Cardiovascular Physiology Regulation of Arterial Pressure PDF

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 comp...

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.