths/minute). This minute ventilation can be used to calculate the portion of dead space ventilation if you know the alveolar ventilation.

Be able to list the mechanisms for O2 and CO2 transport in blood

There are 2 mechanisms of oxygen transport in blood. Oxygen can be carried in solution, but it is very poorly soluble in plasma (0.003 ml/100 ml blood/mmHg PO2) so it is constantly trying to jump out of solution. Oxygen is also transported bound to hemoglobin (the more important transport mechanism 1.34 ml oxygen binds /g of Hb) with cooperative binding (as more O2 binds, it increases the O2 affinity to hemoglobin). Oxygen carried in solution in blood is in equilibrium with oxygen bound to hemoglobin. High O2 in solution must mean that the O2 binding sites of Hb are pretty full otherwise they would be binding to HB. In the lungs, oxygen diffuses across the air-blood barrier into plasma, where it is in solution. It then diffuses into an erythrocyte, where it combines with hemoglobin if a binding site is available. In the peripheral tissues oxygen diffuses down its concentration gradient from erythrocytes, back into solution and then across the vessel wall to the peripheral tissue cells. We directly measure oxygen in solution in plasma to determine the PO2. We can directly measure the concentration of Hb in a blood sample. However, we infer the state of hemoglobin saturation from the PO2. If the patient is anemic, there is less Hb, but PO2 in plasma can still be high, then oxygen content of the blood will be decreased. There are 3 methods by which carbon dioxide is transported in blood. The first is in solution (20 x more soluble than oxygen). The second is bound to the amino group in the Hb molecule (does NOT displace oxygen) at a small amount. The third is diffusion into a red cell, combination with water to form carbonic acid (catalyzed by carbonic anhydrase), and then spontaneous dissociation into H+ and bicarbonate. Bicarbonate than leaves the RBC as Cl- enters (Chloride shift). Transport as bicarbonate is how the vast majority of CO2 occurs. After blood circulates from the peripheral tissues back to the lungs, the carbon dioxide diffuses out of blood into alveolar gas where it is removed during exhalation. Bicarbonate will be converted back to CO2 through the reverse reactions in the RBC. The amount of CO2 in solution is in equilibrium with that carried by the other possible mechanisms. You can measure the CO2 in solution or the HCO3- value. **CO2 is the best measure for alveolar ventilation adequacy** If alveolar ventilation is inadequate, then CO2 can't get out and the HCO3 -->CO2 reaction is stuck giving us a lot of bicarbonate.

Explain the organization of the pulmonary vascular system and macrophages

There are three types of macrophages 1. Alveolar Macrophage: in alveolar space, large, round cell, leave by MCE or lymphatics --> they function to phagocytize organisms & debris, clears surfactant, and cytokine production (generally suppress inflammation and able to adapt to environmental signals rapidly and reversibly) 2. Interstitial Macrophage: in interstitium of alveolar septa 3. Pulmonary Intravascular Macrophages: in the pulmonary capillary, proinflammatory (stimulated by LPS, bacteria and others) and found only in horses, ruminants, pigs, and cats Dual blood supply --> Pulmonary arteries from right side of heart (low O2) --> Bronchial arteries from systemic circulation (high O2) **Anastomoses** Pulmonary veins --> Travel with pulmonary arteries and airways in ruminants, pigs, horses --> Veins travel separately in dogs, cats, humans

Identify the electrically excitable elements of the heart

There are two types of cardiomyocytes: Contractile -Vast majority (> 99%) -Like skeletal muscle these cells have a stable resting membrane potential and must be stimulated to initiate contraction➔ action potentials in these cells lead to generation of force -Unlike skeletal muscle, these myocytes contract due to depolarizing currents that enter through gap junctions. (not through innervation) -Atrial and Ventricular Conduction -Concentrated in certain areas of the heart --> SA node, atrial internodal tracts, AV node, Bundle of His, Purkinje fibers -Generate spontaneous APs by undergoing slow depolarization on their own until they reach threshold ➔ autorhythmically --> most of the time the cardiac rhythm is made by the SA node but other areas can do it -They don't generate force when they depolarize

Understand how to calculate the partial pressure of a gas, knowing its fraction of the total pressure. Know the value for total barometric pressure and understand under what circumstances it would change.

These symbols are used commonly in respiratory physiology. The use of a dot over a symbol indicates a time derivative (ex. gas flow in L/min). Gas partial pressures can be measured at various sites in the respiratory system. Sites of Measurement- Gas I = inspired E = expired A = alveolar T = tidal D = deadspace Sites of Measurement- Blood a = arterial v = venous ῡ = mixed venous (mix of venous drainage from different parts of body) c = capillary Dalton's law (P_ALV = P_H2O + P_O2 + P_CO2 + P_N2) states that in a gas mixture, the partial pressure of each component gas is independent of the others, and all will sum to the total gas pressure, in this case, the barometric pressure of 760 mmHg. The partial pressure of oxygen in a gas mixture depends on the total pressure and the fraction of the mixture that is made up of oxygen P_O2 = F_O2 * P_total where P_total = 760 mmHg **So if the total barometric pressure is 760 mmHg and the fraction of ambient air that is oxygen is 21%, you multiply 0.21*760 and thus, the partial pressure of oxygen is 160 mmHg.

Be able to diagram the alveolar-capillary relationships for a normal exchange unit, for a dead space unit, and for physiological shunt. Use the diagram to explain how V/Q mismatch contributes to hypoxemia.

This diagram shows a normal alveolar-capillary unite in the center where ventilation and perfusion are well matched. Gas exchange is maximal, and the blood leaving this unit has gas partial pressures exactly equivalent to those in the alveolar gas. Gas exchange has been complete. On the right is an alveolar-capillary unit where the airway has become occluded, and ventilation has deteriorated to zero. Thus V/Q = 0, and the unit is effectively a shut area where blood passes from the venous circulation to the arterial with no gas exchange (a shunt). The blood leaving this unit has a gas partial pressure the same as those in venous blood meaning it has low O2. It will then mix with other blood passing by different alveoli and we will have a mix of venous and arterial blood (hypoxemia because of low O2). We can also have the more common situation of ventilation being decreased, but not 0. The blood coming from this unit has lower than normal oxygen partial pressure, causing a low V/Q and it will contribute to hypoxemia as well. This decreased ventilation can be caused for a number of reasons. We can have a lung with parenchymal disease (like pulmonary fibrosis) that causes the lungs to be stiff (restrictive) and poorly compliant. It takes more work to inflate the lung so during inspiration, not as much air is brought into the lung, and thus ventilation is reduced. We can also have a lung with airway disease that partially obstructs the flow of air into the lung (obstructive). During inspiration, the air flows in very slowly, and by the end of inspiration, a lower volume has entered the lung--decreased ventilation. *****When we have a situation where ventilation is decreased, there will be a reflex of pulmonary hypoxic vasoconstriction. This tends to reduce blood flow to this poorly ventilated region of the lung so it can go to other well-ventilated regions. Clinically we often administer drugs that affect the protective hypoxic vasoconstriction reflex, like nitric oxide, which acts as a pulmonary vasodilator. Because the gas is carried to the well-ventilated alveolus, the adjacent capillary bed is vasodilated, improving gas exchange. There is the risk that the vasodilator will also reach the poorly ventilated alveoli and increase blood flow to this region, in which case gas exchange will not be improved. Hypoxemia from larger shunts are not responsive to supplemental oxygen. On the left is a unit that has lost its blood supply due to a pulmonary embolism so we have no perfusion. It is effectively dead space, because there is no opportunity for gas exchange, although ventilation is excellent. The ratio of V/Q is infinity, and there is no blood leaving the unit contributing to the arterial blood gas partial pressures. The blood that would've gone through this path is most likely diverted to another pathway where it will still become oxygenated and create a high V/Q. There are cases where the alveoli that have been passed because of a pulmonary embolism, will pump out inflammatory mediators that decrease ventilation (low V/Q) and cause hypoxemia. It is more common to have a situation in which perfusion to the area is decreased rather than fully 0. In this case, the blood leaving the area is well-oxygenated so we get a high V/Q.

Know the PO2 and PCO2 of ambient air at sea level, of inspired air, and of alveolar gas

This diagram shows partial pressures of oxygen and carbon dioxide in inhaled gas, alveolar gas, venous blood and arterial blood. Remember that pulmonary vessels are named anatomically, and the pulmonary artery carries "venous" blood (in terms of gas partial pressures), while the pulmonary vein carries "arterial" blood. Inspired air has a P_O2 of 150 mmHg because it has been humidified. When we reach the alveolus there is a lower P_O2 because the inhaled air mixed with the residual volume already in the alveoli. This mixing is also why the P_CO2 has increased in the alveolus from the inhaled air. The blood then moves out of the lungs to the heart and then tissues where it releases O2 and consumes CO2 from the tissues. This is then brought back to the alveolus which takes the CO2 and gives the blood the O2.

Define a pneumothorax and explain why it can be a life-threatening lesion

This diagram shows the space between the visceral and parietal pleura, which normally has a slight vacuum. Pneumothorax occurs when there is a defect in the chest wall which has allowed air into the pleural space, and the pressure is no longer negative. As a consequence, the lungs have collapsed, and the patient can no longer ventilate by negative pressure. The chest wall also expands because this air results in the loss its recoil connection with the lung. A surgery that introduces air into this interpleura vacuum causes a loss of negative pressure, so positive pressure must be applied until the air leak is sealed and negative pressure returns.

Explain how inadequate ventilation affects plasma [H+]

This diagram shows tissue cells producing CO2, which diffuses into tissue capillaries and is transported predominantly as bicarbonate to the lungs for removal. The combination of CO2 and water to form carbonic acid and then bicarbonate within erythrocytes generates H+, which can diffuse out of the RBC and change the acid-base balance in blood by affecting the pH. The bicarbonate in the plasma can also affect the acid-base balance. In pulmonary capillaries, CO2 diffuses from capillary blood into alveolar gas for removal by alveolar ventilation. This reverses the acid-base changes, and as long as alveolar ventilation is adequate, plasma pH does not decrease (successfully regulating acid-base status). If there is inadequate ventilation, then the acid-base changes will not be reversed and the plasma pH will decrease. If the reaction moves to the right (towards more bicarbonate formation rather than CO2 formation) because CO2 removal by alveolar ventilation is inadequate, the [H+] will increase (respiratory acidosis).

Be able to draw (with labeled axes) a reasonable Hb-O2 dissociation curve. List the variables that would shift this curve. Contrast the Hb-O2 curve with the CO2 dissociation curve for whole blood.

This important diagram shows the shape of the oxygen-Hb dissociation curve. Basically, the relationship between oxygen partial pressure (horizontal axis) is non-linear with Hb saturation (vertical axis). Percent Hb saturation can be measured by a pulse oximeter (want it to be 95-97%) and it diverges quite a bit from PO2. The sigmoid shape of the curve facilitates oxygen binding at the alveolus even if the alveolar oxygen partial pressure is not optimal. It also facilitates oxygen unloading from Hb to the tissues in peripheral capillaries where PO2 is lower. At high PO2, the curve is relatively flat, so if it drops a little, we don't lose much binding. Note the tiny amount of dissolved oxygen indicated on the diagram because of how insoluble O2 is in solution. Note also the right portion of the horizontal axis where an oxygen partial pressure of 600 mmHg is indicated. At this very high oxygen partial pressure, the Hb is completely saturated and oxygen is being driven into solution. Because of its poor solubility, the total oxygen content (right vertical axis) is only slightly increased at this high partial pressure. If the local pH drops or temperature increases, the affinity of Hb for oxygen decreases (right shift) allowing more oxygen to be unloaded to the tissues. This can occur from increased anaerobic exercise producing more lactate. An increase in pH or temperature decrease (left shift) represents tighter affinity of Hb for oxygen, and less delivery to peripheral tissues. A good example of a left shift is fetal hemoglobin or methemoglobin (Fe3+ instead of Fe2+). **Unlike the relationship with oxygen, the one between PCO2 and %CO2 volume is nearly linear in the range of CO2 partial pressures seen in life. Note that bicarbonate is the major mechanism of carbon dioxide transport.

Define the subdivisions of total lung capacity and understand which ones can be directly measured in the pulmonary function lab and which ones will change with increased activity.

Total lung capacity is the total amount of gas within the lungs. Vital capacity is the air that can be exhaled after a human patient inhales up to total lung capacity. Residual volume is the gas that remains in the lungs after such a maneuver (your lungs are not gas-free after you exhale). The residual volume cannot be exhaled voluntarily. Tidal volume is the amount of air moving in and out of the lungs during normal resting ventilation. With exercise, tidal volume increases. Lastly, Functional Residual capacity is the gas remaining in the lungs at the end of a resting tidal breath. Spirometry is the process of measuring lung volumes, such as vital capacity and tidal volume in a conscious cooperative human patient. **You can only measure exhaled volumes**

Explain 2 ways by which the lungs can be inflated. Under what circumstances would each be used?

Ventilation, the process of getting air into the lungs, is profoundly affected by the mechanical properties of lung tissue, and changes with lung disease will affect ventilation. The inflation of the lung is passive (relies on the attachment to the chest wall and the movement of the chest wall out to pull the lung open). In the tissue next to the lumen of the airways, there is very little tissue and it contains elastin (for lung recoil) and collagen (to determine how stretched the lung will be). There is a connective tissue network that exists in all of the interconnected alveolar walls. When one portion of the lung is inflated, the collagen and elastin fibers are stretched out, and this pulls on the connective tissue in neighboring alveoli, helping them to inflate also. This tethering helps to make lung inflation uniform and also to pull airways open as the lung tissue is inflated. The lungs can be inflated naturally by negative pressure or artificially (CPR, synthetic O2) by positive pressure. Negative pressure can inflate the lungs because of alveolar interdependence where we see connective tissue "tethers' off the alveoli as they attach to the walls of the airways. In the normal lung, inflation of the lung tissue will help pull the airway open. You can think of the negative interpleural pressure as attaching the lungs to the chest wall as if with springs. When the chest wall expands during inspiration, the lungs are pulled open, and air rushes in through the airways. As the chest is pulled up and out and the diaphragm flattens, a vacuum is created in the lungs that helps pull air in and inflates them. Positive pressure is blowing air into the lungs in order to manually inflate them (like CPR).

Explain why V/Q mismatch has more of an effect on PaO2 than on PaCO2

Ventilation/perfusion mismatching, especially in areas of low ventilation, cause hypoxemia out of proportion to the degree of hypercarbia (high PCO2). The increasing PCO2 is the main trigger for faster ventilation. The patient can maintain their CO2 levels at normal by hyperventilating, while the oxygen levels may slightly increase but remain in the hypoxic range. Even with mild V/Q mismatching, the oxygen partial pressure drops to a hypoxemic level. At this same point, the CO2 has not increased above normal. As the V/Q mismatch increases, the difference between the 2 gases continues, although severe V/A mismatch will result in an increase in carbon dioxide partial pressure. We can give patients enriched oxygen mixtures to alter their arterial oxygen partial pressures at different levels of V/Q mismatch. When a normal patient breathes higher than normal oxygen levels, their oxygen partial pressure increases dramatically. Above 100 mmHg, there is not a significant increase in oxygen content in the blood because Hb has been saturated. Once Hb is saturated, the oxygen content of blood does not increase much as oxygen goes into solution (very insoluble). Thus, even in very well-ventilated or over-ventilated alveoli, there is a limit to the amount of oxygen that can be loaded into the blood. CO2 has a nearly linear relationship between partial pressure and content in the blood. There is also no limit to the amount of CO2 that can be "blown off" and removed from the blood by ventilation. The patient with mild or moderate V/Q mismatch, however, who begins in the hypoxemic range, benefits greatly from breathing enriched oxygen, especially in the oxygen partial pressure range up to 100 mmHg, where oxygen is being loaded onto Hb. Above this point, oxygen is being driven into solution, and the content change is minimal. The patient with severe V/Q mismatch is refractory to the benefits of breathing enriched oxygen because the ventilation is so poor that the inspired oxygen may not reach the gas exchange regions. **You can look at a V/Q perfusion scan as well which illustrates the V/Q ratios across the lung. This allows you to see where in the lung the V/Q ratio is deviating from normal to better address the underlying cause.

Be able to calculate oxygen content of blood under varying conditions of PO2 and hemoglobin concentrations

We can calculate the amount of oxygen carried in solution in blood using the equation (0.003 mL O2/ 100 mL x mmHg PO2) * mm Hg PO2. Note that one needs to multiply by the total oxygen partial pressure. The total amount of oxygen carried in solution is very small because of its poor solubility. We can calculate the amount of oxygen carried bound to Hb using the equation (g Hb/100 mL) * (1.34 mL O2/g Hb) * SaO2 Note that one needs to multiply by the % saturation of the Hb (SaO2) and that a normal amount of hemoglobin is 15 g Hb/100 mL. Total oxygen content in arterial blood means that you must add the oxygen bound to hemoglobin with the oxygen in the solution.

List 3 factors that determine fluid flux out of capillaries and explain how 2 of these commonly cause clinically significant pulmonary edema

.Permeability of the capillary membrane, hydrostatic pressure and oncotic pressure together determine fluid flux out of capillaries. The hydrostatic pressure generated by right ventricular contraction provides for some movement of fluid out of the capillary. Interstitial pressure (affects hydrostatic pressure) in pulmonary tissue varies with the respiratory cycle, but is probably mostly negative, which augments fluid exit from the capillary. Oncotic pressure is due to plasma proteins, and acts to keep fluid within the capillaries. Fluid that does leave the capillary for the interstitium is carried away by pulmonary lymphatic drainage, and does not impede gas exchange. When fluid drainage from pulmonary capillaries exceeds the capacity of lymphatics for removal, the fluid accumulates around large blood vessels (in the perivascular space) and airways. This keeps fluid out of the gas exchange region and minimizes the clinical effects of early pulmonary edema. Cardiogenic pulmonary edema is when the pulmonary hydrostatic pressure is increased possibly due to left ventricular failure or mitral valve regurgitation. When the pressure downstream increases (if LV fails to efficiently pump blood out into the systemic vessels), the pressure on the walls of pulmonary vessels increases and fluid begins to move out into the interstitium (fluid begins to leak out into the interstitial space). The oncotic pressure relationships are unchanged, but an elevated pressure would be obtained from a capillary wedge pressure measurement. Adult Respiratory Distress Syndrome (non-cardiogenic pulmonary edema) is where permeability of the pulmonary capillary endothelium has increased due to the effects of toxins in the circulation. The oncotic pressure relationship is changed because proteins can easily leave the vascular space between leaky endothelial cells. The hydrostatic pressure relationships are normal. This cause of pulmonary edema is much more difficult to treat clinically because of the protein loss into the interstitial space and sometimes into the alveolar airspace.

Correlate the structure of vessels, including the different types of capillaries, with their function

Veins and arteries often travel together with their liked size arteries/veins. Nerves also often run with the arteries and veins in this neurovascular bundle. **Microcirculatory beds are made up of the arterioles, capillaries, and postcapillary venules** Arteries (conductance and distribution) -->Elastic arteries: Largest conducting arteries (Aorta, pulmonary arteries, common iliac, brachiocephalic, common carotid, subclavian), walls contain multiple sheets of elastic lamellae so that they can expand and hold more blood (Internal & external elastic membranes are indistinct), and the expansion and recoil of the elastic fibers allow for smoother flow (help push blood along artery) -->Medium/muscular arteries: include brachial, anterior tibial, and coronary arteries -- the Tunica intima is thinner and often appears undulated (don't see much CT), there is prominent IEL +/- EEL, and the Tunica media has more smooth muscle and less elastin (can still stretch but good at contraction to push blood along) -->Small arteries: 6-10 smooth muscle layers and contain an internal elastic lamina -->Arterioles: create resistance in order to regulate how much blood flows into capillary beds (slight thickening before capillary bed = precapillary sphincter which can dilate up to 60-100% or maintain 40% contraction) --contain 1-2 (occasionally more) layers of medial smooth muscle (thin tunica media), have a tiny lumen (often do not need much contraction to close it), inconsistent presence of internal elastic lamina and there is a thin, indistinct adventitia (most of the time you can't really see it) Veins (Conductance and Collection) ***Veins are different from arteries because their tunics are not as distinct, they have larger lumina (larger internal diameter for same external diameter) with thinner walls, more adventitia, less muscle (smaller media), and contain bicuspid flap valves made of elastic tissue (to prevent backflow when further from the heart -- tissue [esp muscle] pumping to assist in blood return). They are also floppier. -->Large veins (parallel elastic artery) include a cava, jugular, renal, pulmonary, and portal veins -- diameter is > 10 mm, Tunica media is thin but present, and the Tunica adventitia is the thickest layer -->Medium Veins (parallel muscular artery): Diameter is up to 10 mm, may contain valves, and the 3 tunics are evident (but NO IEL) -->Small veins (parallel small artery): Thin tunica media is very little with 2-3 muscle layers, diameter is up to 1 mm, and they do NOT have IEL (small artery does have IEL) -->Postcapillary Venules: receive blood from capillaries and are important in inflammatory response (emigration of leukocytes) -- structure similar to the capillary but wider lumen, diameter 0.2-0.5 mm, have endothelium, pericytes, & connective tissue, no true tunica media (no smooth muscle), and fewer cell junctions b/w endothelium (target of vasoactive agents) Capillaries (Diffusion and Gas Exchange) Made of a thin wall w/ a diameter barely large enough to accommodate an erythrocyte. Capillaries are lined by single endothelial cells w/ blood cell lumen. Erythrocytes travel in the same direction as the blood vessel and often have to stack up in a single file b/c of the small capillary diameter. -->Continuous capillaries (most tissues) have a pretty solid wall, tight junctions (things that diffuse out are highly regulated), continuous basement membrane, and pinocytosis & receptor-mediated endocytosis. -->Fenestrated Capillaries (kidney, endocrine organs, ciliary process of eye) are designed to let things out because of their fenestrations (holes) in the endothelial cells (sometimes covered by a thin membrane). They have a continuous basement membrane (H2O, glucose, AAs, and CO2 can still get through but cells cannot). -->Sinusoidal Capillaries or leaky capillaries (liver, spleen, bone marrow) are really permeable in order for there to be an exchange of large molecules and sometimes cells. There are large endothelial gaps and a discontinuous basement membrane to create this permeability.

Discuss the importance of special circulations including the coronary circulation, pulmonary circulation, fetal circulation, and the blood brain barrier.

Fetal Circulation The lungs of a fetus do not need nearly as much blood because they are not performing a gas exchange function in the fetus (fetus is not breathing air). Some blood will then bypass the lungs (still need some blood to lungs for developmental needs). There are two anatomical shunts in the fetal heart. --> Foramen ovale moves blood from the right atrium to the left atrium because no need to go to the right ventricle and then the pulmonary artery --> Ductus arteriosus moves blood from the pulmonary artery to the aorta because no need for the blood to go all the way up to the lungs Since the lungs are not functioning, but the heart still needs oxygenated blood, the umbilical vein will carry oxygen-rich blood to the fetal heart. The umbilical artery will then carry oxygen-depleted blood away from the fetal heart. So, umbilical vessel nomenclature is relative to the FETAL heart, not the maternal heart! There is also another shunt in fetal circulation using the ductus venosus to bypass the liver in order to shunt oxygenated blood to the developing fetal brain. Coronary Circulation Coronary arteries originate at the base of the aorta (close to the aortic valve) and bring oxygenated blood to the heart itself. Coronary veins bring deoxygenated blood from the heart itself back into circulation and will drain into the coronary sinus which drains into the right atrium. The heart is one of those organs that receives a disproportionately large blood supply (0.4% of body mass, 4% of cardiac output, 10-12% total oxygen consumption at rest). The myocardium has a limited capacity for anaerobic metabolism so it requires a relatively high blood supply and extracts a high percentage (70%) of O2 from capillaries at rest (the rest of the body extracts 25% of O2 from capillaries). Coronary blood flow decreases in systole (contraction of the heart muscle) because the arteries are compressed and blood. Blood flow increases in diastole (relaxation of the heart muscle) with the peak blood flow occurring at the beginning of diastole. The heart uses a process called autoregulation to maintain blood flow when diastole is shortened due to a higher heart rate. Blood-Brain Barrier The purpose of the blood-brain barrier is to protect brain cells from fluctuations in the composition of blood. It is made up of the capillary wall, pericytes, and extensions of astrocytes. Lipid-soluble substances can easily cross (O2, CO2, ethanol) the barrier while water-soluble substances require specific transporters. Capillaries (comprised of endothelial cells connected by tight junctions) usually permit some passage of all dissolved substances in the blood except proteins but this is not the case in the central nervous system (where the blood-brain barrier is located). Pulmonary Circulation This circulation is special because it is the exception to the rule that veins carry deoxygenated blood and arteries carry oxygenated blood. In pulmonary circulation, the arteries leaving the heart and going to the lungs carry deoxygenated blood while the veins going to the heart from the lungs carry oxygenated blood.

Contrast the pulmonary arterial and systemic arterial circulations with respect to pressure, vessel compliance, and response to local hypoxia.

The right ventricle pumps the deoxygenated blood through the pulmonary artery to the lungs where it undergoes gas exchange. The now oxygenated blood then returns to the left atrium via the pulmonary vein. There is less cardiac muscle in the RV than in the LV, but the RV must pump the same volume of blood per unit of time. Part of the reason it can do this is because the RV is dealing with blood at a much lower pressure than the LV. A big difference with pulmonary circulation is that all the blood will move through the lungs where as in systemic circulation not all of the blood will go to all of the tissues. Also, the arterioles in the pulmonary circulation do not have such a flow regulating function as in systemic circulation and thus have less smooth muscle in their walls. Pulmonary vessels are more distensible than vessels in the systemic circulation and generate less resistance to flow than systemic vessels. Blood pressure measurements are often done in systemic circulation but are difficult to do in the pulmonary circulation. Pulmonary capillary endothelial cells are metabolically quite active. They activate Angiotensin I, and inactivate many potent inflammatory mediators on a single pass through the lungs. This limits the duration of action of these mediators. The pulmonary circulation receives the entire cardiac output, and thus, there is ample contact of endothelial cells with the circulation, allowing metabolism of active mediators. Injury to these endothelial cells can interrupt the balance between vasodilation and vasoconstriction. Local Hypoxia Smooth muscle cell mitochondria in pulmonary arterioles are thought to be the most likely sensor organelle of local hypoxia, and the response is likely mediated through reactive oxygen species that result in increased intracellular Ca++ and muscle contraction (pulmonary hypoxic vasoconstriction). This vasoconstriction is response to hypoxia is opposite the response of vasodilation in systemic circulation. In pulmonary circulation, vasconstriction is helpful because it reduces blood flow to the poorly ventilated region of the lung so that the majority of the blood will be diverted to functioning and normal alveoli. This ensures that there is as much successful gas exchange occurring as possible. Clinically we often administer drugs that affect the protective hypoxic vasoconstriction reflex. Patients breath nitric oxide, which acts as a pulmonary vasodilator. Because the gas is carried to the well ventilated alveolus, the adjacent capillary bed is vasodilated, improving gas exchange with the functioning alveoli. However, there is a risk that the NO goes to the poorly ventilated alveoli and causes vasodilation. In this scenario, gas exchange is not improved because more blood is flowing passed the alveoli with low O2, so the blood is remaining deoxygenated. **Cells and tissues in the lung tissue and airways are supplied by the bronchial circulation in addition to the pulmonary circulation. Cells in the pleura, walls of blood vessels and airways, and cells around nerve bundles are supplied by branches of the bronchial artery. Smooth muscle control and response to hypoxia in bronchial vessels is similar to that in any systemic vessel (ie dilation in response to low local oxygen partial pressure).