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❖ CASE 14 A 21-year-old woman presents to her primary care physician because she wants to begin an exercise program for weight loss. She is concerned because when she exercised in the past, she noticed that her heart seemed to beat rapidly. She has no known medical history and has no family members with medical problems. She denies chest pain. After a thorough physical examination, everything appears to be normal and the physician reassures the patient that her increased heart rate is probably a normal response to exercise. ◆ ◆ ◆ In what two ways is blood flow to skeletal muscle controlled? What are some differences between cerebral circulation and skeletal circulation? What are some forms of extrinsic control of blood flow? 118 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 14: REGIONAL BLOOD FLOW Summary: A 21-year-old woman who is beginning an exercise program has a normal examination and normal physiologic increased heart rate with exercise. ◆ Control of blood flow in skeletal muscle: Sympathetic innervation and local metabolic control. ◆ Differences between cerebral circulation and skeletal circulation: Cerebral blood flow demonstrates autoregulation and is controlled almost entirely by local metabolic factors. Skeletal muscle relies on input from both sympathetic innervation and local metabolic factors. ◆ Forms of extrinsic control of blood flow: Sympathetic innervation and vasoactive hormones (bradykinin, serotonin, prostaglandins, angiotensin II, antidiuretic hormone [ADH], etc.). CLINICAL CORRELATION A more complete understanding of the cardiovascular changes that take place under varying physiologic conditions and under the influence of medications requires knowledge about the factors that regulate blood flow to specific vascular beds. Exercise is a common physiologic condition during which there are many changes. Increases in blood flow to contracting skeletal muscle are caused by both extrinsic and intrinsic factors. With increased muscle metabolism, there is an increase in vasodilator metabolites such as lactic acid, potassium, and adenosine. The increase in vasodilator metabolites represents intrinsic control over skeletal circulation. Extrinsic factors include sympathetic system activation, which results in increased heart rate and elevated venous pressure, thus increasing cardiac output. If the exercise is intense, sympathetic stimulation results in increased arteriolar resistance in the gastrointestinal tract, kidneys, and other organs, resulting in shunting of blood toward the exercising muscles. Adequate blood flow to a tissue allows for exchange of substrates and metabolites between cells of the tissue and the blood as blood flows through capillaries. APPROACH TO REGIONAL BLOOD FLOW Objectives 1. 2. 3. 4. Describe the mechanisms of intrinsic control of regional blood flow. Describe the mechanisms of extrinsic control of regional blood flow. Compare and contrast the control of blood flow to the heart, brain, skeletal muscle, and skin. Describe the transfer of substrates, metabolites, and volume between capillaries and interstitial fluid. CLINICAL CASES 119 Definitions Autoregulation: The process of maintaining blood flow constant in the face of varying mean arterial pressures. Active hyperemia: The increase in blood flow in response to an increase in metabolic activity. Reactive hyperemia: The temporary increase in blood flow seen following a period of ischemia. Edema safety factor: Compensatory mechanisms (mostly increases in lymph flow) that can accommodate increases in capillary filtration and mitigate edema formation. DISCUSSION Blood flow to any organ of the body over any period of time normally is correlated closely with that organ’s metabolic activity. If activity increases, blood flow increases to that organ, but not to others unless their levels of activity change as well. This local control of blood flow is accomplished by intrinsic and extrinsic factors that act to alter the resistance of small arteries and arterioles in the vascular beds of the organ. Local changes in resistance can result in local changes in blood flow, as described by the following equation: Local flow = mean arterial pressure/local resistance As discussed in Cases 12 and 13, mean arterial pressure (MAP) is maintained at a fairly constant level and is determined by the interplay of cardiac output (CO) and total peripheral resistance (TPR). Because a change in resistance in any vascular bed will affect TPR, the only way MAP can remain constant is for CO to change or for there to be equal and opposite changes in resistance in other vascular beds to keep TPR constant. Normally, unless the local changes in resistance are great, CO will change so that the metabolic demands of all the organs of the body are met. Many organs, especially the brain, exhibit autoregulation of their blood flow. As long as their metabolic activities do not change, they are able to maintain a constant blood flow over a wide range of mean arterial pressures. Thus, in circumstances in which MAP does deviate from normal levels, local arteriolar resistance will change so that blood flow still matches metabolic demand. All organs, especially skeletal and cardiac muscles, exhibit active and reactive hyperemia. Active hyperemia is the increase in blood flow that occurs as the metabolic activity of an organ increases. The mechanism for the increased blood flow is a decrease in local resistance in the face of a stable MAP. The result is a matching of blood flow to metabolic demand. Reactive hyperemia is the increase in blood flow that occurs after restoration of blood flow to an organ that has been deprived temporarily of blood. The mechanism 120 CASE FILES: PHYSIOLOGY also is a decrease in local resistance, but one that develops during the period of ischemia. The changes in local arteriolar resistance that occur during autoregulation, active hyperemia, and reactive hyperemia are due mostly, if not solely, to local intrinsic mechanisms. During autoregulation, a change in MAP initially causes a change in blood flow. If MAP is increased, flow initially increases and local concentrations of metabolites (CO2, K+, H+, adenosine) decrease as a result of washout; local concentrations of substrates (O2) increase because supply is greater than demand. Opposite changes in metabolite and substrate concentrations occur if MAP is decreased to decrease flow initially. Because metabolites relax and substrates support the contraction of arteriolar smooth muscle, changes in their local concentrations alter local resistance to blood flow to bring flow back to its previous state. During active hyperemia, increased organ metabolic activity tends to increase metabolite concentrations and decrease substrate concentrations and thus bring about relaxation of arteriolar smooth muscle, decreased local resistance, and increased local blood flow. During reactive hyperemia, local metabolites accumulate and local substrates decrease during the period of ischemia, causing arteriolar dilation and a decrease in local resistance. Then, when the obstruction causing the ischemia is removed, blood flow is increased as a result of the arteriolar dilation. Most often, reactive hyperemia is thought of in relation to those times when flow is obstructed by resting on an arm or leg in such a way that flow is obstructed temporarily. However, reactive hyperemia also occurs along with active hyperemia during muscle contraction. For example, during contraction of ventricular muscle, vessels embedded in the myocardium are compressed to block flow. Metabolites continue to build further, relaxing resistance vessels, so that when flow can begin again during ventricular relaxation, it is increased. In addition to the intrinsic control described above, regional blood flow may be regulated by extrinsic factors, mainly the sympathetic nervous system. The degree of sympathetic innervation of small arteries and arterioles varies from organ to organ. In some organs (eg, skin, intestine, kidney) it is quite dense, and sympathetic tone exists even under normal resting conditions. The norepinephrine released by these nerves contracts the smooth muscle of these vessels to varying degrees, thus regulating local resistance to blood flow. Under most conditions, this extrinsic mechanism works in concert with intrinsic mechanisms to provide blood flow that is adequate to meet the metabolic demands of the organs or, in the case of the kidney, to fulfill its role in maintaining homeostasis. However, under conditions in which the baroreceptor reflex or other reflexes are elicited, sympathetic tone will increase to override intrinsic mechanisms temporarily. This will result in an increase in both local and total peripheral resistance to restore MAP. The result of this is a decrease in blood flow to organs with a high degree of extrinsic regulation (eg, skin, intestine, kidney) and a maintenance or increase in blood flow to organs with a lower degree of extrinsic control (eg, brain and heart). 121 CLINICAL CASES Capillary Physiology Exchange of substrates and metabolites between the blood and tissues of the body takes place at the level of the capillary. Exchange is possible because every cell of the body is within a few microns of one of the billions of capillaries in the body and because the capillary wall is thin, being composed of a single layer of endothelial cells. In addition, endothelial cells abut one another in such a way that there are clefts between them, resulting in a high permeability. Thus, small molecules such as oxygen, carbon dioxide, ions, glucose, amino acids, urea, and lactate, as well as water, can move readily between the capillary lumen and the interstitial fluid. The majority of exchange between the capillary and the interstitium takes place by means of diffusion. However, the relatively high permeability results in bulk flow of volume either out of (filtration) or into (absorption) the capillary, depending on the balance of forces across the capillary wall. There is a hydrostatic pressure in the capillary (Pc) that is owing to the forces responsible for blood flow. This pressure favors filtration. There also is a hydrostatic pressure exerted by the interstitial fluid (PIF). This pressure, if above atmospheric pressure, will favor absorption into the capillary. The other forces across the wall are osmotic forces that are due mainly to the presence of proteins in the blood and the interstitium. Proteins in the blood, mainly albumin, cannot cross the capillary wall readily and thus exert an osmotic force (often called an oncotic force, πc). This force favors absorption. Proteins in the interstitial fluid exert a force (πIF) that favors filtration. The interaction of all these forces can be expressed in what is called the Starling equation for the capillary: Jv = Kf [(Pc - PIF) - (πc - pIF)] where Jv represents the net flux of volume and Kf is the filtration coefficient (a measure of the permeability of the capillary wall that will vary from one capillary bed to another). If the algebraic sum of the forces favoring filtration exceeds the sum of those favoring absorption, fluid will leave the capillary at a rate determined by Kf and the net force. Capillary hydrostatic force (Pc) changes along the length of the capillary, being higher at the arteriolar end than at the venule end. This can result in net filtration at the arteriolar end and absorption at the venule end. Pc also can change from moment to moment because of contraction and relaxation of arteriolar and precapillary sphincter smooth muscle. The presence of this muscle also means that pressure in the large arteries can increase and decrease with little change in Pc. In contrast, changes in venous pressure always result in changes in Pc. Elevations in venous pressure often lead to a marked increase in filtration and the development of edema. Although capillary oncotic pressure (πc) does not change acutely, decreases in plasma albumin do occur with many liver and kidney diseases. With hypoalbuminemia, the main force responsible for absorption, pc will decrease, and this too can result in edema. 122 CASE FILES: PHYSIOLOGY Interstitial fluid hydrostatic force (PIF) is interesting in that it normally is subatmospheric and thus favors filtration rather than the expected absorption. PIF is subatmospheric as a result of the action of lymphatic vessels. These blind-ended vessels are responsible for the return of the net filtered fluid and protein to the circulation via the thoracic duct. Because of their pumping action, small increases in capillary filtration can be accommodated without interstitial volume increasing to the point of edema. Thus, lymphatics are responsible for an edema safety factor. However, if lymphatic function is impaired, edema will form even if capillary forces are normal. COMPREHENSION QUESTIONS [14.1] A 22-year-old subject who is sitting quietly begins to squeeze a rubber ball repetitively in her right hand, using moderate strength. During this time her mean arterial pressure does not increase. Using her cardiovascular state prior to the exercise as a baseline, which of the following would best describe her cardiovascular state during the exercise? A. B. C. D. E. [14.2] A 25-year-old otherwise healthy patient is involved in a motor vehicle accident, and suffers appreciable blood loss. The cardiac output is falling because of a loss of blood. As a compensatory mechanism, the total peripheral resistance increases to attempt to maintain MAP. Which of the following vasculature corresponding to the listed organ is contributing the least to the elevated TPR? A. B. C. D. E. [14.3] Increased blood flow through her right brachial artery No change in cardiac output Increased total peripheral resistance Decreased blood flow through her left brachial artery Decreased heart rate Brain Small intestine Kidney Skeletal muscle Skin If blood flow to an arm is obstructed for more than 30 seconds or so during the process of a blood pressure measurement, the release of the blood pressure cuff will be followed by a temporarily higher than resting level of blood flow through the arm. Which of the following best describes the temporarily higher blood flow? A. B. C. D. Accompanied by an increase in total peripheral resistance Called active hyperemia Caused by a temporary increase in mean arterial pressure Caused by local vasodilation resulting from the buildup of local metabolites E. Caused by the shifting of blood flow from other organs CLINICAL CASES [14.4] 123 A patient has a renal condition that results in the loss of albumin in the urine that exceeds the body’s albumin production. The resulting hypoalbuminemia will lead to edema of the hands, face, and feet. Which of the following is likely to be noted? A. B. C. D. E. Decrease in interstitial fluid hydrostatic pressure (PIF) Increase in capillary hydrostatic pressure (Pc) Increase in lymph flow Increase in plasma oncotic pressure (πc) Increase in the filtration coefficient (Kf) of capillaries in the skin Answers [14.1] A. The increased metabolic activity of the muscles in the subject’s right arm will induce relaxation of small arteries and arterioles, thus reducing local resistance as well as total peripheral resistance. This, along with no change in mean arterial pressure, will result in an increase in blood flow through her right brachial artery. The increased blood flow to the right arm will be accomplished by an increase in heart rate and cardiac output, not by a decrease in flow to other organs. [14.2] A. In cases in which cardiac output is inadequate, compensatory mechanisms come into play so that blood flow to vital organs such as the heart and brain is preserved as much as possible. One of these mechanisms is activation of sympathetic nerves to constrict small arteries and arterioles in organs whose vessels are heavily innervated. Vessels in the brain and heart undergo the least vasoconstriction. [14.3] D. During the occlusion, metabolites build up in the arm tissues. These metabolites cause relaxation of arteriolar smooth muscle and decreased local vascular resistance. When the dilated local vessels are exposed again to blood under normal mean arterial pressure, flow is greater than it was before occlusion. This reactive hyperemia is temporary because the increased flow will return metabolites to their normal resting value. Neither mean arterial pressure nor blood flow to other organs need be altered during this time. [14.4] C. Hypoalbuminemia results in a decreased πc, the major force favoring absorption. This results in an increase in capillary filtration, an increase in lymph flow, and an increase in PIF to levels above atmospheric. Once the edema safety factor is exceeded, edema results. Unless endothelial cells were damaged, there would be no change in Kf. Also, hypoalbuminemia has no direct effect on Pc (it most likely would decrease as a result of arteriolar constriction to maintain mean arterial pressure). 124 CASE FILES: PHYSIOLOGY PHYSIOLOGY PEARLS ❖ ❖ ❖ ❖ ❖ Local resistance to blood flow in all tissues changes such that blood flow is adequate to meet the metabolic demands of the tissues. In certain tissues—skin, gastrointestinal, renal—but not in others— heart, brain—local regulation can be temporarily overridden by extrinsic factors in attempts to maintain mean arterial pressure. Changes in blood flow through any vascular bed normally are met by changes in cardiac output. The exchange of substrates and metabolites between blood and tissue occurs at the level of the capillaries, mostly by means of diffusion. Fluid filtration out of and absorption into capillaries depend on the balance between hydrostatic and osmotic forces across the capillary wall. Disruptions in this balance can lead to edema. REFERENCES Levy M, Pappano A. Cardiovascular system. In: Levy MN, Koeppen BM, Stanton BA, eds. Berne & Levy, Principles of Physiology. 4th ed. Philadelphia, PA: Mosby; 2006:298-319. Granger DN. Regulation of regional blood flow and capillary exchange. In: Johnson LR, ed. Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:245-258, 235-244.