Cardiovascular Physiology Regulation of Arterial Pressure PDF

Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 1 Relationships between cardiac output and venous return It should be clear from the previous discussion that one of the most important factors determining cardiac output is left ventricular end-diast...

Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 1 Relationships between cardiac output and venous return It should be clear from the previous discussion that one of the most important factors determining cardiac output is left ventricular end-diastolic volume. In turn, left ventricular end-diastolic volume depends on venous return, which also determines right atrial pressure. Thus, it follows that there is not only a relationship between cardiac output and end-diastolic volume but also a relationship between cardiac output and right atrial pressure. Cardiac output and venous return each can be examined separately as a function of right atrial pressure. These separate relationships also can be combined in a single graph to visualize the normal interrelationship between cardiac output and venous return (see Fig. 4.25). The combined graphs can be used to predict the effects of changes in various cardiovascular parameters on cardiac output, venous return, and right atrial pressure. Cardiac function curve The cardiac function curve or cardiac output curve, shown in Figure 4.26, is based on the Frank-Starling relationship for the left ventricle. The cardiac function curve is a plot of the relationship between cardiac output of the left ventricle and right atrial pressure. Again, recall that right atrial pressure is related to venous return, end-diastolic volume, and end- diastolic fiber length: As venous return increases, right atrial pressure increases, and end- diastolic volume and end-diastolic fiber length increase. Increases in end-diastolic fiber length produce increases in stroke volume and cardiac output. Thus, in the steady state, the volume of blood the left ventricle ejects as cardiac output equals or matches the volume it receives in venous return. Increases in end-diastolic volume (i.e., right atrial pressure) produce increases in cardiac output by the Frank-Starling mechanism. However, this “matching” occurs only up to a point: When right atrial pressure reaches a value of approximately 4 mm Hg, cardiac output can no longer keep up with venous return, and the cardiac function curve levels off. This maximum level of cardiac output is approximately 9 L/min. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 2 Vascular function curve The vascular function curve or venous return curve, shown in Figure 4.26, depicts the relationship between venous return and right atrial pressure. Venous return is blood flow through the systemic circulation and back to the right heart. The inverse relationship between venous return and right atrial pressure is explained as follows: Venous return back to the heart, like all blood flow, is driven by a pressure gradient. The lower the pressure in the right atrium, the higher the pressure gradient between the systemic arteries and the right atrium, and the greater the venous return. Thus, as right atrial pressure increases, this pressure gradient decreases, and venous return also decreases. The knee (flat portion) of the vascular function curve occurs at negative values of right atrial pressure. At such negative values, the veins collapse, impeding blood flow back to the heart. Although the pressure gradient has increased (i.e., as right atrial pressure becomes negative), venous return levels off because the veins have collapsed, creating a resistance to blood flow. Mean Systemic Filling Pressure The value for right atrial pressure at which venous return is zero is called the mean systemic filling pressure. It is the point at which the vascular function curve intersects the X-axis (i.e., where venous return is zero and right atrial pressure is at its highest value). Mean systemic filling pressure or mean circulatory pressure is the pressure that would be measured throughout the cardiovascular system if the heart were stopped. Under these conditions, pressure would be the same throughout the vasculature and, by definition, would be equal to the mean systemic filling pressure. When pressures are equal throughout the vasculature, there is no blood flow, and therefore venous return is zero (because there is no pressure gradient or driving force). Two factors influence the value for mean systemic filling pressure: (1) the blood volume and (2) the distribution of blood between the unstressed volume and the stressed volume. In turn, the value for mean systemic filling pressure determines the intersection point (zero flow) of the vascular function curve with the X-axis. Figure 4.27 reviews the concepts of unstressed volume and stressed volume and relates them to mean systemic filling pressure. The unstressed volume (thought of as the volume of blood that the veins can hold) is the volume of blood in the vasculature that produces no pressure. The stressed volume (thought of as the volume in the arteries) is the volume that produces pressure by stretching the elastic fibers in the blood vessel walls. ♦ Consider the effect of changing blood volume on mean systemic filling pressure. When the blood volume ranges from 0 to 4 L, all of the blood will be in the unstressed volume (the veins), producing no pressure, and the mean systemic filling pressure will be zero. When blood volume is greater than 4 L, some of the blood will be in the stressed volume (the arteries) and produce pressure. For example, if the total blood volume is 5 L, 4 L is in the unstressed volume, producing no pressure, and 1 L is in the stressed volume, producing a pressure of Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 3 approximately 7 mm Hg (on the graph, read mean systemic filling pressure as 7 mm Hg at a blood volume of 5 L). It now should be clear how changes in blood volume can alter the mean systemic filling pressure (see Fig. 4.26). If blood volume increases, the amount of blood in the unstressed volume will be unaffected (if it is already full), but the amount of blood in the stressed volume will increase. When stressed volume increases, mean systemic filling pressure increases, and the vascular function curve and its intersection point with the X-axis shift to the right. If blood volume decreases, then stressed volume decreases, mean systemic filling pressure decreases, and the vascular function curve and its intersection point with the X-axis shift to the left. ♦ Redistribution of blood between the unstressed volume and the stressed volume also produces changes in mean systemic filling pressure. For example, if the compliance of the veins decreases (e.g., venoconstriction), the veins can hold less blood, and blood shifts from the unstressed volume to the stressed volume. Although total blood volume is unchanged, the shift of blood increases the mean systemic filling pressure and shifts the vascular function curve to the right. Conversely, if the compliance of the veins increases (e.g., venodilation), the veins can hold more blood. Hence, the unstressed volume will increase, the stressed volume and mean systemic filling pressure will decrease, and the vascular function curve shifts to the left. Increased blood volume and decreased compliance of the veins produce an increase in mean systemic filling pressure and shift the vascular function curve to the right. Decreased blood volume and increased compliance of the veins produce a decrease in mean systemic filling pressure and shift the vascular function curve to the left. Slope of the Vascular Function Curve If mean systemic filling pressure is fixed or constant, the slope of the vascular function curve can change by rotating it. The slope of the vascular function curve is determined by total peripheral resistance (TPR), which reflects the resistance of the arterioles. Changes in the slope indicate how efficiently blood flows back to the heart for a given right atrial pressure: Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 4 ♦ A decrease in TPR causes the vascular function curve to rotate clockwise, resulting in a steeper slope. A steeper slope means that venous return increases more significantly for a given right atrial pressure. Decreased resistance in the arterioles (decreased TPR) reduces the impedance to blood flow, allowing blood to flow more easily from the arterial to the venous side of the circulation and back to the heart. ♦ An increase in TPR causes the vascular function curve to rotate counterclockwise, resulting in a flatter slope. A flatter slope means that venous return decreases for a given right atrial pressure. Increased resistance in the arterioles (increased TPR) increases the difficulty of blood flow from the arterial to the venous side, reducing venous return to the heart. Combining cardiac and vascular function curves Effects of changes in blood volume Changes in blood volume alter mean systemic filling pressure and thereby alter the vascular function curve (Fig. 4.29). The effects of increases in blood volume (e.g., transfusion) are shown in Figure 4.29A. Increases in blood volume increase the amount of blood in the stressed volume and therefore increase the mean systemic filling pressure. Mean systemic filling pressure is the point on the vascular function curve where venous return is zero. Increases in blood volume shift this intersection point to the right and therefore shift the curve to the right in a parallel manner. (The shift is parallel because there is no accompanying change in TPR, which determines the slope of the vascular function curve.) In the new steady state, the cardiac and vascular function curves intersect at a new point at which cardiac output is increased and right atrial pressure is increased. The effects of decreases in blood volume (e.g., hemorrhage) are shown in Figure 4.29B. The decrease in blood volume decreases the amount of blood in the stressed volume and mean systemic filling pressure, which shifts the vascular function curve to the left in a parallel manner. In the new steady state, cardiac output is decreased and right atrial pressure is decreased. Changes in venous compliance produce effects similar to those produced by changes in blood volume. Decreases in venous compliance cause a shift of blood out of the unstressed volume and into the stressed volume and produce changes similar to those caused by increases in blood volume, a parallel shift to the right. Likewise, increases in venous compliance cause a shift of blood into the unstressed volume and out of the stressed volume and produce changes similar to those caused by decreased blood volume, a parallel shift to the left. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 5 Effects of changes in total peripheral resistance Changes in TPR reflect changes in the degree of constriction of the arterioles. Such changes alter the extent to which blood is “held” on the arterial side of the circulation (i.e., in the stressed volume). Thus changes in TPR alter both arterial blood pressure and venous return to the heart. For example, an increase in TPR, by restricting the flow of blood out of the arteries, produces an increase in arterial blood pressure and, concomitantly, a decrease in venous return. The effects of changes in TPR on the cardiac and vascular function curves are therefore more complicated than those produced by changes in contractility or blood volume. Changes in TPR alter both curves: The cardiac function curve changes because of a change in afterload (arterial blood pressure), and the vascular function curve changes because of a change in venous return (Fig. 4.30). ♦ The effects of an increase in TPR (i.e., constriction of the arterioles) are shown in Figure 4.30 A. (1) Increases in TPR cause an increase in arterial pressure by “holding” blood in the arteries. This increase in arterial pressure produces an increase in afterload on the heart, which decreases cardiac output. The cardiac function curve shifts downward as a result of the increased afterload. (2) The increase in TPR produces a counterclockwise rotation of the vascular function curve. This rotation means that less blood returns to the heart for a given right atrial pressure—venous return is decreased. (3) The combination of these two changes is shown in Figure 4.30 A. The curves intersect at a new steady state point at which both cardiac output and venous return are decreased. In the figure, right atrial pressure is shown as unchanged. Actually, the final effect of increased TPR on right atrial pressure is not easily predictable because TPR has different directional effects via the cardiac and vascular function curves. An increase in TPR decreases cardiac output, which increases right atrial pressure (less blood is pumped out of the heart). And, an increase in TPR decreases venous return, which decreases right atrial pressure (less flow back to the heart). Depending on the relative magnitude of the effects on the cardiac and vascular function curves, right atrial pressure can be slightly increased, slightly decreased, or unchanged. The figure shows it as unchanged—the compromise position. ♦ The effects of a decrease in TPR (i.e., dilation of the arterioles) are shown in Figure 4.30 B. (1) Decreases in TPR cause a decrease in arterial pressure and a decrease in afterload, causing the cardiac function curve to shift upward. (2) The decrease in TPR produces a clockwise rotation of the vascular function curve, which means that more blood returns to the heart for a given right atrial pressure—venous return is increased. The curves intersect at a new steady state point at which both cardiac output and venous return are increased. In the figure, right atrial pressure is shown as unchanged. However, the effect of decreased TPR on right atrial pressure is not easily predicted because a change in TPR has different effects via the cardiac and vascular function curves. A decrease in TPR increases cardiac output, which decreases right atrial pressure (more blood is pumped out of the heart). And a decrease in TPR increases venous return, which increases right atrial pressure (increased Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 6 flow back to the heart). Depending on the relative magnitude of the effects, right atrial pressure can be slightly increased, slightly decreased, or unchanged. In the figure, it is shown as the compromise, or unchanged. Regulation of arterial pressure Regulation of Arterial Pressure The overall function of the cardiovascular system is to deliver blood to the tissues so that O₂ and nutrients can be provided and waste products carried away. Blood flow to the tissues is driven by the difference in pressure between the arterial and venous sides of the circulation. Mean arterial pressure (Pₐ) is the driving force for blood flow, and it must be maintained at a high, constant level of approximately 100 mm Hg. Because of the parallel arrangement of arteries off the aorta, the pressure in the major artery serving each organ is equal to Pₐ. (The blood flow to each organ is then independently regulated by changing the resistance of its arterioles through local control mechanisms.) The mechanisms that help to maintain Pₐ at a constant value are discussed in this section. The basis for this regulation can be appreciated by examining the equation for Pₐ: Pₐ = Cardiac output × TPR where Pₐ = Mean arterial pressure (mm Hg) Cardiac output = Cardiac output (mL/min) TPR = Total peripheral resistance (mm Hg/mL/min) Notice that the equation for Pₐ is simply a variation of the familiar equation for pressure, flow, and resistance, used previously in this chapter. Inspection of the equation reveals that Pₐ can be changed by altering the cardiac output (or any of its parameters), altering the TPR (or any of its parameters), or altering both cardiac output and TPR. Be aware that this equation is deceptively simple because cardiac output and TPR are not independent variables. In other words, changes in TPR can alter cardiac output and changes in cardiac output can indirectly alter TPR. Therefore it cannot be stated that if TPR doubles, Pₐ also doubles. (In fact, when TPR doubles, cardiac output simultaneously is almost halved and Pₐ will increase only modestly.) Likewise, it cannot be stated that if cardiac output is halved, Pₐ also will be halved. (Rather, if cardiac output is halved, there is a compensatory increase in TPR and Pₐ will decrease but not be halved.) This section discusses the mechanisms responsible for maintaining a constant value for arterial pressure. These mechanisms closely monitor Pₐ and compare it with the set-point value of approximately 100 mm Hg. If Pₐ increases above the set point or decreases below the set point, the cardiovascular system makes adjustments in cardiac output, in TPR, or in both, attempting to return Pₐ to the set-point value. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 7 Pₐ is regulated by two major systems. The first system is neurally mediated and known as the baroreceptor reflex. The baroreceptor reflex attempts to restore Pₐ to its set-point value in a matter of seconds. The second system is hormonally mediated and includes the renin– angiotensin II–aldosterone system, which regulates Pₐ more slowly, primarily by its effect on blood volume. Baroreceptor Reflex The baroreceptor mechanisms are fast, neurally mediated reflexes that attempt to keep arterial pressure constant via changes in the output of the sympathetic and parasympathetic nervous systems to the heart and blood vessels. Pressure sensors, the baroreceptors, are located within the walls of the carotid sinus and the aortic arch and relay information about blood pressure to cardiovascular vasomotor centers in the brain stem. The vasomotor centers, in turn, coordinate a change in output of the autonomic nervous system to effect the desired change in Pₐ. Thus, the reflex arc consists of sensors for blood pressure; afferent neurons, which carry the information to the brain stem; brain stem centers, which process the information and coordinate an appropriate response; and efferent neurons, which direct changes in the heart and blood vessels. Renin–Angiotensin II–Aldosterone System The renin–angiotensin II–aldosterone system regulates Pₐ primarily by regulating blood volume. This system is much slower than the baroreceptor reflex because it is hormonally, rather than neurally, mediated. The renin–angiotensin II–aldosterone system is activated in response to a decrease in Pₐ. Activation of this system, in turn, produces a series of responses that attempt to restore arterial pressure to normal. This mechanism, shown in Figure 4.33, has the following steps: 1. A decrease in Pₐ causes a decrease in renal perfusion pressure, which is sensed by mechanoreceptors in afferent arterioles of the kidney. The decrease in Pₐ causes prorenin to be converted to renin in the juxtaglomerular cells (by mechanisms not entirely understood). Renin secretion by the juxtaglomerular cells is also increased by stimulation of renal sympathetic nerves and by β₁ agonists such as isoproterenol; renin secretion is decreased by β₁ antagonists such as propranolol. 2. Renin is an enzyme. In plasma, renin catalyzes the conversion of angiotensinogen (renin substrate) to angiotensin I, a decapeptide. Angiotensin I has little biologic activity, other than to serve as a precursor to angiotensin II. 3. In the lungs and kidneys, angiotensin I is converted to angiotensin II, catalyzed by angiotensin-converting enzyme 1 (ACE 1). An angiotensin-converting enzyme inhibitor (ACEi), such as captopril, blocks the production of angiotensin II and all of its physiologic actions. 4. Angiotensin II is an octapeptide with the following biologic actions in the adrenal cortex, vascular smooth muscle, kidneys, and brain, where it activates type 1 G protein–coupled angiotensin II receptors (AT₁ receptors). Inhibitors of AT₁ receptors, such as losartan, block the actions of angiotensin II at the level of the target tissues. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 8 o Angiotensin II acts on the zona glomerulosa cells of the adrenal cortex to stimulate the synthesis and secretion of aldosterone. Aldosterone then acts on the principal cells of the renal distal tubule and collecting duct to increase Na⁺ reabsorption and, thereby, to increase ECF volume and blood volume. The actions of aldosterone require gene transcription and new protein synthesis in the kidney. These processes require hours to days to occur and account for the slow response time of the renin–angiotensin II–aldosterone system. o Angiotensin II also has its own direct action on the kidney, independent of its actions through aldosterone. Angiotensin II stimulates Na⁺–H⁺ exchange in the renal proximal tubule and increases the reabsorption of Na⁺ and HCO₃⁻. o Angiotensin II acts on the hypothalamus to increase thirst and water intake. It also stimulates secretion of antidiuretic hormone (ADH), which increases water reabsorption in collecting ducts. By increasing total body water, these effects complement the increases in Na⁺ reabsorption (caused by aldosterone and Na⁺– H⁺ exchange), thereby increasing ECF volume, blood volume, and blood pressure. o Angiotensin II also acts directly on the arterioles by binding to G protein– coupled AT₁ receptors and activating an inositol 1,4,5-triphosphate (IP₃)/Ca²⁺ second messenger system to cause vasoconstriction. The resulting increase in TPR leads to an increase in Pₐ. o Additional actions of angiotensin II (not shown in Fig. 4.33) are pro- inflammatory, pro-oxidative stress, pro-proliferative, and pro-fibrotic. In summary, a decrease in Pₐ activates the renin–angiotensin II–aldosterone system, producing a set of responses that attempt to increase Pₐ back to normal. The most important of these responses is the effect of aldosterone to increase renal Na⁺ reabsorption. When Na⁺ reabsorption is increased, total body Na⁺ content increases, which increases ECF volume and blood volume. Increases in blood volume produce an increase in venous return and, through the Frank-Starling mechanism, an increase in cardiac output. The increase in cardiac output produces an increase in Pₐ. There also is a direct effect of angiotensin II to constrict arterioles, increasing TPR and contributing to the increase in Pₐ (Box 4.2). Also shown in Figure 4.33 is the pathway that degrades angiotensin II to Ang 1-7 via angiotensin-converting enzyme 2 (ACE 2). The actions of Ang 1-7 are opposite those of angiotensin II. Ang 1-7 acts via a different receptor, Mas R, to produce vasodilation, and thus is counterregulatory to angiotensin II. Other actions of Ang 1-7 are also opposite those of angiotensin II: it is anti-inflammatory, anti-oxidative stress, anti-proliferative, and anti- fibrotic. ACE 2 is believed to be the receptor and point of entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for causing coronavirus disease (COVID-19). Other Regulatory Mechanisms In addition to the baroreceptor reflex and the renin–angiotensin II–aldosterone system, other mechanisms that may aid in regulating mean arterial pressure include chemoreceptors for O₂ in the carotid and aortic bodies, chemoreceptors for CO₂ in the brain, ADH, and atrial natriuretic peptide (ANP). Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 9 Peripheral Chemoreceptors in Carotid and Aortic Bodies Peripheral chemoreceptors for O₂ are located in the carotid bodies near the bifurcation of the common carotid arteries and in the aortic bodies along the aortic arch. The carotid and aortic bodies have high blood flow, and their chemoreceptors are primarily sensitive to decreases in the partial pressure of O₂ (Pₒ₂). The chemoreceptors also are sensitive to increases in the partial pressure of CO₂ (Pₒ₂) and decreases in pH, particularly when Pₒ₂ is simultaneously decreased. In other words, the response of the peripheral chemoreceptors to decreased arterial Pₒ₂ is greater when the Pₒ₂ is increased or the pH is decreased. When arterial Pₒ₂ decreases, there is an increased firing rate of afferent nerves from the carotid and aortic bodies that activates sympathetic vasoconstrictor centers. As a result, there is arteriolar vasoconstriction in skeletal muscle, renal, and splanchnic vascular beds. In addition, there is an increase in parasympathetic outflow to the heart that produces a transient decrease in heart rate. The slowing of the heart rate is only transient, however, because these peripheral chemoreceptors are primarily involved in the control of breathing (see Chapter 5). The decrease in arterial Pₒ₂ also produces an increase in ventilation that independently decreases parasympathetic outflow to the heart, which increases the heart rate (lung inflation reflex). Central Chemoreceptors The brain is intolerant of decreases in blood flow, and therefore it is not surprising that chemoreceptors are located in the medulla itself. These chemoreceptors are most sensitive to CO₂ and pH and less sensitive to O₂. Changes in Pₒ₂ or pH stimulate the medullary chemoreceptors, which then direct changes in outflow of the medullary cardiovascular centers. The reflex that involves cerebral chemoreceptors operates as follows: If the brain becomes ischemic (i.e., there is decreased cerebral blood flow), cerebral Pₒ₂ immediately increases and pH decreases. The medullary chemoreceptors detect these changes and direct an increase in sympathetic outflow that causes intense arteriolar vasoconstriction in many vascular beds and an increase in TPR. Blood flow is thereby redirected to the brain to maintain its perfusion. As a result of this vasoconstriction, Pₐ increases dramatically, even to life-threatening levels. The Cushing reaction illustrates the role of the cerebral chemoreceptors in maintaining cerebral blood flow. When intracranial pressure increases (e.g., tumors, head injury), there is compression of cerebral arteries, which results in decreased perfusion of the brain. There is an immediate increase in Pₒ₂ and a decrease in pH because CO₂ generated from brain tissue is not adequately removed by blood flow. The medullary chemoreceptors respond to these changes in Pₒ₂ and pH by directing an increase in sympathetic outflow to the blood vessels. Again, the overall effect of these changes is to increase TPR and dramatically increase Pₐ. Antidiuretic Hormone ADH, a hormone secreted by the posterior lobe of the pituitary gland, regulates body fluid osmolarity and participates in the regulation of arterial blood pressure. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 10 There are two types of receptors for ADH: V₁ receptors, which are present in vascular smooth muscle, and V₂ receptors, which are present in principal cells of the renal collecting ducts. When activated, the V₁ receptors cause vasoconstriction of arterioles and increased TPR. The V₂ receptors are involved in water reabsorption in the collecting ducts and the maintenance of body fluid osmolarity. ADH secretion from the posterior pituitary is increased by two types of stimuli: by increases in serum osmolarity and by decreases in blood volume and blood pressure. The blood volume mechanism is discussed at this time, and osmoregulation is discussed in Chapter 6. Cardiopulmonary (Low-Pressure) Baroreceptors In addition to the high-pressure baroreceptors that regulate arterial pressure (i.e., baroreceptor reflex), there are also low-pressure baroreceptors located in the veins, atria, and pulmonary arteries. These so-called cardiopulmonary baroreceptors sense changes in blood volume, or the “fullness” of the vascular system. They are located on the venous side of the circulation because that is where most of the blood volume is held. For example, when there is an increase in blood volume, the resulting increase in venous and atrial pressure is detected by the cardiopulmonary baroreceptors. The function of the cardiopulmonary baroreceptors is then coordinated to return blood volume to normal, primarily by increasing the excretion of Na⁺ and water. The responses to an increase in blood volume include the following: Increased secretion of ANP. ANP is secreted by the atria in response to increased atrial pressure. ANP has multiple effects, but the most important is binding to ANP receptors (NPR₁) on vascular smooth muscle, causing relaxation, vasodilation, and decreased TPR. In the kidneys, this vasodilation leads to increased Na⁺ and water excretion, thereby decreasing total body Na⁺ content, ECF volume, and blood volume. Decreased secretion of ADH. Pressure receptors in the atria also project to the hypothalamus, where the cell bodies of neurons that secrete ADH are located. In response to increased atrial pressure, ADH secretion is inhibited and, as a consequence, there is decreased water reabsorption in collecting ducts, resulting in increased water excretion. Renal vasodilation. There is inhibition of sympathetic vasoconstriction in renal arterioles, leading to renal vasodilation and increased Na⁺ and water excretion, complementing the action of ANP on the kidneys. Increased heart rate. Information from the low-pressure atrial receptors travels in the vagus nerve to the nucleus tractus solitarius (as does information from the high- pressure arterial receptors involved in the baroreceptor reflex). The difference lies in the response of the medullary cardiovascular centers to the low- and high-pressure receptors. Whereas an increase in pressure at the arterial high-pressure receptors produces a decrease in heart rate (trying to lower arterial pressure back to normal), an increase in pressure at the venous low-pressure receptors produces an increase in heart rate (Bainbridge reflex). The low-pressure atrial receptors, sensing that blood volume is too high, direct an increase in heart rate and thus an increase in cardiac output; the Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 11 increase in cardiac output leads to increased renal perfusion and increased Na⁺ and water excretion. Microcirculation The term “microcirculation” refers to the functions of the smallest blood vessels, the capillaries and the neighboring lymphatic vessels. Delivery of blood to and from the capillaries is critically important because the capillaries are the site of exchange of nutrients and waste products in the tissues, as well as the site of fluid exchange between the vascular and interstitial compartments. The anatomy of capillary beds has been discussed previously. To briefly review, blood is delivered to the capillary beds via the arterioles. The capillaries merge into venules, which carry effluent blood from the tissues to the veins. The capillaries are the site of the exchange of nutrients, wastes, and fluid. Capillaries are thin-walled and are composed of a single layer of endothelial cells with water-filled clefts between the cells. The degree of constriction or relaxation of the arterioles markedly affects blood flow to the capillaries (in addition to determining TPR). The capillaries themselves branch off metarterioles; a band of smooth muscle, called the precapillary sphincters, precedes the capillaries. The precapillary sphincters function like “switches”: By opening or closing, these switches determine blood flow to the capillary bed. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 12 Regulation of Microcirculation The contractile state of arteriolar vascular smooth muscle regulates blood flow into the capillaries. Contraction of arterioles (i.e., vasoconstriction) decreases flow into capillaries, whereas relaxation of arterioles (i.e., vasodilation) increases flow into capillaries. There is neural (sympathetic and parasympathetic), endocrine, and paracrine regulation of arteriolar tone, as summarized in Table 4.6. Mediator Receptor Second Messenger Sympathetic (skin, splanchnic, α₁ IP₃/Ca²⁺ renal) Angiotensin II AT₁ IP₃/Ca²⁺ Vasopressin V₁ IP₃/Ca²⁺ Endothelin IP₃/Ca²⁺ IP₃/Ca²⁺ Adenosine A₃ IP₃/Ca²⁺ ATP Purinergic IP₃/Ca²⁺ Sympathetic adrenal, epinephrine β₂ cAMP (skeletal muscle) Parasympathetic (erectile) M₃ NO Sympathetic cholinergic (sweat M₃ NO glands) Histamine H₂ cAMP Vasoactive intestinal peptide cAMP cAMP Atrial natriuretic peptide NPR₁ cGMP Nitric oxide (endothelial cells) cGMP cGMP Bradykinin NO NO Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 13 Exchange of Substances Across the Capillary Wall The exchange of solutes and gases across the capillary wall occurs by simple diffusion. Some solutes can diffuse through the endothelial cells, and others must diffuse between the cells. Generally, the route for diffusion depends on whether the solute or gas is lipid soluble. Gases such as O₂ and CO₂ are highly lipid soluble. These gases readily cross the capillary wall by diffusing through the endothelial cells; diffusion is driven by the partial pressure gradient for the individual gas. Recall that the rate of diffusion depends on the driving force (in the case of O₂ and CO₂, the partial pressure difference for the gas) and the surface area available for diffusion. Thus the greater the number of open capillaries, the greater the surface area for diffusion. Water-soluble substances such as water itself, ions, glucose, and amino acids are not lipid soluble; thus they cannot cross the endothelial cell membranes. The diffusion of water-soluble substances is limited to the aqueous clefts between endothelial cells; hence, the surface area for their diffusion is much less than that for the lipid-soluble gases. By far, the most important mechanism for fluid transfer across the capillary wall is osmosis, driven by hydrostatic and osmotic pressures. These pressures are called the Starling pressures or Starling forces. Proteins are generally too large to cross the capillary walls via the clefts between endothelial cells and are retained in the vascular compartment. In some tissues, such as the brain, the clefts are particularly “tight,” and little protein leaves these capillaries. In the kidney and intestine, the capillaries are fenestrated or perforated, which permits the passage of limited amounts of protein. In other capillaries, proteins may cross in pinocytotic vesicles. Fluid Exchange Across Capillaries Fluid movement by osmosis is described in Chapter 1. Briefly, fluid will flow by osmosis across a biologic membrane (or the capillary wall) if the membrane has aqueous pores (i.e., permits the passage of water) and if there is a pressure difference across the membrane. The pressure difference can be a hydrostatic pressure difference, an effective osmotic pressure difference, or a combination of hydrostatic and effective osmotic pressures. In capillaries, fluid movement is driven by the sum of hydrostatic and effective osmotic pressures. Recall that solutes with reflection coefficients of 1.0 contribute most to the effective osmotic pressure. When the reflection coefficient is 1.0, the solute cannot cross the membrane and it exerts its full osmotic pressure. In capillary blood, only protein contributes to the effective osmotic pressure because it is the only solute whose reflection coefficient at the capillary wall is approximately 1.0. The effective osmotic pressure contributed by protein is called the colloid osmotic pressure or oncotic pressure. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 14 Lymph The lymphatic system is responsible for returning interstitial fluid and proteins to the vascular compartment. The lymphatic capillaries lie in the interstitial fluid, close to the vascular capillaries. The lymphatic capillaries possess one-way flap valves, which permit interstitial fluid and protein to enter, but not leave, the capillaries. These capillaries merge into larger lymphatic vessels and eventually into the largest lymphatic vessel, the thoracic duct, which empties lymph into the large veins. The lymphatic vessels have a smooth muscle wall, which has intrinsic contractile ability. Lymph flow back to the thoracic duct is promoted by contraction of the smooth muscle in the lymph vessels and by compression of the lymph vessels by activity of the surrounding skeletal muscle. An increase in interstitial fluid volume is called edema (swelling). By definition, edema forms when the volume of interstitial fluid (due to filtration out of the capillaries) exceeds the ability of the lymphatics to return it to the circulation. Thus edema can form when there is increased filtration or when lymphatic drainage is impaired (Table 4.7). Cause Examples ↑ Pₐ (capillary hydrostatic pressure) Arteriolar dilation Venous constriction Increased venous pressure Heart failure Extracellular fluid volume expansion ↓ πₐ (capillary oncotic pressure) Decreased plasma protein concentration Severe liver failure (failure to synthesize protein) Protein malnutrition Nephrotic syndrome (loss of protein in urine) ↑ Kf (hydraulic conductance) Burn Inflammation (release of histamine; cytokines) Impaired lymphatic drainage Standing (lack of skeletal muscle compression of lymphatics) Removal or irradiation of lymph nodes Parasitic infection of lymph nodes Special Circulations Blood flow is variable between one organ and another, depending on the overall demands of each organ system (see Fig. 4.1). For example, blood flow to the lungs is equal to the cardiac output because all blood must pass through the lungs, allowing O₂ to be added to it and CO₂ to be removed from it. No other organ receives the entire cardiac output! The kidneys, gastrointestinal tract, and skeletal muscle all have high blood flow, each receiving approximately 25% of cardiac output. Other organs receive smaller percentages of the cardiac output. These interorgan differences in blood flow are the result of differences in vascular resistance. Furthermore, blood flow to a specific organ or organ system can increase or decrease, depending on its metabolic demands. For example, exercising skeletal muscle has greater Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 15 demand for O₂ than does resting skeletal muscle. To meet the greater demand for O₂, blood flow to skeletal muscle must temporarily increase above the resting level. Changes in blood flow to an individual organ are achieved by altering arteriolar resistance. The mechanisms that regulate blood flow to the various organs are broadly categorized as local (intrinsic) control and neural or hormonal (extrinsic) control. Local control of blood flow is the primary mechanism utilized for matching blood flow to the metabolic needs of a tissue. Local control is exerted through the direct action of local metabolites on arteriolar resistance. Neural or hormonal control of blood flow includes such mechanisms as the action of the sympathetic nervous system on vascular smooth muscle and the actions of vasoactive substances such as histamine, bradykinin, and prostaglandins. Mechanisms for Control of Regional Blood Flow Local Control of Blood Flow There are several examples of local (intrinsic) control of blood flow, including autoregulation, active hyperemia, and reactive hyperemia. Each example of local control is discussed generally, followed by a more detailed explanation of the mechanism. Autoregulation is the maintenance of a constant blood flow to an organ in the face of changing arterial pressure. Several organs exhibit autoregulation of blood flow, including the kidneys, brain, heart, and skeletal muscle. For example, if arterial pressure in a coronary artery suddenly decreases, an attempt will be made to maintain constant blood flow through this coronary artery. Such autoregulation can be achieved by an immediate compensatory vasodilation of the coronary arterioles, decreasing the resistance of the coronary vasculature and keeping flow constant in the face of decreased pressure. Active hyperemia illustrates the concept that blood flow to an organ is proportional to its metabolic activity. As noted previously, if metabolic activity in skeletal muscle increases as a result of strenuous exercise, then blood flow to the muscle will increase proportionately to meet the increased metabolic demand. Reactive hyperemia is an increase in blood flow in response to or reacting to a prior period of decreased blood flow. For example, reactive hyperemia is the increase in blood flow to an organ that occurs following a period of arterial occlusion. During the occlusion, an O₂ debt is accumulated. The longer the period of occlusion, the greater the O₂ debt and the greater the subsequent increase in blood flow above the preocclusion levels. The increase in blood flow continues until the O₂ debt is “repaid.” Two basic mechanisms are proposed to explain the phenomena of autoregulation and active and reactive hyperemia: the myogenic hypothesis and the metabolic hypothesis. Myogenic hypothesis. The myogenic hypothesis can be invoked to explain autoregulation, but it does not explain active or reactive hyperemia. The myogenic hypothesis states that when vascular smooth muscle is stretched, it contracts. Thus, if arterial pressure is suddenly increased, the arterioles are stretched, and the vascular smooth muscle in their walls contracts in response to this stretch. Contraction of Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 16 arteriolar vascular smooth muscle causes constriction (i.e., increased resistance), thereby maintaining a constant flow in the face of increased pressure (recall that Q = ΔP/R). Conversely, if arterial pressure suddenly decreases, there is less stretch on the arterioles, causing them to relax and arteriolar resistance to decrease. Thus, constant flow can be maintained in the face of increased or decreased arterial pressure by changing arteriolar resistance. One can also think about the myogenic mechanism in terms of maintaining arteriolar wall tension. Blood vessels, such as arterioles, are built to withstand the wall tensions they normally “see.” In the example of a sudden increase in arterial pressure, the increased pressure, if unopposed, will cause an increase in arteriolar wall tension. Such an increase in wall tension is undesirable for the arteriole. Thus, in response to the stretch, arteriolar vascular smooth muscle contracts, decreasing the arteriolar radius and returning wall tension back to normal. This relationship is explained by the law of Laplace for a cylinder, which states that T = P × r. If pressure (P) increases and radius (r) decreases, then wall tension (T) can remain constant. Metabolic hypothesis. The metabolic hypothesis can be invoked to explain each of the phenomena of local control of blood flow. The basic premise of this hypothesis is that O₂ delivery to a tissue can be matched to O₂ consumption of the tissue by altering the resistance of the arterioles, which in turn alters blood flow. As a result of metabolic activity, the tissues produce various vasodilator metabolites (e.g., CO₂, H⁺, K⁺, lactate, and adenosine). The greater the level of metabolic activity, the greater the production of vasodilator metabolites. These metabolites produce vasodilation of arterioles, which decreases resistance and therefore increases flow to meet the increased demand for O₂. The following two examples illustrate how the metabolic hypothesis explains active hyperemia: 1. Strenuous exercise. During strenuous exercise, metabolic activity in the exercising skeletal muscle increases, and production of vasodilator metabolites, such as lactate, increases. These metabolites cause local vasodilation of skeletal muscle arterioles, which increases local blood flow and increases O₂ delivery to meet the increased demand of the exercising muscle. 2. Spontaneous increase in arterial pressure. Initially, the increased pressure will increase blood flow, which will deliver more O₂ for metabolic activity and “wash out” vasodilator metabolites. As a result of this washout, there will be a local dilution of vasodilator metabolites, resulting in arteriolar vasoconstriction, increased resistance, and a compensatory decrease in blood flow back to the normal level. Coronary Circulation Blood flow through the coronary circulation is controlled almost entirely by local metabolites, with sympathetic innervation playing only a minor role. The most important local metabolic Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 17 factors are hypoxia and adenosine. For example, if there is an increase in myocardial contractility, there is increased O₂ demand by the cardiac muscle and increased O₂ consumption, causing local hypoxia. This local hypoxia causes vasodilation of the coronary arterioles, which then produces a compensatory increase in coronary blood flow and O₂ delivery to meet the demands of the cardiac muscle (i.e., active hyperemia). An unusual feature of the coronary circulation is the effect of mechanical compression of the blood vessels during systole in the cardiac cycle. This compression causes a brief period of occlusion and reduction of blood flow. When the period of occlusion (i.e., systole) is over, reactive hyperemia occurs to increase blood flow and O₂ delivery and to repay the O₂ debt that was incurred during the compression. Cerebral Circulation The cerebral circulation is controlled almost entirely by local metabolites and exhibits autoregulation, active hyperemia, and reactive hyperemia. The most important local vasodilator in the cerebral circulation is CO₂ (or H⁺). An increase in cerebral PCO₂ (producing an increase in H⁺ concentration and a decrease in pH) causes vasodilation of the cerebral arterioles, which results in an increase in blood flow to assist in removal of the excess CO₂. It is interesting that many circulating vasoactive substances do not affect the cerebral circulation because their large molecular size prevents them from crossing the blood-brain barrier. Pulmonary Circulation The regulation of pulmonary circulation is discussed fully in Chapter 5. Briefly, the pulmonary circulation is controlled by O₂. The effect of O₂ on pulmonary arteriolar resistance is the exact opposite of its effect in other vascular beds: In the pulmonary circulation, hypoxia causes vasoconstriction. This seemingly counterintuitive effect of O₂ also is explained in Chapter 5. Briefly, regions of hypoxia in the lung cause local vasoconstriction, which effectively shunts blood away from poorly ventilated areas where the blood flow would be “wasted” and toward well-ventilated areas where gas exchange can occur. Renal Circulation The regulation of renal blood flow is discussed in detail in Chapter 6. Briefly, renal blood flow is tightly autoregulated so that flow remains constant even when renal perfusion pressure changes. Renal autoregulation is independent of sympathetic innervation, and it is retained even when the kidney is denervated (e.g., in a transplanted kidney). Autoregulation is presumed to result from a combination of the myogenic properties of the renal arterioles and tubuloglomerular feedback (see Chapter 6). 4o Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 18 Skeletal Muscle Circulation Blood flow to skeletal muscle is controlled both by local metabolites and by sympathetic innervation of its vascular smooth muscle. Incidentally, the degree of vasoconstriction of skeletal muscle arterioles is a major determinant of TPR because the mass of skeletal muscle is so large compared with that of other organs. At rest, blood flow to skeletal muscle is regulated primarily by its sympathetic innervation. Vascular smooth muscle in the arterioles of skeletal muscle is densely innervated by sympathetic nerve fibers that are vasoconstricting (α₁ receptors). There are also β₂ receptors on the vascular smooth muscle of skeletal muscle that are activated by epinephrine and cause vasodilation. Thus, activation of α₁ receptors causes vasoconstriction, increased resistance, and decreased blood flow. Activation of β₂ receptors causes vasodilation, decreased resistance, and increased blood flow. Usually, vasoconstriction predominates because norepinephrine, released from sympathetic adrenergic neurons, stimulates primarily α₁ receptors. On the other hand, epinephrine released from the adrenal gland during the fight-or-flight response or during exercise activates β₂ receptors and produces vasodilation. During exercise, blood flow to skeletal muscle is controlled primarily by local metabolites. Each of the phenomena of local control is exhibited: autoregulation, active hyperemia, and reactive hyperemia. During exercise, the demand for O₂ in skeletal muscle varies with the activity level, and, accordingly, blood flow is increased or decreased to deliver sufficient O₂ to meet the demand. The local vasodilator substances in skeletal muscle are lactate, adenosine, and K⁺. Mechanical compression of the blood vessels in skeletal muscle can also occur during exercise and cause brief periods of occlusion. When the period of occlusion is over, a period of reactive hyperemia will occur, which increases blood flow and O₂ delivery to repay the O₂ debt. Skin Circulation The skin has blood vessels with dense sympathetic innervation, which controls its blood flow. The principal function of the sympathetic innervation is to alter blood flow to the skin for regulation of body temperature. For example, during exercise, as body temperature increases, sympathetic centers controlling cutaneous blood flow are inhibited. This selective inhibition produces vasodilation in cutaneous arterioles so that warm blood from the body core can be shunted to the skin surface for dissipation of heat. Local vasodilator metabolites have little effect on cutaneous blood flow. The effects of vasoactive substances such as histamine have been discussed previously. In skin, the effects of histamine on blood vessels are visible. Trauma to the skin releases histamine, which produces a triple response in skin: a red line, a red flare, and a wheal. The wheal is local edema and results from histaminic actions that vasodilate arterioles and vasoconstrict veins. Together, these two effects produce increased Pc, increased filtration, and local edema. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 19 Integrative Functions of the Cardiovascular System The cardiovascular system always operates in an integrated manner. Thus, it is impossible to discuss a change only in cardiac function (e.g., a change in contractility) without then considering the effect such a change would have on arterial pressure, on hemodynamics, on the reflexes involving the sympathetic and parasympathetic nervous systems, on the renin– angiotensin II–aldosterone system, on filtration from capillaries and lymph flow, and on the distribution of blood flow among the organ systems. The best and most enduring way to understand the integrative functions of the cardiovascular system is by describing its responses to exercise, to hemorrhage, and to changes in posture. Responses to Exercise The cardiovascular responses to exercise involve a combination of central nervous system (CNS) and local mechanisms. The CNS responses include a central command from the cerebral motor cortex, which directs changes in the autonomic nervous system. The local responses include effects of metabolites to increase blood flow and O₂ delivery to the exercising skeletal muscle. Changes in arterial Po₂, Pco₂, and pH apparently play little role in directing these responses because none of these parameters changes significantly during moderate exercise. Responses to Exercise The cardiovascular responses to exercise involve a combination of central nervous system (CNS) and local mechanisms. The CNS responses include a central command from the cerebral motor cortex, which directs changes in the autonomic nervous system. The local responses include the effects of metabolites to increase blood flow and O₂ delivery to the exercising skeletal muscle. Changes in arterial Po₂, Pco₂, and pH apparently play little role in directing these responses because none of these parameters changes significantly during moderate exercise. Responses to Exercise The cardiovascular responses to exercise involve a combination of central nervous system (CNS) and local mechanisms. The CNS responses include a central command from the cerebral motor cortex, which directs changes in the autonomic nervous system. The local responses include effects of metabolites to increase blood flow and O₂ delivery to the exercising skeletal muscle. Changes in arterial Po₂, Pco₂, and pH apparently play little role in directing these responses because none of these parameters changes significantly during moderate exercise. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 20 Central Command The central command refers to a series of responses, directed by the cerebral motor cortex, which are initiated by the anticipation of exercise. These reflexes are triggered by muscle mechanoreceptors, and possibly muscle chemoreceptors, when exercise is anticipated or initiated. Details concerning the afferent limb of this reflex (i.e., information traveling from the muscles to the CNS) are lacking. It is clear, however, that the efferent limb of the reflex produces increased sympathetic outflow to the heart and blood vessels and decreased parasympathetic outflow to the heart. One consequence of the central command is an increase in cardiac output. This increase is the result of two simultaneous effects on the heart: 1. The increase in sympathetic activity (β₁ receptors) and the decrease in parasympathetic activity cooperate to produce an increase in heart rate. 2. The increase in sympathetic activity (β₁ receptors) produces an increase in contractility and a resulting increase in stroke volume. Together, the increases in heart rate and stroke volume produce an increase in cardiac output. The increase in cardiac output is essential in the cardiovascular response to exercise. It ensures that more O₂ and nutrients are delivered to the exercising skeletal muscle. (If cardiac output did not increase, for example, the only way to increase blood flow to the skeletal muscle would be through redistribution of blood flow from other organs.) Recall that cardiac output cannot increase without a concomitant increase in venous return (Frank-Starling relationship). In exercise, this concomitant increase in venous return is accomplished by two effects on the veins: The contraction of skeletal muscle around the veins has a mechanical (squeezing) action. Activation of the sympathetic nervous system produces venoconstriction. Together, these effects on the veins decrease the unstressed volume and increase venous return to the heart. Again, the increase in venous return makes the increase in cardiac output possible. Another consequence of the increased sympathetic outflow in the central command is selective arteriolar vasoconstriction: 1. In the circulation of the skin, splanchnic regions, kidney, and inactive muscles, vasoconstriction occurs via α₁ receptors, which results in increased resistance and decreased blood flow to those organs. 2. In the exercising skeletal muscle, however, local metabolic effects override any sympathetic vasoconstricting effects, and arteriolar vasodilation occurs. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 21 3. Other locations where vasoconstriction does not occur include the coronary circulation (where blood flow increases to meet the increased level of myocardial O₂ consumption) and the cerebral circulation. 4. In the cutaneous circulation, there is a biphasic response. Initially, vasoconstriction occurs (due to increased sympathetic outflow); later, as body temperature increases, there is selective inhibition of sympathetic cutaneous vasoconstriction, resulting in vasodilation and dissipation of heat through the skin. In summary, there is vasoconstriction in some vascular beds so that blood flow can be redistributed to the exercising skeletal muscle and the heart, with blood flow being maintained in essential organs such as the brain. Local Responses in Muscle Local control of blood flow in the exercising skeletal muscle is orchestrated by active hyperemia. As the metabolic rate of the skeletal muscle increases, production of vasodilator metabolites such as lactate, K⁺, and adenosine also increases. These metabolites act directly on the arterioles of the exercising muscle to produce local vasodilation. Vasodilation of the arterioles results in increased blood flow to meet the increased metabolic demand of the muscle. This vasodilation in the exercising muscle also produces an overall decrease in TPR. (If these local metabolic effects in the exercising muscle did not occur, TPR would increase because the central command directs an increase in sympathetic outflow to the blood vessels, which produces vasoconstriction.) Overall Responses to Exercise The two components of the cardiovascular response to exercise, the central command and the effects of local metabolites, can now be viewed together. The central command directs an increase in sympathetic outflow and a decrease in parasympathetic outflow. This produces an increase in cardiac output and vasoconstriction in several vascular beds (excluding exercising skeletal muscle, coronary, and cerebral circulations). The increase in cardiac output has two components: Increased heart rate. Increased contractility, which results in increased stroke volume and is represented by an increased pulse pressure (increased volume is pumped into the low-compliance arteries). Increased cardiac output is possible because venous return increases (Frank-Starling relationship). Venous return increases because there is sympathetic constriction of the veins (which reduces unstressed volume) and because of the squeezing action of the exercising skeletal muscle on the veins. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 22 Responses to hemorrhage When a person loses a large quantity of blood, arterial pressure decreases rapidly, followed by a series of compensatory cardiovascular responses that attempt to restore arterial pressure back to normal and to sustain life (Fig. 4.36 and Box 4.3). Compensatory Responses to Hemorrhage 1. Carotid sinus nerve firing rate: Decreases (↓) 2. Heart rate: Increases (↑) 3. Contractility: Increases (↑) 4. Cardiac output: Increases (↑) 5. Unstressed volume: Decreases (↓), which produces an increase in venous return 6. Total peripheral resistance (TPR): Increases (↑) 7. Renin: Increases (↑) 8. Angiotensin II: Increases (↑) 9. Aldosterone: Increases (↑) 10. Circulating epinephrine: Increases (↑) (secreted from the adrenal medulla) 11. Antidiuretic hormone (ADH): Increases (↑) (stimulated by decreased blood volume) Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 23 Responses to changes in posture The cardiovascular responses to a change in posture (or gravity) are illustrated in a person who changes from a supine (lying) position to a standing position. A person who stands up too quickly may briefly experience orthostatic hypotension (i.e., a decrease in arterial blood pressure upon standing), light-headedness, and possibly fainting. Normally, a series of fast compensatory cardiovascular responses involving the baroreceptor reflex occurs to offset this brief, initial decrease in Pa_aa (Fig. 4.38 and Table 4.11). Compensatory Parameter Initial Response to Standing Response Mean arterial pressure ↓ ↑ (toward normal) Heart rate — ↑ Stroke volume ↓ (decreased venous return) ↑ (toward normal) Cardiac output ↓ (decreased stroke volume) ↑ (toward normal) Total peripheral resistance — ↑ (TPR) ↓ (pooling of blood in lower Central venous pressure ↑ (toward normal) extremities) Responses to Acute Stress The response to acute emotional stress can resemble the fight or flight response or it can present as vasovagal syncope (fainting). Each response integrates multiple components of cardiovascular physiology. Fight or Flight Response When a person perceives an imminent threat, the fight or flight response is mobilized by the central nervous system (Fig. 4.39). The cerebral cortex coordinates the response, which is communicated to the hypothalamus and ultimately to the brainstem. Specifically, medullary cardiovascular centers are activated and direct an increase in sympathetic activity of the adrenal medulla and sympathetic postganglionic neurons. Epinephrine, the primary secretion of the adrenal medulla, activates β₁ receptors to increase heart rate and contractility and β₂ receptors to dilate skeletal muscle arterioles. Norepinephrine, the transmitter secreted by sympathetic postganglionic neurons, activates β₁ receptors to increase heart rate and contractility and α₁ receptors to constrict splanchnic and renal arterioles. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 24 The overall, coordinated cardiovascular response optimizes the ability for “fight or flight”: cardiac output is increased (through increased heart rate and contractility) and blood flow is redirected from splanchnic and renal vascular beds toward skeletal muscle. Fig. 4.39: Cardiovascular Responses to Acute Stress (Fight-or-Flight) The question may arise: in fight or flight, is Pₐ increased or decreased? The increase in cardiac output would clearly tend to increase Pₐ. However, the other determinant of Pₐ, TPR, may be increased, decreased, or be unchanged, depending on the relative balance of vasodilation of skeletal muscle versus vasoconstriction of splanchnic and renal vascular beds (Pₐ = cardiac output × TPR). If vasoconstriction is greater than vasodilation, then TPR and Pₐ will increase. If vasodilation is greater than vasoconstriction, then TPR will decrease, and the effect on Pₐ is difficult to predict. Vasovagal Syncope Approximately 25% of persons faint at the sight of blood, when receiving an injection, or in extreme emotional distress. A benign faint, or vasovagal syncope, occurs most commonly in the heat, with prolonged standing, during bowel movements, or when the person is volume depleted. It is a parasympathetic response that results in decreased Pₐ and decreased cerebral blood flow (Fig. 4.40). Fig. 4.40: Vasovagal Syncope Cardiovascular responses in vasovagal syncope that lead to fainting. Pₐ: Mean arterial pressure. TPR: Total peripheral resistance. Vasovagal syncope is caused by the Bezold-Jarish reflex, which is initiated in the cerebral cortex. There is activation of medullary centers, leading to a massive increase in parasympathetic outflow to the heart and a decrease in sympathetic outflow to the heart and blood vessels. As a result, there is decreased heart rate and cardiac output (increased parasympathetic and decreased sympathetic activity); in addition, there is decreased TPR (decreased sympathetic activity). Together, decreased cardiac output and decreased TPR produce a sudden fall in Pₐ, which causes decreased cerebral blood flow and fainting. Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 25 Summary The cardiovascular system is composed of the heart and blood vessels. The heart, by contracting, pumps blood through the systemic and pulmonary vasculatures. Blood vessels act as conduits that deliver blood to the tissues. The thin-walled capillaries serve as the site of exchange of nutrients and waste products. Hemodynamics are the principles that govern blood flow: velocity of flow; flow, pressure, and resistance relationships; and compliance of blood vessels. Velocity of blood flow is proportional to the rate of volume flow and inversely proportional to the cross-sectional area. Velocity is lowest in the capillaries, which have the largest cross-sectional area. Blood flow is proportional to the size of the pressure gradient and inversely proportional to the resistance of the blood vessels. Resistance to blood flow is proportional to the viscosity of blood and vessel length and inversely proportional to vessel radius to the fourth power. The arterioles are the site of highest resistance in the vasculature. Resistances can be arranged in series or in parallel. Compliance is the relationship between volume and pressure: The higher the compliance of a blood vessel, the greater the volume contained at a given pressure. Veins have high compliance and hold large volumes of blood (the unstressed volume) at low pressure. Arteries have low compliance and hold small volumes of blood (the stressed volume) at high pressure. The cardiac action potential is initiated in the SA node, which depolarizes spontaneously. The action potential spreads in a specific sequence throughout the myocardium via a specialized conducting system. Conduction is rapid, except through the AV node, where slow conduction ensures ample time for ventricular filling prior to contraction. In atria and ventricles, the upstroke of the action potential is the result of an inward Na⁺ current. The action potential in the atria and ventricles exhibits a plateau, which is the result of an inward Ca²⁺ current. This plateau accounts for the action potential’s long duration and long refractory period. In the SA node, the upstroke of the action potential is the result of an inward Ca²⁺ current. The SA node exhibits slow, spontaneous depolarization during phase 4, which brings the cells to threshold to fire action potentials. Slow depolarization is the result of an inward Na⁺ current (Iₑ). Excitation-contraction coupling in myocardial cells is similar to that in skeletal muscle. In myocardial cells, however, Ca²⁺ entering the cell during the plateau of the action potential serves as a trigger for the release of more Ca²⁺ from the sarcoplasmic reticulum. Ca²⁺ then binds to troponin C to allow actin-myosin interaction and cross-bridge formation. Inotropism or contractility is the ability of the myocardial cell to develop tension at a given cell length: Intracellular [Ca²⁺] determines the degree of inotropism, with positive inotropic agents increasing intracellular [Ca²⁺] and contractility. Myocardial cells and the myocardium exhibit a length-tension relationship based on the degree of overlap of contractile elements. The Frank-Starling law of the heart describes this relationship between cardiac output and end-diastolic volume. End- Week 5: Cardiovascular Physiology Regulation of Arterial Pressure 26 diastolic volume reflects venous return. Therefore cardiac output is determined by venous return, and in the steady state, cardiac output and venous return are equal. Pₐ is the product of cardiac output and TPR. Pₐ is carefully monitored and maintained at a normal value of 100 mm Hg. The baroreceptor reflex is a fast, neural mechanism that detects changes in Pₐ and orchestrates changes in sympathetic and parasympathetic outflow to the heart and blood vessels to restore Pₐ back to normal. The renin– angiotensin II–aldosterone system is a slower, hormonal mechanism that detects changes in Pₐ and, via aldosterone, restores Pₐ to normal through changes in blood volume. The exchange of fluid across capillary walls is determined by the balance of Starling forces. The net Starling pressure determines whether there will be filtration out of the capillary or absorption into the capillary. If filtration of fluid exceeds the ability of the lymphatics to return it to the circulation, then edema occurs. The blood flow to the organ systems is a variable percentage of the cardiac output. Blood flow is determined by arteriolar resistance, which can be altered by vasodilator metabolites or by sympathetic innervation.