cardiology 19,21

capillary

- A thin walled tube, generally formed by one layer of endothelial cells, surrounded by a basement membrane. [In the brain the capillaries are surrounded by a second set of cells that contributes to the formation of the blood-brain barrier]. - Endothelial cells are not attached tightly to each other but are separated by narrow, water-filled spaces called intercellular cleft. - Capillaries permeate almost every tissue of the body and they play an essential role in the function of the tissues. For this reason the capillary development and growth called angiogenesis is a necessary and fundamental process for the survival of the tissue after an injury. Angiogenesis is controlled by angiogenic factors such as the Vascular Endothelial Growth Factor or VEGF, which is secreted locally by various tissue cells such as fibroblast and endothelial cells. - The endothelial cells generally contain large number of endocytotic and exocytotic vesicles and sometimes these vesicles(endocytotic and exocytotic vesicles) fuse together to form continuous fused-vesicles channels. ------------------------------------- 3 types of capillaries : remember permeability and substances 1) Continuous capillaries: are the most common type of capillaries and they are found mainly in the skin or in muscles. The endothelial cells of continuous capillaries are joined together by tight junctions. 2) Fenestrated capillaries in intestine and kidney 3) sinusoidal capillary : capillaries that have fenestration and an incomplete basement membrane. They are found mainly in the liver, bone marrow and lymphoid tissues. They have continuous fused-vesicles channels(x in continuous capillaries). pericytes? check below

capillary blood flow

- Blood enters capillaries not directly from arterioles but from vessels called metarterioles. metarteriole is surrounded by a ring of smooth muscle which is called the precapillary sphincter. Precapillary sphincter relaxes or contracts in response to local metabolic factors, thereby increasing or reducing the blood flow through the capillary bed. Capillary Blood Flow The capillaries have a passive behavior. In fact the blood flow through capillaries depends on: • Vasodilation and Vasoconstriction of arterioles • Contraction of the precapillary sphincter in metarterioles (where present) - Blood velocity is not dependent on the proximity to the heart, but on the total cross-sectional area of the vessel type. - The huge number of capillaries provides such a large cross-sectional area that the total resistance of all the capillaries is much lower than that of arterioles. Each capillary, considered alone, is very small and have a very small radius, thus it offers a great resistance to blood flow. However if we consider the cross-sectional area of all the capillary network, the resistance of all the capillaries will be lower than the resistance due to arterioles. In all capillaries, excluding those in the brain, diffusion is the only important means. Through small water-filled channels in the endothelial lining between adjacent cells. cells. Another type of water-filled channel is the one created by the fusion of endocytotic and exocytotic vesicle. Variation in the size of this channels accounts for great differences in permeability of capillaries in different organs. In the brain there is no intercellular cleft, only tight junction - so water soluble substances need a carrier. In the liver instead there are sinusoid capillaries characterized by large inter-cellular clefts and large fused-vesicles channels Nutrients diffuse first from the plasma to the interstitial fluid. Metabolism is thus a major factor in establishing the transcapillary diffusion gradients(!!!!!!!). --------------------------------- Capillary filtration and absorption (Bulk flow-protein free plasma) play a minimal role in the exchange of nutrients and metabolic end products between capillaries and tissues. The function of this process is not the exchange of nutrients and metabolic end products but the main aim of this process is the distribution of the extracellular fluid volume (between capillary and interstitial fluid) ECF : interstitial fluid + plasma Normally there are approximately11L of interstitial fluid and only 3 L of plasma, and the interstitial fluid is a reservoir used to keep plasma volume constant. water and most solute move across the endothelial wall of the capillaries by bulk flow passing through water-filled channels, but proteins are retained in the plasma-a very low concenration in interstitial fluid; that the water concentration of the plasma is slightly lower than that of interstitial fluid, inducing an osmotic flow of water from the interstitial compartment into the capillary. The magnitude of the bulk flow is determined by four opposing forces that together are called Starlin's Forces: • Capillary Hydrostatic Pressure(Pc): It favors filtration out of the capillary • Interstitial Fluid Hydrostatic Pressure(Pif) • Osmotic Force due to plasma protein concentration(πc): results from differences in protein concentration. It favors the absorption of interstitial fluid into the capillary. • Osmotic Force due to interstitial fluid protein concentration(πif) NFP (net filtration pressure) = Pc + πif - Pif - πc high osmotic pressure = water really wants to go in! the bulk flow phenomenon from a quantitative point of view. • At the arterial end of a typical capillary NFP (net filtration pressure) = Pc + πif - Pif - πc 10 = 35 + 3 - 0 - 28 At the venous end of a typical capillary: The only substantial difference is that the Capillary Hydrostatic Pressure has decreased from 35 mmHg to 15 mmHg due to the resistance of the capillaries to flow. so absorption of fluid occurs. -10 =15 +3 - 0 - 28 Thus the net movement of fluid from the plasma to the interstitial fluid at the arterial end of the capillaries tends to be balanced by fluid flow in the opposite direction at the venous end of the capillaries. [In actuality, the net outward force is normally larger than the inward, so there is a net filtration that amounts to 4L/day which is then reabsorbed by lymphatic vessels ] The capillary hydrostatic pressure is not perfectly 35 mmHg and 15 mmHg at the two extremities of a capillary. Capillary Hydrostatic Pressure is different in different parts of the body , but it also varies according to the position of the body. Slso under physiologic regulation and it can be modulated by changing the resistance of the arterioles. In vasodilation, the arterioles in a particular tissue raise capillary hydrostatic pressure (higher amount of blood) pulmonary circulation • low hydrostatic pressure : 7 mmHg • higher [protein] in lung interstitial fluid than other tissue? • small filtration towards interstitium -> very active lymphatic drainage (x to accumulate fluid in ecm) Another factor which is involved in the filtration, is the capillary filtration coefficient. how much fluid will filter per mmHg net filtration pressure. This factor is often ignored because most capillaries are not under physiological control. A major exception : the capillaries of the kidneys.

the causes of Edema

1) Heart failure : elevated venous return -> elevated hydrostatic pressure -> excess filtration -> accumulation of fluid in interstitial fluid 2) injury : occurs histamine and other chemical factors are released locally -> vasodilation -> filtration up chemicals -> distort, increasing the size of the inter-cellular clefts and allowing plasma proteins to escape from the bloodstream -> filtration up 3) decrease in plasma protein by liver, kidney disease or malnutrition -> increase filtration

Local control

1) The change of chemical factors in ECF, inducing active hyperemia • Decrease in oxygen concentration, due to an increase in metabolism which produce vasodilation • Increase in CO2 as end product of oxidative metabolism induces vasodilation • Increase in Hydrogen Ions, cause the pH to decrease and induces vasodilation • Increase in Adenosine because of ATP breakdown induces vasodilation • Increase in K+ ions. This increase in potassium ions comes from repeated action potential repolarization. The increase in K+ ions leads to vasodilation • Increase in Eicosanoid which are produced from the breakdown of the membrane phospholipids. The increase in eicosanoid produces vasodilation • Increase in Osmotically active products • Bradykinin is a peptide generated locally from kininogen via enzymatic activity of kallikrein. • Nitric Oxide 2) Flow auto regulation When there's a change in blood pressure, there's also a change in arteriolar resistance, and therefore a change in blood supply, in order to keep the blood flow nearly constant. This phenomenon is called flow auto-regulation. When blood pressure increases vasoconstriction occurs. Vasoconstriction, induced by flow auto-regulation, is due to a faster removal of chemical vasodilator. messenger. The local vasodilator chemical factors are removed faster than they are produced, causing the arterioles to contract. Another mechanism is possible. Vasoconstriction due to flow auto-regulation also involves directly smooth muscle. muscle. Arteriolar smooth muscle can responds directly to an increase in stretch, caused by increased arteriolar pressure and they contract as a reflexive response. These contraction which involves stretch receptors and arteriolar smooth muscle is a reflex, which is called myogenic response.

control of CO

1. Heart rate - normal discharge rate of SA node = 100 bpm but normal heart rate is lower (70 bpm), it means vagus tone(tonic parasympathetic stimuli) is higher than sympathetic tone. pacemaker activity: Sympathetic stimulation (b) increases the slope of the pacemaker potential by increasing F-type channel permeability. Na+ ions enter the cells and cause a faster depolarization in SA node cells and heart rate increases. parasympathetic stimulation (c), first ✓decreases the slope of the pacemaker potential • effect on F-type channel ✓second, causes hyperpolarization • increases permeability to K+ also other factors, •sympathetic nerve •Epinephrine, increases heart rate acting on beta adrenergic receptors in the SA node cells. • Body temperature: increase in heart rate • Concentration of plasma electrolytes and metabolites: In particular adenosine is a metabolite produced by cardiac muscle cells. It acts on coronary blood flow. other hormones : thyroid hormone 2. SV Knowing that the heart do not completely empty during contraction, it is possible to define the stroke volume using the relation: SV= EDV-ESV Where EDV is the End Diastolic Volume (volume of blood in the ventricle at the end of the diastole) and ESV is the End Systolic Volume (volume of blood in the ventricle at the end of the systole). factors affect SV 1) Changes in EDV Frank-Starling's mechanism : an increase in stretch of cardiac muscle (increase in sacomere's length) -> increase in force of contraction. An increase in venous return, corresponds to an increase in EDV. This produce a stretching of the sarcomeres of cardiac muscle cells and the result is a forceful contraction and therefore an increase in Stroke Volume. This phenomenon is shown by ventricular-functional curve (an increase of the EDV ->an increase of a Stroke Volume) this law is basically a length-tension relationship(an example of heterometric regulation); both in skeletal muscle and in cardiac muscle, there is an optimal length of the sarcomere at which the contraction is powerful and more efficient. The difference is the length of cardiac muscle at resting state is not its optimal length as skeletal muscle's is. the optimal length for contraction is on rising phase of curve. So it can fill the greater amount of blood in ventricle; Greater filling of the ventricle causes additional stretching on cardiac muscle fibers and increases the force of contraction. (if you can't understand this law, read 16p of note) => correct! In Frank-Starling's mechanism, the increase in sarcomere length can cause • Optimal length that produce a better overlap between thin and thick filaments • Decrease in spacing between the thick and thin filaments (allowing more cross bridges to bind during a twitch) • increase in sensitivity of Troponin C for binding Ca2+, • Increase in Ca2+ release from sarcoplasmic reticulum -> In an individual at rest the cardiac muscle cells do not work at their maximum and the power of their contraction can therefore be increased. -> in the skeletal muscle, force of contraction is regulated by selective activation of motor units. in myocardial cells, all cells contract together. depends on other factors such as Ca2+ release or sensitivity of troponin C. However, the change in length of the sarcomeres is produce only by a greater filling of the ventricles. EDV depends on: • The venous return • The intrapericardial pressure • The ventricular compliance The significance of Frank-Starling law is that at any given heart rate, an increase in venous return, automatically cause an increase in cardiac output by increasing end diastolic volume and therefore stroke volume(so venous return from left cardiac output = diastolic volume = stroke volume of right cardiac output). An important function of that is to maintain the equality of the right and left cardiac output. so the equalization of the two cardiac outputs is an intrinsic automatic mechanism, which depends on sarcomere's length and does not depends on external factors. 2) homeometric regulation, the length of sacromere is constant, change the contractility a) sympathetic nerve - ventricular contractility - The sympathetic neurotransmitter norepinephrine is acts on the Beta adrenergic receptors to increase the contractility. - plasma epinephrine -> the beta-1-receptors in heart are activated by epinephrine. This causes an increase in heart rate (decrease in cardiac cycle duration), but at the same time has a positive ionotropic effect (increase in contractility). This decrease in the duration of cardiac cycle is due to a phosphorylation on the Ca2+ channels that are responsible for the uptake of Ca2+ into the sarcoplasmic reticulum. The phosphorylation makes this event faster. Note) The increase in contractility does not depend on EDV changes. Contractility : intrinsic ability of heart to contract. Increasing contractility is done primarily through increasing the influx of calcium or maintaining higher calcium levels in the cytosol of cardiac myocytes during an action potential. b) other substances - +ionotroffic effect : digitalis - -ionotroffic effect : hypoxia, hypercapnia, pharmacologic depressants, acidosis, barbiturates, quinidine & procainamide, loss of myocardium 3) Change in Arterial pressure or Afterload A change in arterial pressure is another type of heterometric regulation which affects the Stroke Volume. It also termed afterload. • An increase in the resistance of blood outflow cause an increase in the afterload. • This increase in afterload corresponds to a decrease in SV. • The decrease in SV causes a increase in the ESV • If ESV increases, the EDV increases. • EDV increase cause an increase in the force of contraction according to Frank-Starling mechanisms. • The increase in contraction cause the SV to return to normal value(70mm). => can keep constant SV, regardless of peripheral pressure change!

explain cardiac cycle

1. ventricle filling and last diastole(다이아스털) Atrial constriction(not necessary) occurs after most of ventrical filling (80%). Ventrical filling is passive phenomena due to pressure gradient between atria and ventricles. AV valve is held open. *inside heart - very low pressure, few milimiter mercury 2. isovolumic contraction : first part of systole, ventricular walls develop tension without shortening but raise blood pressure when all valves are closed. (isometric contraction) . *to overcome aorta pressure - 80mmHg 3. ventricular ejection : when pressure exceed that in aorta and pulmonary trunk, semilunar valve opens. 4. isovolumetric relaxation : during the first part of dastole, all valves are closed *most filling occurs at early diastole, so even though diastole is shortened, still heart has an enough filling *two forces to fill ventricle : pulling force created by relaxation of heart muscle+pressure of atrium by venous return(?)

EXTRINSIC CONTROL

<neural controls> 1) sympathetic nerves Most arterioles receive a rich supply of sympathetic postganglionic nerve fibers. Control of the sympathetic nerves can be used to produce both vasoconstriction and vasodilation. Vasoconstriction is produced by a increase in the sympathetic tone. The postganglionic sympathetic neurons release norepinephrine, which binds to alpha-adrenergic receptors on the vascular smooth muscle and cause vasoconstriction.[But in the heart the receptors for norepinephrine are mainly beta-adrenergic] *plasma epinephrine - b2 receptor - vasodilation Vasodilation instead can be achieved by decreasing the rate of discharge of the sympathetic nerves (sympathetic tone). * arterioles - x parasympathetic innervation ---------------------------------- The main aim oft the sympathetic nervous system on arteriolar resistance is to obtain a systemic control of blood vessel mediating reflexes that are relevant for the whole body - DUE TO Always some degree of tonic constriction, sympathetic tone. The primary function of sympathetic innervation to blood vessels are concerned not with the coordination of local metabolic needs and blood flow(local control), but with reflexes that serve whole body needs(systemic control!). With few exception there is little or no important parasympathetic innervation of arterioles. In other words, the great majority of blood vessels receive only sympathetic inputs. 2) Noncholinergic, Noadrenergic, Autonomic Neurons - release other vasodilator, NO - prominent in the gastrointestinal blood vessels which controls the GI functions and in penis and clitoris, where they mediate erection. * for erection : sildenafil (viagra), tadalafil... <hormone controls> 1) epinephrine epinephrines released from sympathetic system (when exercise). However, many arteriolar smooth muscle cells posses the Beta-2- adrenergic receptors as well as the Alpha-adrenergic receptors and be relaxed by epinephrines. Skeletal muscle have a significant number of Beta-2-adrenergic receptors, and therefore, circulating epinephrine can contribute to vasodilation more than vasoconstriction. peripheral blood pressure might be the same. because epinephrine vasodilates for skeletal muscle and vasoconstrict for other tissues. epinephrine - more vasodilate norepinephrine - more vasoconstrict pic 43p/23.slides 2) ANP Atrial Natriuretic Peptide is a potent vasodilator which is secreted by cardiac atria. It regulates blood pressure through blood vessels but also through regulation of Na+ balance and blood volume in kidney. 3) vasoconstrictor Angiotensin II is an hormone which is part of the renin-angiotensin system. It is an important vasoconstrictor. also vasopressin...

substances released by endothelial cell <local control>

<vasodilators by endothelial cell> Nitric oxide : a paracrine, vasodilator (to distinguish it from the NO released by post-ganglionic autonomic neurons). Its secretion increases in response to histamine and bradykinin. Prostacyclin is a vasodilator, also called PGI2. <vasoconstrictor by endothelial cell> Endothelin-1 (ET-1) is an important paracrine vasoconstrictor. ------------------------------ The force exerted by the blood flowing in the vessels on the endothelial cells it is called the shear stress. An increase in the shear stress -> with the release of higher amounts of PGI2 and NO, and a decrease in the concentration of ET-1 from endothelium of arteries -> induce and arterial vasodilation, by relaxing arterial smooth muscles The overall phenomenon is called flow-induced arterial vasodilation and is important in remodeling the arteries and in optimizing blood supply to tissues.

CARDIAC CYCLE DESCRIBED THROUGH PRESSURE VOLUME CURVES

A : the end of the isovolumetric ventricular relaxation at the end of the systole. ESV = 65ml B : End Diastolic Volume at the end of the diastole (low pressure) C : the end of the isovolumetric ventricular contraction D : the end of the ventricular ejection phase The line from point C to D is not a straight line, because the decrease in volume(the blood which is pumped in arteries) is associated by a n increase in pressure (because of the contraction of the ventricular walls). D->A->B->C ------------------------------- systolic dysfunction : contract abnormally, SV is small(b'c') but diastolic volume is higher(a'b') diastolic dyfunction : contract normally, less stretchable, SV and diastolic volume is small.

arteries

Arteries and veins both have vascular smooth muscle cells, endothelial cells and adventia made of fibrous connective tissue, however the amount of each component varies. ARTERIES are divided, as they branch, into: • Elastic Arteries: which are the big vessels. They are elastic as the name implies and act as conduit of blood. No exchange of substance occurs at the level of elastic arteries. Because arteries have large radii, they serve as low resistance tubes conducting blood to the various organs. Their second function is to act as a "pressure reservoir" for maintaining blood flow during diastole because of the elastic recoil that allow pressure to remain high and to push blood in arterioles also during diastole. Arterial blood pressure The pressure inside these tubes depends on: • The volume of fluid they contain. • The stretchability or compliance of the tube. Compliance = ΔVolume/ ΔPressure During cardiac ejection only one-third of the SV leaves the arteries. The remaining two-thirds of the SV remains in the arteries and stretches the wall, and generates a raise in arterial pressure (picture 15p slides 23). Then during diastole, blood is pushed progressively into arterioles by the passive recoil of arterial walls. This mechanism allows pressure to decrease progressively and therefore arterial pressure does not decrease to zero. *if the heart is rigid, the pressure in rigid tube decreases to zero (because nothing can keep the pressure), we can keep fluctuating continuous pressure -> due to elastic characteristic of vessel ---------------------------------- The maximum arterial pressure reached during peak ventricular ejection is called systolic pressure (SP)=120. The minimum arterial pressure occurs just before ventricular ejection begins and is called diastolic pressure (DP)=80. The difference between systolic and diastolic pressure is called the pulse pressure and in normal condition is of 40 mmHg. This pulse is due to expansion of the walls of the arteries. *if strechablity of aorta is less, systole pressure increases, diastole pressure decreases -> difference of pressure increases! Specifically the pulse pressure is greater if the volume of blood ejected increases, if the speed at which it is ejected increases or if the arteries are less compliant. The arteries can be less compliant in a pathologic condition known as Arteriosclerosis in which a stiffening of the arteries produce a higher resistance to flow, which is counterbalanced by an increase in blood pressure. The average pressure or Mean Arterial Pressure (MAP) is not simply the value halfway between the systolic and diastolic pressure, because diastole lasts longer than systole. The true MAP is described by the following equation: MAP= DP + ⅓ (SP-DP) Mean Arterial Pressure= Diastolic pressure +⅓ Pulse Pressure, In normal condition MAP= 93mmHg DP : The diastolic pressure is specifically the minimum arterial pressure during relaxation and dilatation of the ventricles of the heart when the ventricles fill with blood - It is possible to define a Mean Arterial Pressure only because Aorta and other elastic arteries offer only little and negligible resistance to blood flow and the mean pressures are therefore similar everywhere in the large arteries. - MAP is not always a good index of alteration in the arteries, because in arteriosclerosis for example and increase in systolic pressure due to stiffening of the arterial walls is counterbalanced by a decrease in diastolic pressure. This allow to keep the MAP around normal value. In this case the pulse pressure(you can know maximum/minimum values) is a better index of pathology. -------------------------------------- • Muscular arteries : which deliver blood to specific organs such as the mesenteric artery, the renal artery between the elastic arteries and the arterioles. a well developed tonaca media, rich in smooth muscle fibers that contract resulting in vasoconstriction. Therefore these vessels can play a large role in the regulation of blood pressure • Arterioles: these are the vessels that more easily change the radius affecting the resistance to blood flow and thus the pressure (according to Laplace's law). surrounded by a single layer of smooth muscle in the tonaca media which spirals around the endothelium. *Arterioles play two major roles: • They control the blood that flows to an organ • All together, the arterioles are a major factor determining MAP itself. In fact the highest drop in blood pressure occurs in the arterioles (you can see in the graph), because they offer the highest resistance to flow; decreases from 90 to 35mmHg, and no or less pulsatile after arterioles. The blood flow (F) through any organ F= ΔP /R = (MAP-Venous pressure)/ Resistance = MAP/Resistance Because the MAP is the same in all the part of the body, difference in flows between organs depend entirely on the relative resistance of their respective arterioles. ---------------------------------- how to change resistance? by controlling the level of contraction; Arteriolar smooth muscles posses a large degree of spontaneous contractile activity which is called intrinsic tone. The control of the level of contraction of the arteriolar smooth muscle layer is fundamental in order to increase or to decrease the flow of blood arriving to a specific organ or tissue; by local control and extrinsic control local control : independent of nerves or hormones by autocrine/paracrine agents. It is a spontaneous self regulation of the muscle tone which modulates the intrinsic tone of the arteriolar smooth muscle. - Active hyperemia is the increase in blood flow due to a change in metabolic activity. • Extrinsic control is based on mechanisms that rely on reflexes in order to control the level of contraction.

left ventricle volume

Blood flows from Atria to the ventricles, therefore increasing Left ventricle's volume. The volume increases to approximately 135 mL, then the atria stop contracting. The pressure in the atria falls causing the atrioventricular valve of the left side of the heart to close. The closure of this valves is followed by a isovolumetric contraction of the ventricle in which the volume remains constant, but there's a sharp increase in pressure (S). The isovolumetric contraction is then followed by ventricular ejection phase, in which ventricular contraction pump the blood in the aorta. Therefore, there is a large decrease in volume to a value of 65 mL which is called ESV. When the pressure in ventricles decrease below the level of the aortic pressure, the aortic valve closes. The closure of the aortic valve is followed by the isovolumetric ventricular relaxation, in which there is a decrease in pressure of the ventricle without increase in volume. Finally during diastole the recoil of ventricular walls forms a pressure gradient that "calls" the blood from the atrium. The pressure gradient cause the AV valve to open and blood passively flow into the left ventricle filling it. check the pic at 8p of note.

Cardiac output and exercise

During exercise there is an increased rate in sympathetic discharge which produces an increase in HR and in myocardial contractility. There is also an increase in venous return due to the increased pumping action of the muscle and the increase in ventilation (change in intrapleural pressure recalls more blood to the alveolar capillaries). Muscular exercise also affect the peripheral resistance and therefore decreases afterload because it is associated with vasodilation. during the exercise, to transplanted patients, the increase in CO is due to an increase in the Stroke Volume, not due to heart rate.

the function of endothelial cells

Endothelial cells have a large number of active functions: • Physical lining that blood cells do not normally adhere to in heart and vessels • Permeability barrier for the exchange of nutrients, gases, metabolic end products, fluids. The endothelium regulates the transport of molecules and macromolecules • Secretion of paracrine substances and agents that act on adjacent smooth muscle cells • Mediators of new capillaries growth. • Endothelial cells play a role in vascular remodeling by detecting signals and releasing paracrine agents that act on adjacent cells • Production of Growth factors in response to damage • Secrete substances that regulates platelet clumping, clotting, and phenomena regarding coagulation. • Synthesis of active hormones from inactive precursor • Secretion of cytokines during immune response • Influence vascular smooth muscle proliferation

flow is depend on

F = dP / R

pulmonary circulation pressure

In fact, the pulmonary circulation is a low pressure system, characterized by a systolic pressure in pulmonary arteries of 25 mmHg and by a diastolic pressure of 10 mmHg. -> *the resistance of pulmonary vessels is much lower, so despite the low pressure, the same amount of blood can circulate, that's because the pressure of capillaries around alveoli should be smaller - should be below 25mmHg to make sure the exchange between capillaries

Lymph

Lymph is a fluid derived from interstitial fluid. The main aims of the lymphatic system are: • Collect the lymph and return it to the cardiovascular system. Most of the lymph is derived from the interstitial fluid which is composed mostly by the fluids that are lost from the capillaries net filtration > net absorption the fluids are lost 4L/day • House the phagocytes and lymphocytes that play a role in the immune system • Take up cells, proteins, cellular debris • Participate actively in the immune response • Participate in the GI tract in the absorption of fat which are complexed in to macromolecules called chylomicrons which are too large to pass across the endothelium of the capillaries. • cancer cells can spread from a tissue to another through lymphatic vessel. ---------------------- small lymphatic capillaries - collect into lymphatic vessels of larger and larger diameter -> right/left lymphatic duct The movement of interstitial fluid from the lymphatics to the cardiovascular system is very important because, the amount of fluid filtered out of all the blood vessel capillaries (except the kidneys) exceeds that absorbed by approximately 4L each day. Failure of the lymphatic system due to occlusion by infection organism (such as in elephantiasis) allows the accumulation of excessive interstitial fluid. The result can be massive edema Causes of increased interstitial fluid volume and edema: 1. Venular constriction 2. Increased venous pressure 3. Decreased osmotic pressure gradient across the capillaries. 4. Increased capillary permeability 5. Inadequate lymph flow. The smooth muscle in the walls of the lymphatics exerts a pump-like action by inherent rhythmic contractions. also have valves. the smooth muscle of the lymphatic vessels receive a sympathetic innervation. Beyond the capillaries, the flow of lymph is assured by the following mechanisms: • Intrinsic rhythmic contractions and valves • Sympathetic innervation • Skeletal muscle pump • Respiratory muscle pump When instead fluid accumulates, more stress is applied to the wall which are stretched and the smooth muscle contracts more.

pericytes

Pericytes are contractile elongated cells in CNS which are wrapped around the capillaries via long processes and share the basement membrane with endothelial cells. They play a large role in the maintenance of the blood-brain barrier. Pericytes form direct connections with endothelial cells and with neighboring cells by forming gap junctions. Pericytes can also release vasoactive agents and can synthesize and constituents of the basement membrane and of the extracellular matrix, participating in the reparation processes of the capillaries. With their contractile ability pericytes can regulate the flow of substances through the junctions between endothelial cells. Pericytes are also associated with endothelial cells stimulating their growth, differentiation and allowing them to survive to apoptotic signals.

explain the conduction system of the heart

SA node(pace maker) ---gap junction---> internodal pathway -> AV node -> common bundle -> bundle branches -> purkinje fiber -> ventricular muscle(also papillary muscle)

The pressure IN THE SYSTEMIC AND PULMONARY CIRCULATION

The X axis represent the various districts of the vascular system, while the Y axis reports the values of pressure. As the diagram illustrates the pressure in larger arteries ranges between 120 and 80 mm Hg, and remains more or less constant along this big vessels. Then in arterioles, the largest decrease in pressure occurs. Arterioles are so elastic as arteries, and so they exert a very high resistance to blood flow. In capillaries, he pressure continues decreasing and the pulsate behavior is lost at this level and completely disappears in venules and veins. Finally in veins the pressure range between 15 -17 mm Hg and the pressure is very low as it returns to the heart (approximately to zero). arteries - pressure reservoir vessels At the beginning of the graph the pressure in the left ventricle range between 120 mm Hg and 0 mm Hg. This is due to the contraction of the heart that reduce pressure almost to zero during diastole. Instead in arteries the pressure range between 120 and 80 mm Hg, showing the fact that arteries are "pressure reservoir" vessels, that maintains blood pressure always at a certain value, even when during the diastole the ventricular pressure falls down to low values. As the graph illustrates the pressure in the pulmonary circulation are much more lower than the pressure found in the systemic one. This is because very low pressure values are required in order to avoid fluid and plasma to leak the alveolar capillaries and so to avoid accumulation of fluid in the lungs.

cardiac output

The cardiac output is defined by the volume of blood pumped by one (!!!!!) ventricle in a minute. also defined as volume of blood flowing through systemic or pulmonary circuit per minite CO = HR (heart rate) x SV (stroke volume) A normal value of the Cardiac Output for a resting average-sized adult is of 5.0-5.5 L/min. CO= 70 bpm x 0.07L/beat= 5.0 L/min Total blood volume is also approximately 5L , so essentially all the blood is pumped around the circuit once each minute. two factors controlling CO = heart rate, stroke volume ------------------------

explain microcirculation

The microcirculation : the small vessels which are embedded within organs and are responsible for the distribution of blood within tissue. The vessels on the arterial side of the microcirculation are called the arterioles which are well innervated, are surrounded by smooth muscle cells, and are 10-100μm in diameter. In addition to blood vessels, the microcirculation also includes lymphatic capillaries and collecting ducts. The main functions of the microcirculation include the regulation of 1. blood flow and tissue perfusion 2. blood pressure, 3. tissue fluid(swelling or edema), 4. delivery of oxygen and other nutrients and removal of CO2 and other metabolic waste products,and 5.body temperature.

heart beta 1 adrenergic receptor

The molecular mechanism for this is based on a the action of Beta-1-adrenergic receptors which are GPCRs. Once activated, these receptors activate adenylyl cyclase which converts ATP in cAMP. CAMP activates cAMP dependent protein kinase or PKA. PKA is able to transiently phosphorylates several substrates. Its main target are: • L-Type Ca2+ channels which are responsible for the plateau of AP • Ryanodine receptors which triggers more Ca2+ release from the sarcoplasmic reticulum • Troponin C which becomes more sensible to Ca2+ binding • Cross Bridges which are more easily activated.

the numbers of cardio cycle

The typical heart rate is of 72 bpm and each cardiac cycle lasts 0.8 sec, with 0.3 sec in systole and 0.5 sec in diastole. The duration of each cardiac cycle for an accelerated heart rate of 200 beats per minute s of 0.30 sec. At the end of ventricular diastole, the amount of blood in the ventricle is called the EDV or End Diastolic Volume and it is of 135 mL. At the end of the systole the amount of blood remaining in the ventricle is called the ESD or End Systolic Volume and it is of 65 mL. The stroke volume is the volume of blood ejected from each ventricle during systole. The stroke volume is approximately of 70 mL. *visceral organ is designed to empty completely, heart is different.

Laplace's law and the ventricular work

The ventricular work is finally related to Laplace's law. Laplace's law states that the tension developed in the wall of a hollow organ is proportionate to the radius of the organ. Fort this reason a dilated heart will develop more tension in order to generate a given pressure. The work can increase by affecting the SV and thus the EDV (The venous return) but also affecting or changing the resistance of vessels to the flow. If the resistance increase, a higher tension will be required to generate a given pressure. The increase in resistance of the vessels affects ventricular work more than the increase in stroke volume.

Heart sounds

These sounds are the result from vibrations generated by the closing valves. Two sounds are normally heard: 1. The first sound (slow pitched lub) - AV valves, the onset of the systole 2. The second sound (a louder dup) - the pulmonary and aortic valves. the onset of the diastole ----------------------------- Abnormal sounds or noises are called heart murmurs, x physiological but pathological sign. Because Blood flow becomes turbulent instead of laminar 1) Blood flows rapidly in usual direction due to an abnormally narrow valve or [Stenosis, produce whistling murmur!!] 2) Blood flows backward through a leaky valve [Insufficiency produce a low pitched gurgling murmur!!!] 3) Blood flows from one atrium or ventricle to the other through a small hole (congenital defect) ----------------------- summary A murmur through the systole can be due to : • Stenosis of the pulmonary or aortic valve • Insufficiency of the AV valves (the failure of the heart's tricuspid valve to close properly, leaky valve-turbulent backflow) • Holes in the inter-ventricular septum A murmur during diastole may be the sign of: • Stenosis of AV valve • Insufficiency of pulmonary or aortic valves.

local control for reactive hyperemia and tissue injury

This phenomenon is called reactive hyperemia and is essentially an extreme form of flow autoregulation. Reactive hyperemia is due to the fact that during the period of no blood flow, the arterioles in the affected organ or tissue dilate, owing to the local factors described previously. As soon as the occlusion to arterial flow is removed, blood flow increases greatly through these wide-open arterioles. This effect can be demonstrated by wrapping a string tightly around the base of your finger for 1-2 minutes. When it is removed, your finger will turn bright red due to the increase in blood flow. Tissue injury causes a variety of substances to be released locally from cells or generated from plasma precursors. These substances make arteriolar smooth muscle to relax and cause vasodilation. e.g. inflammation

explain latch-bridge mechanism

VASCULAR SMOOTH MUSCLE The tunica media of the arterioles contains vascular smooth muscle, contributes to change the radius (and thus the resistance) of the vessels. These vascular smooth muscle has the ability of sustaining force. This sustained phase has been attributed to certain myosin cross-bridges, termed latch-bridges, that are cycling very slowly. In latch-bridge mechanism, myosin cross-bridge remain attached to actin after cytoplasmic [Ca2+] falls. In this way contraction is often tonic and force is maintained at a low energy cost. The events are the following: • Influx of Ca2+ through voltage-gated Ca2+ channels. • Ca2+ binds to Calmodulin. • Ca2+/Calmodulin Complex activated Calmodulin-dependent myosin light chain kinase (MLCK) • MLCK catalyzes the phosphorylation of myosin light chains activating them • Actin slides on myosin producing contraction During relaxation myosin is dephosphorylated by myosin light chain phosphatase but relaxation does not necessarily occur.

veins

VEINS: are divided, as they return to the heart into: • Venules formed mainly by endothelium and fibrous connective tissue • Veins: formed by fibrous connective tissue externally but they also have a tonaca media with elastic connective tissue and smooth muscle cells. Both venules (small diameter veins) and Veins are expandable vessels and their degree of expansion depends on the degree of contraction of the smooth muscle in their walls. the force driving this venous return is the pressure difference between the peripheral veins and the right atrium.The total driving pressure for flow from peripheral veins(10-15) to right atrium(0) is only 10 to 15 mmHg on average. two main functions Veins are low resistance tubes; thin and compliant walls and the peripheral veins of the arms and legs contain valves. act as a reservoir of blood - 60% - major determinant of the end diastolic volume. The factors determining pressure in any elastic tube are 1) Volume of fluid within the tube 2) Compliance or stretchability of the vessel walls. The walls of the veins contain smooth muscle innervated by sympathetic neurons. [When arterioles contracts, the contraction reduces the flow, whereas constriction of veins increases forward flow.] The forces determining venous return are: • Vis a Tergo or Pushing mechanisms: ◦ Cardiac pump: is the pressure generated by the heart. ◦ Skeletal muscle pump : during skeletal muscle contraction, the veins running through the muscle are partially compressed. • Vis a Fronte or Pulling mechanisms: ◦ Respiratory pump: during the inspiration, an increase of the pressure differences between the peripheral veins and the heart. [Therefore breathing deeply and frequently, helps blood flow toward the heart.] ◦ Cardiac Sucking: during the non- isovolumic relaxation of the ventricles, this phase of the cardiac cycle a negative pressure is generated in the cardiac chambers , which generate a pressure gradient and therefore a flow of blood.

Wiggers diagrams

Wigger diagrams are a useful way to summarize and compare all the events that take place in the left atrium, ventricle and aorta during the cardiac cycle. 1. basic atrium pressure 2. atrial contraction - very small *compression of atrium compress the vena cava - so prevent the back flow to vein 3. 100ms delay between contraction of atrium and ventricle, after relaxation of atrium, ventricle starts to contract 4. the pressure of aorta are still going down 11. slightly increase of pressure in atrium during the ventricle contraction, due to contraction papillary muscles toward atrium decrease of pressure - during the ejection to aorta, due to contraction papillary muscles toward ventricle 14. semilunar valve opens 21. myocytes generate less force between 21, 23 - pressure goes down : valve closed, other valve also closed 25. dicrotic(다이크로틱) notch - valve opens, myocyte can relengthen -> generate pulling force, when myocyte has normal length, the fulling force is smaller * variance of pressure in aorta is smaller than ventricle's up to 120mmHg -------------------------------- 5. 8-9, isometric contraction (135ml) 9 : very quickly decrease at early phase 27 : early diastole - very quick filling ------------------------------- mid/late diastole - AV valve is held open and semilunal valves are closed. - Near he end of diastole , the SA node discharges and the atria depolarize , forming the P wave on the ECG trace. - Contraction of the atrium causes an increase in atrial pressure. The elevated atrial pressure forces a small volume of blood into the ventricle (atrial kick). - At the end of ventricular diastole the amount of blood in the ventricle is the EDV and it is approximately 135 mL. systole After atrial contraction, there's a delay in the transmission of electrical impulses triggering the ventricular depolarization and their contraction. This delay is of 0.1 sec and is fundamental in order to give the atria enough time to relax. Creating QRS complex and triggering ventricular contraction. For a brief time all the valves are closed. (Isovolumetric ventricular contraction). Ventricular pressure then rise exceeding aortic pressure. The amount of blood remaining in ventricle after ejection is called the ESV. The peak in ventricular and aortic pressure is reached before the end of ventricular ejection. The pressure starts decreasing during the last part of the systole. early diastole - T wave of ECG - As the ventricles relax, the ventricular pressure decrease below the aortic pressure, which forces the aortic valves to close. >The blood rebounding against the valve causes a decrease and then a rebound of aortic pressure called dicrotic notch. >The aortic pressure remains significantly high because of: ◦ The amount of blood just entered ◦ The elastic recoil of the walls of the arteries. The walls of arteries distend as during ventricular ejection and then recoil, exerting a pressure on the blood. [ Pressure is progressively decreased but is maintained. When semilunar valves close in the early diastole, the pressure in aorta is still of 100 mmHg] - After isovolumetric ventricular relaxation pressure decreases below atrial pressure. This change in pressure gradient results in the opening of the AV valve. - The rate of blood flowing is enhanced during early diastole by a rapid decrease in ventricular pressure because suppressed ventricle tend to recoil quickly. The relaxation of the myocardium aids filling of the ventricle (passive phenomenon). - Most ventricular filling occurs during early diastole. Even though the duration of diastole is shortened during exercise, filling is not seriously impaired it already occurs during early diastole.

jugular venous pressures

important!! a wave : because some blood flow back regurgitate in great veins during atrial systole. • c wave: corresponds to isovolumetric ventricular Contraction. This deflection of the curve is due to the bulging of the tricuspid valves(AV valve) into the atrium during isovolumetric systole • v wave: corresponds to a rise in atrial pressure due to Venous return(Venous return is the rate of blood flow back to the heart) before the opening of the tricuspid valve. The v wave occurs during isovolumetric Ventricular relaxation.

explain the innervation of heart

sympathetic nerve - all heart muscles and nodal cells beta 1 receptor - E, NE parasympathetic nerve - nodal cells muscarinic receptor - Ach

The functional and structural characteristics of the blood vessels (x important, just remember general features)

the cardiovascular system has one structural component in common which is the endothelium, a single layer of cells that lines the inner surface of the vessels. [Capillaries consist only of endothelium and associated extracellular basement membrane] In general vessels (not capillaries) are formed by the following layers: • Tonaca Adventitia: is the most outer layer and it is composed of connective tissue. • Tonaca Media: is the middle layer and contains various amount of smooth muscle cells and somewhat elastic tissue • Tonaca intima: is the inner layer and is formed by the endothelial cells.

hematocrit

the percentage of blood volume which is erythrocytes (blood volume 5.5L, erythrocyte volume 2.5L, 45, 42%)

sphygmomanometer

upper left arm - where branchial artery lies - put pressure greater than systolic BP - prevent blood flow - decrease pressure just below systolic BP - partial blood flow through artery - turbulent/high velocity/vibration - korotkoff's sound (of the systolic BP) - the pressure decreases further - all sounds stop when the flow is continuous and x turbulent, which is diastolic pressure

resistance depend on

viscosity(n), length of tube, radius of tube - most important control of R

The values of the pressure in the systemic and pulmonary circulations:

• Left Ventricle: 120/0 mmHg • Aorta: 120/80 mmHg • Arteries: 93 mmHg (MAP) • Arterioles 35 mmHg • Systemic Capillaries : 20 mm Hg • Venules: 17-15 mmHg • Veins: 10 mmHg • Righ Atrium: 2 mm Hg • Right ventricle: 25/0 mmHg • Pulmonary Arteries: 20/15 mmHg • Pulmonary circulation capillaries: 10 mmHg • Pulmonary veins: 5 mmHg