﻿ REGULATION OF ARTERIAL PRESSURE - Cardiovascular Physiology - Physiology 5th Ed.

## Physiology 5th Ed.

### 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:

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 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, Paalso 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.

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-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 (Fig. 4-31). 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.

Figure 4–31 Response of baroreceptor reflex to increased arterial pressure. The + symbol shows increases in activity; the − symbol shows decreases in activity; the dashed lines show inhibitory pathways.

Baroreceptors

The baroreceptors are located in the walls of the carotid sinus, where the common carotid artery bifurcates into the internal and external carotid arteries, and in the aortic arch. The carotid sinus baroreceptors are responsive to increases or decreases in arterial pressure, whereas the aortic arch baroreceptors are primarily responsive to increases in arterial pressure.

The baroreceptors are mechanoreceptors, which are sensitive to pressure or stretch. Thus, changes in arterial pressure cause more or less stretch on the mechanoreceptors, resulting in a change in their membrane potential. Such a change in membrane potential is a receptor potential, which increases or decreases the likelihood that action potentials will be fired in the afferent nerves that travel from the baroreceptors to the brain stem. (If the receptor potential is depolarizing, then action potential frequency increases; if the receptor potential is hyperpolarizing, then action potential frequency decreases.)

Increases in arterial pressure cause increased stretch on the baroreceptors and increased firing rate in the afferent nerves. Decreases in arterial pressure cause decreased stretch on the baroreceptors and decreased firing rate in the afferent nerves.

Although the baroreceptors are sensitive to the absolute level of pressure, they are even more sensitive to changes in pressure and the rate of change of pressure. The strongest stimulus for the baroreceptors is a rapid change in arterial pressure!

The sensitivity of the baroreceptors can be altered by disease. For example, in chronic hypertension (elevated blood pressure), the baroreceptors do not “see” the elevated blood pressure as abnormal. In such cases, the hypertension will be maintained, rather than corrected, by the baroreceptor reflex. The mechanism of this defect is either decreased sensitivity of the baroreceptors to increases in arterial pressure or an increase in the blood pressure set point of the brain stem centers.

Information from the carotid sinus baroreceptors is carried to the brain stem on the carotid sinus nerve, which joins the glossopharyngeal nerve (cranial nerve [CN] IX). Information from the aortic arch baroreceptors is carried to the brain stem on the vagus nerve (CN X).

Brain Stem Cardiovascular Centers

Brain stem cardiovascular centers are located in the reticular formations of the medulla and in the lower one third of the pons. These centers function in a coordinated fashion, receiving information about blood pressure from the baroreceptors and then directing changes in output of the sympathetic and parasympathetic nervous systems to correct the blood pressure as needed.

As described, blood pressure is sensed by baroreceptors in the carotid sinus and aortic arch. Afferent information about blood pressure is then sent to the medulla via the glossopharyngeal (CN IX) and vagus (CN X) nerves. This information is integrated in the nucleus tractus solitarius, which then directs changes in the activity of several cardiovascular centers. These cardiovascular centers are tonically active, and the nucleus tractus solitarius simply directs, via the centers, increases or decreases in outflow from the sympathetic and parasympathetic nervous systems.

The parasympathetic outflow is the effect of the vagus nerve on the SA node to decrease the heart rate. The sympathetic outflow has four components: an effect on the SA node to increase heart rate, an effect on cardiac muscle to increase contractility and stroke volume, an effect on the arterioles to produce vasoconstriction and increase TPR, and an effect on veins to produce venoconstriction and decrease unstressed volume.

The cardiovascular brain stem centers are as follows:

The vasoconstrictor center (also called C1) is located in the upper medulla and the lower pons. Efferent neurons from this vasomotor center are part of the sympathetic nervous system and synapse in the spinal cord, then in sympathetic ganglia, and finally on the target organs, producing vasoconstriction in the arterioles and venules.

The cardiac accelerator center. Efferent neurons from the cardiac accelerator center are also part of the sympathetic nervous system and synapse in the spinal cord, in sympathetic ganglia, and finally in the heart. In the heart, the effects of this activity are an increased firing rate of the SA node (to increase heart rate), increased conduction velocity through the AV node, and increased contractility.

The cardiac decelerator center. Efferent fibers from the cardiac decelerator center are part of the parasympathetic nervous system: They travel in the vagus nerve and synapse on the SA node to decrease heart rate.

Integrated Function of the Baroreceptor Reflex

The function of the baroreceptor reflex can be illustrated by examining its response to an increase in arterial pressure as follows (see Fig. 4-31):

1.          An increase in Pa is detected by baroreceptors in the carotid sinus and in the aortic arch. This increase in pressure results in increased firing rate of the carotid sinus nerve (glossopharyngeal nerve, CN IX) and in afferent fibers in the vagus nerve (CN X).

2.          The glossopharyngeal and vagus nerve fibers synapse in the nucleus tractus solitarius of the medulla, where they transmit information about blood pressure. In this example, the Pa sensed by the baroreceptors is higher than the set-point pressure in the medulla.

3.          The nucleus tractus solitarius directs a series of coordinated responses, using the medullary cardiovascular centers, to reduce Pa back to normal. These responses include an increase in parasympathetic outflow to the heart and a decrease in sympathetic outflow to the heart and blood vessels.

4.          The increase in parasympathetic activity to the SA node (via the vagus nerve) results in a decrease in heart rate. The decrease in sympathetic activity to the SA node complements the increase in parasympathetic activity and also decreases heart rate. Decreased sympathetic activity also decreases cardiac contractility. Together, the decreased heart rate and decreased cardiac contractility produce adecrease in cardiac output, which tends to reduce Pa back to normal. (Recall that Pa = Cardiac output × TPR.)

The decrease in sympathetic activity also affects the tone of the blood vessels. First, there is decreased constriction of arterioles, or arteriolar vasodilation, which decreases TPR and reduces Pa. (Again, recall that Pa = Cardiac output × TPR.) Second, there is decreased constriction of veins, which increases the compliance of the veins, thereby increasing the unstressed volume. When unstressed volume increases, stressed volume decreases, which further contributes to a reduction in Pa.

5.          Once these coordinated reflexes reduce Pa back to the set-point pressure (i.e., to 100 mm Hg), then activity of the baroreceptors and the cardiovascular brain stem centers will return to the tonic (baseline) level.

Response of the Baroreceptor Reflex to Hemorrhage

A second example of the operation of the baroreceptor reflex is the response to loss of blood volume or hemorrhage. Hemorrhage produces a decrease in Pa because, as blood volume decreases, stressed volume also decreases (see Fig. 4-27). In response to an acute reduction in Pa, the baroreceptor reflex is activated and attempts to restore blood pressure back toward normal (Fig. 4-32).

Figure 4–32 Response of the baroreceptor reflex to acute hemorrhage. The reflex is initiated by a decrease in mean arterial pressure (Pa). The compensatory responses attempt to increase Pa back to normal. TPR, Total peripheral resistance.

The responses of the baroreceptor reflex to a decrease in Pa are the exact opposite of those described previously for the response to an increase in Pa. Decreases in Pa produce decreased stretch on the baroreceptors and decreased firing rate of the carotid sinus nerve. This information is received in the nucleus tractus solitarius of the medulla, which produces a coordinated decrease in parasympathetic activity to the heart and an increase in sympathetic activity to the heart and blood vessels. Heart rate and contractility increase, which, together, produce an increase in cardiac output. There is increased constriction of arterioles, which produces an increase in TPR, and increased constriction of the veins, which decreases unstressed volume. The constriction of the veins increases venous return to contribute to the increase in cardiac output (Frank-Starling mechanism).

Test of Baroreceptor Reflex: Valsalva Maneuver

The integrity of the baroreceptor reflex can be tested with the Valsalva maneuver, which is expiring against a closed glottis as during coughing, defecation, or heavy lifting. When the subject expires against a closed glottis, there is an increase in intrathoracic pressure, which decreases venous return to the heart. This decrease in venous return produces a decrease in cardiac output (Frank-Starling mechanism) and a consequent decrease in arterial pressure. If the baroreceptor reflex is intact, the decrease in arterial pressure is sensed by the baroreceptors, and the nucleus tractus solitarius directs an increase in sympathetic outflow and a decrease in parasympathetic outflow to the heart and blood vessels. In the test, an increase in heart rate is noted. When the subject stops the maneuver, there is a rebound increase in venous return, cardiac output, and arterial pressure. The increase in arterial pressure is sensed by the baroreceptors, and they direct a decrease in heart rate.

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 the 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:

Figure 4–33 Renin–angiotensin II–aldosterone system. The system is described in terms of the response to a decrease in Pa. TPR, Total peripheral resistance.

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 β1antagonists 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 (ACE). Angiotensin-converting enzyme inhibitors (ACEi), such as captopril, block 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.

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.

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.

Angiotensin II acts on the hypothalamus to increase thirst and water intake. It also stimulates secretion of antidiuretic hormone, 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.

Angiotensin II also acts directly on the arterioles by binding to G protein–coupled receptors and activating an IP3/Ca2+ second messenger system to cause vasoconstriction. The resulting increase in TPRleads to an increase in Pa.

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).

BOX 4–2 Clinical Physiology: Renal Vascular Hypertension

DESCRIPTION OF CASE. A 65-year-old woman visits her physician complaining of “not feeling well” and decreased urination. Her diastolic blood pressure is elevated at 115 mm Hg, and she has abdominal bruits (sounds). She is immediately admitted to the hospital and has a workup for hypertension.

Laboratory tests reveal the following information: Her blood pressure continues to be dangerously elevated, and her glomerular filtration rate (GFR) is significantly decreased, at 30 mL/min. Renal vascular disease is suspected. Renal angiography shows 90% stenosis of the right renal artery. Her plasma renin activity is elevated, and renin levels are much higher in right renal venous blood than in left renal venous blood.

An attempt to dilate the right renal artery with angioplasty is unsuccessful. The woman is treated with captopril, an ACE inhibitor.

EXPLANATION OF CASE. The woman has stenosis of her right renal artery, which reduces blood flow to her right kidney. The abdominal bruits are heard because blood flow through the stenosed renal artery is turbulent (i.e., Reynolds number is increased). As a result of the decreased renal blood flow, her GFR and her urine output are decreased.

The woman’s hypertension is secondary to the decrease in renal blood flow. Renal perfusion pressure to the right kidney is significantly decreased. The right kidney “thinks” that arterial pressure is low and that aldosterone is needed. Thus, renin secretion by the right kidney increases, which results in renin levels in the right renal vein higher than those in the left renal vein. Increased circulating renin activity results in increased production of angiotensin II and aldosterone. Angiotensin II causes vasoconstriction of arterioles, which elevates TPR and mean arterial pressure. Aldosterone increases renal Na+reabsorption, elevating total body Na+ content, ECF volume, and blood volume. The increase in blood volume leads to the increased diastolic blood pressure.

TREATMENT. Because an attempt to dilate the stenosed renal artery is unsuccessful, the woman is treated with an ACE inhibitor to interrupt the cycle that produced the hypertension (i.e., to block the conversion of angiotensin I to angiotensin II). Although the right kidney will continue to secrete high levels of renin and plasma renin activity will continue to be elevated, angiotensin II will not be produced if the angiotensin converting enzyme is inhibited. Likewise, aldosterone secretion will decrease, and Na+ reabsorption also will decrease.

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, antidiuretic hormone, and atrial natriuretic peptide.

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 (PCO2) 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 PCO2 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 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 (the 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 PCO2 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 PCO2 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 PCO2 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 PCO2 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

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.

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 atrial natriuretic peptide (ANP). ANP is secreted by the atria in response to increased atrial pressure. ANP has multiple effects, but the most important is to cause relaxation of vascular smooth muscle, which results in 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 increase in cardiac output leads to increased renal perfusion and increased Na+ and water excretion.

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