Blood Flow - Blood Flow Coronary Anatomy and Blood Flow The...

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Unformatted text preview: Blood Flow Coronary Anatomy and Blood Flow The major vessels of the coronary circulation are the left main coronary that divides into left anterior descending and circumflex branches, and the right main coronary artery. The left and right coronary arteries originate at the base of the aorta from openings called the coronary ostia located behind the aortic valve leaflets. The left and right coronary arteries and their branches lie on the surface of the heart, and therefore are sometimes referred to as the epicardial coronary vessels. These vessels distribute blood flow to different regions of the heart muscle. When the vessels are not diseased, they have a low vascular resistance relative to their more distal and smaller branches that comprise the microvascular network. As in all vascular beds, it is the small arteries and arterioles in the microcirculation that are the primary sites of vascular resistance, and therefore the primary site for regulation of blood flow. The arterioles branch into numerous capillaries that lie adjacent to the cardiac myocytes. A high capillary-to-cardiomyocyte ratio and short diffusion distances ensure adequate oxygen delivery to the myocytes and removal of metabolic waste products from the cells (e.g., CO2 and H+). Capillary blood flow enters venules that join together to form cardiac veins that drain into the coronary sinus located on the posterior side of the heart, which drains into the right atrium. There are also anterior cardiac veins and thesbesian veins drain directly into the cardiac chambers. Although there is considerable heterogeneity among people, the following table indicates the regions of the heart that are generally supplied by the different coronary arteries. This anatomic distribution is important because these cardiac regions are assessed by 12-lead ECGs to help localize ischemic or infarcted regions, which can be loosely correlated with specific coronary vessels; however, because of vessel heterogeneity, actual vessel involvement in ischemic conditions needs to be verified by coronary angiograms or other imaging techniques. Anatomic Region of Heart Coronary Artery (most likely associated) Inferior Right coronary Anteroseptal Left anterior descending Anteroapical Left anterior descending (distal) 1 Blood Flow Anatomic Region of Heart Coronary Artery (most likely associated) Anterolateral Circumflex Posterior Right coronary artery The following summarizes important features of coronary blood flow: Flow is tightly coupled to oxygen demand. This is necessary because the heart has a very high basal oxygen consumption (8-10 ml O2/min/100g) and the highest A-VO2 difference of a major organ (10-13 ml/100 ml). In non-diseased coronary vessels, whenever cardiac activity and oxygen consumption increases, there is an increase in coronary blood flow (active hyperemia) that is nearly proportionate to the increase in oxygen consumption. Good autoregulation between 60 and 200 mmHg perfusion pressure helps to maintain normal coronary blood flow whenever coronary perfusion pressure changes due to changes in aortic pressure. Adenosine is an important mediator of active hyperemia and autoregulation. It serves as a metabolic coupler between oxygen consumption and coronary blood flow. Nitric oxide is also an important regulator of coronary blood flow. Activation of sympathetic nerves innervating the coronary vasculature causes only transient vasoconstriction mediated by a1-adrenoceptors. This brief (and small) vasoconstrictor response is followed by vasodilation caused by enhanced production of vasodilator metabolites (active hyperemia) due to increased mechanical and metabolic activity of the heart resulting from b1-adrenoceptor activation of the myocardium. Therefore, sympathetic activation to the heart results in coronary vasodilation and increased coronary flow due to increased metabolic activity (increased heart rate, contractility) despite direct vasoconstrictor effects of sympathetic activation on the coronaries. This is termed "functional sympatholysis." Parasympathetic stimulation of the heart (i.e., vagal nerve activation) elicits modest coronary vasodilation (due to the direct effects of released acetylcholine on the coronaries). However, if parasympathetic activation of the heart results in a significant decrease in myocardial oxygen demand due to a reduction in heart rate, then intrinsic metabolic mechanisms will increase coronary vascular resistance by constricting the vessels. Progressive ischemic coronary artery disease results in the growth of new vessels (termed angiogenesis) and collateralization within the myocardium. Collateralization increases myocardial blood supply by increasing the number of parallel vessels, thereby reducing vascular resistance within the myocardium. Extravascular compression (shown to the right) during systole markedly affects coronary flow; therefore, most of the coronary flow occurs during diastole. Because of extravascular compression, the endocardium is more susceptible to ischemia especially at lower perfusion pressures. Furthermore, with tachycardia there is relatively less time available for coronary flow during diastole to occur this is particularly significant in patients with coronary artery disease where coronary flow reserve (maximal flow capacity) is reduced. In the presence of coronary artery disease, coronary blood flow may be reduced. This will increase oxygen extraction from the coronary blood and decrease the venous 2 Blood Flow oxygen content. This leads to tissue hypoxia and angina. If the lack of blood flow is due to a fixed stenotic lesion in the coronary artery (because of atherosclerosis), blood flow can be improved within that vessel by 1) placing a stent within the vessel to expand the lumen, 2) using an intracoronary angioplasty balloon to stretch the vessel open, or 3) bypassing the diseased vessel with a vascular graft. If the insufficient blood flow is caused by a blood clot (thrombosis), a thrombolytic drug that dissolves clots may be administered. Anti-platelet drugs and aspirin are commonly used to prevent the reoccurrence of clots. If the reduced flow is due to coronary vasospasm, then coronary vasodilators can be given (e.g., nitrodilators, calcium-channel blockers) to reverse and prevent vasospasm. 3 Blood Flow Vascular tone Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All arterial and venous vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. Basal vascular tone differs among organs. Those organs having a large vasodilatory capacity (e.g., myocardium, skeletal muscle, skin, splanchnic circulation) have high vascular tone, whereas organs having relatively low vasodilatory capacity (e.g., cerebral and renal circulations) have low vascular tone. Vascular tone is determined by many different competing vasoconstrictor and vasodilator influences acting on the blood vessel. These influences can be separated into extrinsic factors that originate from outside of the organ or tissue in which the blood vessel is located, and intrinsic factors that originate from the vessel itself or the surrounding tissue. The primary function of extrinsic factors is to regulate arterial blood pressure by altering systemic vascular resistance, whereas intrinsic mechanisms are important for local blood flow regulation within an organ. Vascular tone at any given time is determined by the balance of competing vasoconstrictor and vasodilator influences. In general, extrinsic factors (neurohumoral) such as sympathetic nerves and circulating angiotensin II increase vascular tone (i.e., cause vasoconstriction); however, some circulating factors (e.g., atrial natriuretic peptide) decrease vascular tone. Intrinsic factors include: Myogenic mechanisms (originating from vascular smooth muscle), which increase tone. Endothelial factors such as nitric oxide and endothelin can either decrease or increase tone, respectively. Local hormones/chemical substances (e.g., arachidonic acid metabolites, histamine and bradykinin can either increase or decrease tone. Metabolic by-products or hypoxia, which generally decrease tone. The mechanisms by which the above influences either constrict or relax blood vessels involve a variety of signal transduction mechanisms that ultimately influence the interaction between actin and myosin in the smooth muscle. 4 Blood Flow Local regulation of blood flow Tissues and organs within the body are able to intrinsically regulate, to varying degree, their own blood supply in order to meet their metabolic and functional needs. This is termed local or intrinsic regulation of blood flow. Several mechanisms are responsible for local blood flow regulation. Some mechanisms originate from within blood vessels (e.g., myogenic and endothelial factors), whereas others originate from the surrounding tissue. The tissue mechanisms are linked to tissue metabolism or other biochemical pathways (e.g., arachidonic acid metabolites, histamine and bradykinin). Local regulatory mechanisms act independently of extrinsic control mechanisms such as sympathetic nerves and circulating hormones. Therefore, they can be demonstrated in isolated, perfused organs having no neural or hormonal influences. Ultimately, the balance between local regulatory mechanisms and extrinsic factors in vivo determines the vascular tone and therefore the blood flow within the tissue. Examples of local regulation of blood flow include the following: autoregulation active hyperemia reactive hyperemia. Autoregulation Autoregulation is a manifestation of local blood flow regulation. It is defined as the intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. For example, if perfusion pressure is decreased to an organ (e.g., by partially occluding the arterial supply to the organ), blood flow initially falls, then returns toward normal levels over the next few minutes. This autoregulatory response occurs in the absence of neural and hormonal influences and therefore is intrinsic to the organ. When perfusion pressure (arterial minus venous pressure, PA-PV) initially decreases, blood flow (F) falls because of the following relationship between pressure, flow and resistance: When blood flow falls, arterial resistance (R) falls as the resistance vessels (small arteries and arterioles) dilate. Many studies suggest that that metabolic, myogenic and endothelial mechanisms are responsible for this vasodilation. As resistance decreases, blood flow increases despite the presence of reduced perfusion pressure. 5 Blood Flow This autoregulatory response is shown in the top panel of the figure. For example, if perfusion pressure is reduced from 100 to 70 mmHg, this causes flow to decrease initially by approximately 30%. Over the next few minutes, however, flow begins to increase back toward control if the organ is capable of autoregulating (red lines). This occurs because vascular resistance falls. If autoregulation does not occur, the flow will remain decreased. If an organ is subjected to an experimental study in which perfusion pressure is both increased and decreased over a wide range of pressures, and the steadystate autoregulatory flow response measured, then the relationship between steadystate flow and perfusion pressure can be plotted as shown in the bottom panel of the figure. The red line represents the autoregulatory responses in which flow changes relatively little despite a large change in perfusion pressure. If a vasodilator drug is infused into an organ so that it is maximally dilated and incapable of autoregulatory behavior, the curve labeled "Passive Dilated" is generated as perfusion pressure is changed. It is non-linear because blood vessels passively dilate with increasing pressures, thereby reducing resistance to flow. If a vasodilator is not infused so that the organ can undergo autoregulation, then there will be a range of perfusion pressures where flow will not follow the "Passive Dilated" curve. In fact, the flow over a particular range of perfusion pressures (i.e., autoregulatory range) may change very little as shown in this example (e.g., as found in coronary and cerebral circulations). The "Passive Constricted" curve represents the pressure-flow relationship when the vasculature is maximally constricted. The bottom panel also shows that there is a pressure below which an organ is incapable of autoregulating its flow because it is maximally dilated. This perfusion pressure, depending upon the organ, may be between 50-70 mmHg. Below this perfusion pressure, blood flow decreases passively in response to further reductions in perfusion pressure. This has clinical implications for 6 Blood Flow coronary, cerebral, and peripheral arterial disease. There is an upper limit to the autoregulatory range; however, this upper limit is seldom reached physiologically. Different organs display varying degrees of autoregulatory behavior. The renal, cerebral, and coronary circulations show excellent autoregulation, whereas skeletal muscle and splanchnic circulations show moderate autoregulation. The cutaneous circulation shows little or no autoregulatory capacity. Under what conditions does autoregulation occur and why is it important? A change in systemic arterial pressure, as occurs for example with hypotension caused by hypovolemia or circulatory shock, can lead to autoregulatory responses in certain organs. In hypotension, despite baroreceptor reflexes that constrict much of the systemic vasculature, blood flow to the brain and myocardium does not decline appreciably (unless the arterial pressure falls below the autoregulatory range) because of the strong capacity of these organs to autoregulate. Autoregulation, therefore, ensures that these critical organs have an adequate blood flow and oxygen delivery. There are situations in which arterial pressure does not change, yet autoregulation is very important. Whenever a distributing artery to an organ becomes narrowed (e.g., atherosclerotic narrowing of lumen, vasospasm, or partial occlusion with a thrombus) this can result in an autoregulatory response. Narrowing (see stenosis) of distributing arteries increases their resistance and hence the pressure drop along their length. This results in a reduced pressure at the level of smaller arteries and arterioles, which are the primary vessels for regulating blood flow within an organ. These resistance vessels dilate in response to reduced pressure and blood flow. This autoregulation is particularly important in organs such as the brain and heart in which partial occlusion of large arteries can lead to significant reductions in oxygen delivery, thereby leading to tissue hypoxia and organ dysfunction. 7 Blood Flow Active Hyperemia Active hyperemia is the increase in organ blood flow (hyperemia) that is associated with increased metabolic activity of an organ or tissue. An example of active hyperemia is the increase in blood flow that accompanies muscle contraction, which is also called exercise or functional hyperemia in skeletal muscle. Blood flow increases because the increased oxygen consumption of during muscle contraction stimulates the production of vasoactive substances that dilate the resistance vessels in the skeletal muscle. Other examples include the increase in gastrointestinal blood flow during digestion of food, the increase in coronary blood flow when heart rate is increased, and the increase in cerebral blood flow associated with increased neuronal activity in the brain. The figure shows that there is a resting flow associated with the basal oxygen consumption of the tissue. As the oxygen consumption increases, there is generally a near-linear increase in blood flow until the vessels begin to achieve a maximally dilated state. The magnitude of active hyperemia responses differ among organs because of the relative changes in metabolic activity from rest and their vasodilatory capacity. Active hyperemia can result in up to a 50-fold increase in muscle blood flow with maximal exercise, whereas cerebral blood flow may only increase 2-fold with increased neuronal activity. Active hyperemia can also be influenced by competing vasoconstrictor mechanisms. For example, sympathetic activation during exercise can reduce the maximal skeletal muscle active hyperemia compared to what would occur in the absence of sympathetic activation. Active hyperemia may be due to a combination of tissue hypoxia and the generation of vasodilator metabolites such as potassium ion, carbon dioxide, nitric oxide, and adenosine. Reactive Hyperemia Reactive hyperemia is the transient increase in organ blood flow that occurs following a brief period of ischemia (e.g., arterial occlusion). Reactive hyperemia occurs following the removal of a tourniquet, unclamping an artery during surgery, or restoring flow to a coronary artery after recanalization (reopening a closed artery using an angioplasty balloon or clot dissolving drug).In general, the ability of an organ to display reactive hyperemia is similar to its ability to display autoregulation. 8 Blood Flow In the following figure, the left panel shows the effects of a 2 min arterial occlusion on blood flow. In this example, blood flow goes to zero during arterial occlusion. When the occlusion is released, blood flow rapidly increases (i.e., hyperemia occurs) that lasts for several minutes. The hyperemia occurs because during the period of occlusion, tissue hypoxia and a build up of vasodilator metabolites (e.g., adenosine) dilate arterioles and decrease vascular resistance. Then when perfusion pressure is restored (i.e., occlusion released), flow becomes elevated because of the reduced vascular resistance. During the hyperemia, the tissue becomes reoxygenated and vasodilator metabolites are washed out of the tissue. This causes the resistance vessels to regain their normal vascular tone, thereby returning flow to control. The longer the period of occlusion, the greater the metabolic stimulus for vasodilation leading to increases in peak reactive hyperemia and duration of hyperemia. Depending upon the organ, maximal vasodilation as indicated by peak flow, may occur following less than one minute (e.g., coronary circulation) of complete arterial occlusion, or may require several minutes of occlusion (gastrointestinal circulation). Myogenic mechanisms may also contribute to reactive hyperemia in some tissues. By this mechanism, arterial occlusion results in a decrease in pressure downstream in arterioles, which can lead to myogenic-mediated vasodilation. 9 Blood Flow Metabolic Mechanisms of Vasodilation Blood flow is closely coupled to tissue metabolic activity in most organs of the body. For example, an increase in tissue metabolism, as occurs during muscle contraction or during changes in neuronal activity in the brain, leads to an increase in blood flow (active hyperemia). There is considerable evidence that actively metabolizing cells surrounding arterioles release vasoactive substances that cause vasodilation. This is termed the metabolic theory of blood flow regulation. Increases or decreases in metabolism lead to increases or decreases in the release of these vasodilator substances. These metabolic mechanisms ensure that the tissue is adequately supplied by oxygen and that products of metabolism (e.g., CO2, H+, lactate) are removed. Another mechanism that may couple blood flow and metabolism involves changes in the partial pressure of oxygen. Several different mechanisms that may be involved in the metabolic regulation of blood flow are summarized below: Hypoxia: Decreased tissue pO2 resulting from reduced oxygen supply or increased oxygen demand causes vasodilation. Hypoxia-induced vasodilation may be direct (inadequate O2 to sustain smooth muscle contraction) or indirect via the production of vasodilator metabolites. Note, however, that hypoxia induces vasoconstriction in the pulmonary circulation (i.e., hypoxic vasoconstriction), which likely involves the formation of reactive oxygen species, endothelin-1 or productions of arachidonic acid metabolism. Tissue Metabolites and Ions: Adenosine is formed from cellular AMP acted upon by 5'-nucleotidase. The AMP is derived from hydrolysis of intracellular ATP and ADP. Adenosine formation increases during hypoxia and increased oxygen consumption, especially if the latter is accompanied by inadequate oxygen delivery. Adenosine formation is a particularly important mechanism for regulating coronary blood flow. Potassium ion is released by contracting cardiac and skeletal muscle. Small increases in extracellular K+ produces hyperpolarization of vascular smooth muscle and relaxation through stimulation of the electrogenic Na+/K+-ATPase pump and increasing membrane conductance to K+ (K+ activated K+ channels). Extracellular K+ increases when there is an increase in action potential frequency, because with each action potential K+, leaves the cell. Normally, the Na+/K+-ATPase pump is able to restore the ionic gradients; however, the pump does not keep up with rapid depolarizations (i.e., there is a time lag) during muscle contractions and this causes K + to accumulate in the extracellular space. Potassium ion appears to play a significant role in causing active hyperemia in contracting skeletal muscle. Carbon dioxide formation increases during states of increased oxidative metabolism. It readily diffuses from parenchymal cells in which it is produced to the vascular 10 Blood Flow smooth muscle of blood vessels where it causes vasodilation. CO2 plays a significant role in regulating cerebral blood flow. Hydrogen ion increases when CO2 increases or during states of increased anaerobic metabolism, which can produce metabolic acidosis. Like CO2, increased H+ (decreased pH) causes vasodilation, particularly in the cerebral circulation. Lactic acid, a product of anaerobic metabolism, is a vasodilator, although in large part because of its pH effect. Inorganic phosphate is released by the hydrolysis of adenine nucleotides. It may have some vasodilatory activity in contracting skeletal muscle. Myogenic Mechanisms Myogenic mechanisms are intrinsic to the smooth muscle blood vessels, particularly in small arteries and arterioles. If the pressure within a vessel is suddenly increased, the vessel responds by constricting. Diminishing pressure within the vessel causes relaxation and vasodilation. This response is observed in vivo and in isolated, pressurized blood vessels. The myogenic mechanism may play a role in autoregulation of blood flow and in reactive hyperemia. Myogenic behavior has not been clearly identified in all vascular beds, but it has been noted in the splanchnic and renal circulations, and may be present to a small degree in skeletal muscle. Electrophysiological studies have shown that vascular smooth muscle cells depolarize when stretched, leading to contraction. Stretching also increases the rate of smooth muscle pacemaker cells that spontaneously undergo depolarization and repolarization. 11 Blood Flow Nitric Oxide Nitric oxide (NO) is produced by many cells in the body; however, its production by vascular endothelium is particularly important in the regulation of blood flow. Because of its importance in vascular function, abnormal production of NO, as occurs in different disease states, can adversely affect blood flow and other vascular functions. NO Biosynthesis NO is produced from the amino acid L-arginine by the enzymatic action of nitric oxide synthase (NOS). There are two endothelial forms of NOS: constitutive NOS (cNOS; type III) and inducible NOS (iNOS; type II). Cofactors for NOS include oxygen, NADPH, tetrahydrobiopterin and flavin adenine nucleotides. In addition to endothelial NOS, there is a neural NOS (nNOS; type I) that serves as a transmitter in the brain and in different nerves of the peripheral nervous system, such as non-adrenergic, non-cholinergic (NANC) autonomic nerves that innervate penile erectile tissues and other specialized tissues in the body to produce vasodilation. Under normal, basal conditions in blood vessels, NO is continually being produced by cNOS. The activity of cNOS is calcium and calmodulin dependent. There are two basic pathways for the stimulation of cNOS, both of which involve release of calcium ions from subsarcolemmal storage sites. First, shearing forces acting on the vascular endothelium generated by blood flow causes a release of calcium and subsequent cNOS activation. Therefore, increases in blood flow stimulate NO formation (flowdependent NO formation). Second, endothelial receptors for a variety of ligands stimulate calcium release and subsequent NO production (receptor-stimulated NO formation). Included are receptors for acetylcholine, bradykinin, substance-P, adenosine, and many others vasoactive substances. In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980 he and others identified this substance as being NO. 12 Blood Flow The other isoform of endothelial NOS is iNOS. It differs, in part, from cNOS in that its activation is calcium independent. Under normal, basal conditions, the activity of iNOS is very low. The activity of iNOS is stimulated during inflammation by bacterial endotoxins (e.g., lipopolysaccharide) and cytokines such as tumor necrosis factor (TNF) and interleukins. During inflammation, the amount of NO produced by iNOS may be a 1,000-fold greater than that produced by cNOS. Intracellular Mechanisms When NO forms, it has a half-life of only a few seconds, in large part because superoxide anion has a high affinity for NO (both molecules have an unpaired electron making them highly reactive). Therefore, superoxide anion reduces NO bioavailability. NO also avidly binds to the heme moiety of hemoglobin (in red blood cells) and the heme moiety of the enzyme guanylyl cyclase, which is found in vascular smooth muscle cells and most other cells of the body. Therefore, when NO is formed by vascular endothelium, it rapidly diffuses into the blood where it binds to hemoglobin and subsequently broken down. It also diffuses into the vascular smooth muscle cells adjacent to the endothelium where it binds to and activates guanylyl cyclase. This enzyme catalyzes the dephosphorylation of GTP to cGMP, which serves as a second messenger for many important cellular functions, particularly for signalling smooth muscle relaxation. Cyclic GMP induces smooth muscle relaxation by multiple mechanisms including 1. increased intracellular cGMP, which inhibits calcium entry into the cell, and decreases intracellular calcium concentrations (click here for details) 2. activates K+ channels, which leads to hyperpolarization and relaxation 3. stimulates a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to smooth muscle relaxation. Because of the central role of cGMP in NO-mediated vasodilation, drugs (e.g., Viagra) that inhibit the breakdown of cGMP (cGMP-dependent phosphodiesterase inhibitors) are used to enhance NO-mediated vasodilation, particularly in penile erectile tissue in the treatment of erectile dysfunction. Increased cGMP also has an important antiplatelet, anti-aggregatory effect. Vascular Effects of NO Vascular actions of NO include the following: Direct vasodilation (flow dependent and receptor mediated) Indirect vasodilation by inhibiting vasoconstrictor influences (e.g., inhibits angiotensin II and sympathetic vasoconstriction) Anti-thrombotic effect - inhibits platelet adhesion to the vascular endothelium Anti-inflammatory effect - inhibits leukocyte adhesion to vascular endothelium; scavenges superoxide anion Antiproliferative effect - inhibits smooth muscle hyperplasia 13 Blood Flow Because of the above actions of NO, when its production is impaired or its bioavailability is reduced, the following can result: Vasoconstriction (e.g., coronary vasospasm, elevated systemic vascular resistance, hypertension) Thrombosis due to platelet aggregation and adhesion to vascular endothelium Inflammation due to upregulation of leukocyte and endothelial adhesion molecules Vascular hypertrophy and stenosis 14 Blood Flow Skeletal Muscle Blood Flow The regulation of skeletal muscle blood flow is important for two reasons. First, skeletal muscle serves important locomotory functions in the body because of its contractile properties. This is important for voluntary movement (e.g., walking, swimming), postural control, and involuntary movement (e.g., respiration). Contracting muscle consumes large amounts of oxygen to replenish ATP that is hydrolyzed during contraction; therefore, contracting muscle needs to be able to increase its blood flow and oxygen delivery in order to support its metabolic and contractile activities. Second, about 20% of the cardiac output at rest goes to skeletal muscle, which means that about 20% of resting systemic vascular resistance is determined by the vascular resistance of skeletal muscle. For this reason, changes in skeletal muscle resistance and blood flow can greatly influence arterial pressure. As in all tissues, the microcirculation, particularly small arteries and arterioles, is the most important site for the regulation of vascular resistance and blood flow within the muscle. Like cardiac muscle, each muscle fiber (cell) is surrounded by several capillaries. This reduces diffusion distances for the efficient exchange of gasses (O2 and CO2) and other molecules between the blood and the skeletal muscle cells. Characteristics of Skeletal Muscle Blood Flow 1. Skeletal muscle accounts for about 20% of cardiac output and systemic vascular resistance. During extreme physical exertion, more than 80% of cardiac output can be directed to contracting muscles; therefore, skeletal muscle resistance becomes the primary determinant of systemic vascular resistance during exercise. 2. At rest, skeletal muscle blood flows may be 1-4 ml/min per 100g; maximal blood flows may reach 50-100 ml/min per 100g depending upon the muscle type. Therefore, blood flow can increase 20 to 50-fold with maximal vasodilation or active hyperemia. 3. Coordinated, rhythmical contractions (e.g., running) enhance blood flow by means of the skeletal muscle pump mechanism. 4. Sympathetic innervation produces vasoconstriction through alpha1 and alpha2 adrenoceptors located on the vascular smooth muscle. There is a significant amount of sympathetic tone at rest so that abrupt removal of sympathetic influences (e.g., by using an alpha-adrenoceptor blocker) can increase resting flow 2 to 3-fold. 5. Vascular beta2-adrenoceptors produce vasodilation when stimulated by agonists such as epinephrine. 6. There is evidence for sympathetic cholinergic innervation of skeletal muscle arteries, particularly large arteries. Activation of these autonomic nerves during exercise can cause neural-mediated vasodilation through the release of acetylcholine binding to muscarinic receptors. 7. There is a close coupling between oxygen consumption and blood flow. 8. Blood flow is strongly determined by local regulatory (tissue and endothelial) factors such as tissue hypoxia, adenosine, K+, CO2, H+, and nitric oxide. During exercise, these local regulatory mechanisms override the sympathetic vasoconstrictor influences (termed functional sympatholysis). 15 Blood Flow 9. Skeletal muscle blood flow shows a moderate degree of autoregulation. 10. Like the coronary circulation, muscle blood flow can be significantly compromised by extravascular compression that occurs during strong muscular contractions, especially during sustained tetanic contractions. The figure below shows how blood flow changes during phasic contractions. An example of this would be measuring brachial artery inflow during rhythmical contraction of the forearm. When the contractions first begin, blood flow briefly decreases because of compressive forces exerted by the contracting muscles on the vasculature within the muscle. Each time the muscles contract arterial inflow decreases due to extravascular compression, and then arterial inflow increases as the muscles relax. This is repeated each time the muscles contract and relax. If flow were measured in the outflow vein, the venous outflow would increase during contraction and decrease during relaxation - the opposite of what occurs on the arterial side of the circulation. After just a couple of seconds, mean and peak flows begin to increase (active hyperemia). After 15-20 seconds the increased flow will reach a steady state that is determined by the force and frequency of contraction, and the metabolic demands of the tissue. When contractions cease, blood flow may transiently increase because of the loss of compressive forces, and then over the next minute or so the flow will return to control. 16 ...
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