After studying this chapter, you should be able to:
Outline the neural mechanisms that control arterial blood pressure and heart rate, including the receptors, afferent and efferent pathways, central integrating pathways, and effector mechanisms involved.
Describe the direct effects of CO2 and hypoxia on the rostral ventrolateral medulla.
Describe how the process of autoregulation contributes to control of vascular caliber.
Identify the paracrine factors and hormones that regulate vascular tone, their sources, and their mechanisms of action.
In humans and other mammals, multiple cardiovascular regulatory mechanisms have evolved. These mechanisms increase the blood supply to active tissues and increase or decrease heat loss from the body by redistributing the blood. In the face of challenges such as hemorrhage, they maintain the blood flow to the heart and brain. When the challenge faced is severe, flow to these vital organs is maintained at the expense of the circulation to the rest of the body.
Circulatory adjustments are effected by altering the output of the pump (the heart), changing the diameter of the resistance vessels (primarily the arterioles), or altering the amount of blood pooled in the capacitance vessels (the veins). Regulation of cardiac output is discussed in Chapter 30. The caliber of the arterioles is adjusted in part by autoregulation (Table 32–1). It is also increased in active tissues by locally produced vasodilator metabolites, is affected by substances secreted by the endothelium, and is regulated systemically by circulating vasoactive substances and the nerves that innervate the arterioles. The caliber of the capacitance vessels is also affected by circulating vasoactive substances and by vasomotor nerves. The systemic regulatory mechanisms synergize with the local mechanisms and adjust vascular responses throughout the body.
TABLE 32–1 Summary of factors affecting the caliber of the arterioles.
The terms vasoconstriction and vasodilation are generally used to refer to constriction and dilation of the resistance vessels. Changes in the caliber of the veins are referred to as venoconstriction or venodilation.
NEURAL CONTROL OF THE CARDIOVASCULAR SYSTEM
INNERVATION OF THE BLOOD VESSELS
Most of the vasculature is an example of an autonomic effector organ that receives innervation from the sympathetic but not the parasympathetic division of the autonomic nervous system. Sympathetic noradrenergic fibers terminate on vascular smooth muscle in all parts of the body to mediate vasoconstriction. In some species, resistance vessels in skeletal muscles of the limbs are also innervated by vasodilator fibers, which, although they travel with the sympathetic nerves, are cholinergic (sympathetic cholinergic vasodilator system). These nerve are inactive at rest but can be activated during stress or exercise. Evidence for a sympathetic cholinergic vasodilator system in humans is lacking. It is more likely that vasodilation of skeletal muscle vasculature in response to activation of the sympathetic nervous system is due to the actions of epinephrine released from the adrenal medulla. Activation of β2-adrenoceptors on skeletal muscle blood vessels promotes vasodilation.
There are a few exceptions to the rule that only the sympathetic nervous system controls the vascular smooth muscle. The arteries in the erectile tissue of the reproductive organs, uterine and some facial blood vessels, and blood vessels in salivary glands, may also be controlled by parasympathetic nerves.
Although the arterioles and the other resistance vessels are most densely innervated, all blood vessels except capillaries and venules contain smooth muscle and receive motor nerve fibers from the sympathetic division of the autonomic nervous system. The fibers to the resistance vessels regulate tissue blood flow and arterial pressure. The fibers to the venous capacitance vessels vary the volume of blood “stored” in the veins. The innervation of most veins is sparse, but the splanchnic veins are well innervated. Venoconstriction is produced by stimuli that also activate the vasoconstrictor nerves to the arterioles. The resultant decrease in venous capacity increases venous return, shifting blood to the arterial side of the circulation.
When the sympathetic nerves are sectioned (sympathectomy), the blood vessels dilate. A change in the level of activity (increase or decrease) in sympathetic nerves is just one of the many factors that mediate vasoconstriction or vasodilation (Table 32–1).
INNERVATION OF THE HEART
The heart is one example of an effector organ that receives opposing influences from the sympathetic and parasympathetic divisions of the autonomic nervous system. Release of norepinephrine from postganglionic sympathetic nerves activates β1-adrenoceptors in the heart, notably on the sinoatrial (SA) node, atrioventricular (AV) node, His-Purkinje conductive tissue, and atrial and ventricular contractile tissue. In response to stimulation of sympathetic nerves, the heart rate (chronotropy), rate of transmission in the cardiac conductive tissue (dromotropy), and the force of ventricular contraction (inotropy) are increased. On the other hand, release of acetylcholine from postganglionic parasympathetic (vagus) nerves activates nicotinic receptors in the heart, notably on the SA and AV nodes and atrial muscle. In response to stimulation of the vagus nerve, the heart rate, the rate of transmission through the AV node, and atrial contractility are reduced.
The above description presents an oversimplified explanation of autonomic control of cardiac function. There are adrenergic and cholinergic receptors on autonomic nerve terminals that modulate transmitter release from nerve endings. For example, release of acetylcholine from vagal nerve terminals inhibits the release of norepinephrine from sympathetic nerve terminals, so this can enhance the effects of vagal nerve activation on the heart.
There is a moderate amount of tonic discharge in the cardiac sympathetic nerves at rest, but there is considerable tonic vagal discharge (vagal tone) in humans and other large animals. After the administration of nicotinic cholinergic receptor antagonists such as atropine, the heart rate in humans increases from 70, its normal resting value, to 150–180 beats/min because the sympathetic tone is unopposed. In humans in whom both noradrenergic and cholinergic systems are blocked, the heart rate is approximately 100 beats/min.
The cardiovascular system is under neural influences coming from several parts of the brain stem, forebrain, and insular cortex. The brain stem receives feedback from sensory receptors in the vasculature (eg, baroreceptors and chemoreceptors). A simplified model of the feedback control circuit is shown in Figure 32–1. An increase in neural output from the brain stem to sympathetic nerves leads to a decrease in blood vessel diameter (arteriolar vasoconstriction) and increases in stroke volume and heart rate, which contribute to a rise in blood pressure. This in turn causes an increase in baroreceptor activity, which signals the brain stem to reduce the neural output to sympathetic nerves.
FIGURE 32–1 Feedback control of blood pressure. Brain stem excitatory input to sympathetic nerves to the heart and vasculature increases heart rate and stroke volume and reduces vessel diameter. Together these increase blood pressure, which activates the baroreceptor reflex to reduce the activity in the brain stem.
Venoconstriction and a decrease in the stores of blood in the venous reservoirs usually accompany increases in arteriolar constriction, although changes in the capacitance vessels do not always parallel changes in the resistance vessels. In the presence of an increase in sympathetic nerve activity to the heart and vasculature, there is usually an associated decrease in the activity of vagal fibers to the heart. Conversely, a decrease in sympathetic activity causes vasodilation, a fall in blood pressure, and an increase in the storage of blood in the venous reservoirs. There is usually a concomitant decrease in heart rate, but this is mostly due to stimulation of the vagal innervation of the heart.
MEDULLARY CONTROL OF THE CARDIOVASCULAR SYSTEM
One of the major sources of excitatory input to sympathetic nerves controlling the vasculature is a group of neurons located near the pial surface of the medulla in the rostral ventrolateral medulla (RVLM; Figure 32–2). This region is sometimes called a vasomotor area. The axons of RVLM neurons course dorsally and medially and then descend in the lateral column of the spinal cord to the thoracolumbar intermediolateral gray column (IML). They contain phenylethanolamine-N-methyltransferase (PNMT; see Chapter 7), but it appears that the excitatory transmitter they secrete is glutamate rather than epinephrine. Neurovascular compression of the RVLM has been linked to some cases of essential hypertension in humans (see Clinical Box 32–1).
FIGURE 32–2 Basic pathways involved in the medullary control of blood pressure. The rostral ventrolateral medulla (RVLM) is one of the major sources of excitatory input to sympathetic nerves controlling the vasculature. These neurons receive inhibitory input from the baroreceptors via an inhibitory neuron in the caudal ventrolateral medulla (CVLM). The nucleus of the tractus solitarius (NTS) is the site of termination of baroreceptor afferent fibers. The putative neurotransmitters in the pathways are indicated in parentheses. Ach, acetylcholine; GABA, γ-aminobutyric acid; Glu, glutamate; IML, intermediolateral gray column; IVLM, intermediate ventrolateral medulla; NE, norepinephrine; NTS, nucleus of the tractus solitarius; IX and X, glossopharyngeal and vagus nerves.
CLINICAL BOX 32–1
Essential Hypertension & Neurovascular Compression of the RVLM
In about 88% of patients with elevated blood pressure, the cause of the hypertension is unknown, and they are said to have essential hypertension (see Chapter 31). There are data available to support the view that neurovascular compression of the RVLM is associated with essential hypertension in some subjects. For example, patients with a schwannoma (acoustic neuroma) or meningioma lying close to the RVLM also have hypertension. Magnetic resonance angiography (MRA) has been used to compare the incidence of neurovascular compression in hypertensive and normotensive individuals and to correlate indices of sympathetic nerve activity with the presence or absence of compression. Some of these studies showed a higher incidence of coexistence of neurovascular compression with essential hypertension than in other forms of hypertension or normotension, but others showed the presence of a compression in normotensive subjects. On the other hand, there was a strong positive relationship between the presence of neurovascular compression and increased sympathetic activity.
In the 1970s, Dr. Peter Jannetta, a neurosurgeon in Pittsburgh, PA, developed a technique for “microvascular decompression” of the medulla to treat trigeminal neuralgia and hemifacial spasm, which he attributed to pulsatile compression of the vertebral and posterior inferior cerebellar arteries impinging on the fifth and seventh cranial nerves. Moving the arteries away from the nerves led to reversal of the neurologic symptoms in many cases. Some of these patients were also hypertensive, and they showed reductions in blood pressure postoperatively. Later, a few human studies claimed that surgical decompression of the RVLM could sometimes relieve hypertension. There are also reports that hypertension is relieved after surgical decompression in patients with a schwannoma or meningioma in the vicinity of the RVLM.
The activity of RVLM neurons is determined by many factors (see Table 32–2). They include not only the very important fibers from arterial baroreceptors, but also fibers from other parts of the nervous system and from the carotid and aortic chemoreceptors. In addition, some stimuli act directly on the vasomotor area.
TABLE 32–2 Factors affecting the activity of the RVLM.
There are descending tracts to the vasomotor area from the cerebral cortex (particularly the limbic cortex) that relay in the hypothalamus. These fibers are responsible for the blood pressure rise and tachycardia produced by emotions such as stress, sexual excitement, and anger. The connections between the hypothalamus and the vasomotor area are reciprocal, with afferents from the brain stem closing the loop.
Inflation of the lungs causes vasodilation and a decrease in blood pressure. This response is mediated via vagal afferents from the lungs that inhibit vasomotor discharge. Pain usually causes a rise in blood pressure via afferent impulses in the reticular formation converging in the RVLM. However, prolonged severe pain may cause vasodilation and fainting. The activity in afferents from exercising muscles probably exerts a similar pressor effect via a pathway to the RVLM. The pressor response to stimulation of somatic afferent nerves is called the somatosympathetic reflex.
The medulla is also a major site of origin of excitatory input to cardiac vagal motor neurons in the nucleus ambiguus (Figure 32–3). Table 32–3 is a summary of factors that affect the heart rate. In general, stimuli that increase the heart rate also increase blood pressure, whereas those that decrease the heart rate lower blood pressure. However, there are exceptions, such as the production of hypotension and tachycardia by stimulation of atrial stretch receptors and the production of hypertension and bradycardia by increased intracranial pressure.
FIGURE 32–3 Basic pathways involved in the medullary control of heart rate by the vagus nerves. Neurons in the nucleus of the tractus solitarius (NTS) project to and excite cardiac preganglionic parasympathetic neurons primarily in the nucleus ambiguus. Some are also located in the dorsal motor nucleus of the vagus; however, this nucleus primarily contains vagal motor neurons that project to the gastrointestinal tract. AP, area postrema; Pyr, pyramid; XII, hypoglossal nucleus.
TABLE 33–3 Factors affecting heart rate.
The baroreceptors are stretch receptors in the walls of the heart and blood vessels. The carotid sinus and aortic arch receptors monitor the arterial circulation. Receptors are also located in the walls of the right and left atria at the entrance of the superior and inferior venae cavae and the pulmonary veins, as well as in the pulmonary circulation. These receptors in the low-pressure part of the circulation are referred to collectively as the cardiopulmonary receptors.
The carotid sinus is a small dilation of the internal carotid artery just above the bifurcation of the common carotid into external and internal carotid branches (Figure 32–4). Baroreceptors are located in this dilation. They are also found in the wall of the arch of the aorta. The receptors are located in the adventitia of the vessels. The afferent nerve fibers from the carotid sinus form a distinct branch of the glossopharyngeal nerve, the carotid sinus nerve. The fibers from the aortic arch form a branch of the vagus nerve, the aortic depressor nerve.
FIGURE 32–4 Baroreceptor areas in the carotid sinus and aortic arch. One set of baroreceptors (stretch receptors) is located in the carotid sinus, a small dilation of the internal carotid artery just above the bifurcation of the common carotid into external and internal carotid branches. These receptors are innervated by a branch of the glossopharyngeal nerve, the carotid sinus nerve. A second set of baroreceptors is located in the wall of the arch of the aorta. These receptors are innervated by a branch of the vagus nerve, the aortic depressor nerve.
The baroreceptors are stimulated by distention of the structures in which they are located, and so they discharge at an increased rate when the pressure in these structures rises. Their afferent fibers pass via the glossopharyngeal and vagus nerves to the medulla. Most of them end in the nucleus of the tractus solitarius (NTS), and the excitatory transmitter they secrete is glutamate (Figure 32–2). Excitatory (glutamate) projections extend from the NTS to the caudal ventrolateral medulla (CVLM), where they stimulate γ-aminobutyrate (GABA)-secreting inhibitory neurons that project to the RVLM. Excitatory projections also extend from the NTS to the vagal motor neurons in the nucleus ambiguus and dorsal motor nucleus (Figure 32–3). Thus, increased baroreceptor discharge inhibits the tonic discharge of sympathetic nerves and excites the vagal innervation of the heart. These neural changes produce vasodilation, venodilation, hypotension, bradycardia, and a decrease in cardiac output.
BARORECEPTOR NERVE ACTIVITY
Baroreceptors are more sensitive to pulsatile pressure than to constant pressure. A decline in pulse pressure without any change in mean pressure decreases the rate of baroreceptor discharge and provokes a rise in systemic blood pressure and tachycardia. At normal blood pressure levels (about 100 mm Hg mean pressure), a burst of action potentials appears in a single baroreceptor fiber during systole, but there are few action potentials in early diastole (Figure 32–5). At lower mean pressures, this phasic change in firing is even more dramatic with activity only occurring during systole. At these lower pressures, the overall firing rate is considerably reduced. The threshold for eliciting activity in the carotid sinus nerve is approximately 50 mm Hg; maximal activity occurs at approximately 200 mm Hg, with activity throughout the cardiac cycle.
FIGURE 32–5 Discharges (vertical lines) in a single afferent nerve fiber from the carotid sinus at various levels of mean arterial pressures, plotted against changes in aortic pressure with time. Baroreceptors are very sensitive to changes in pulse pressure as shown by the record of phasic aortic pressure. (Reproduced with permission from Levy MN & Pappano AJ: Cardiovascular Physiology, 9th ed. Mosby, 2007.)
When one carotid sinus is isolated and perfused and the other baroreceptors are denervated, there is no discharge in the afferent fibers from the perfused sinus and no drop in the animal’s arterial pressure or heart rate when the perfusion pressure is below 30 mm Hg (Figure 32–6). At carotid sinus perfusion pressures of 70–110 mm Hg, there is a near linear relationship between perfusion pressure and the fall in systemic blood pressure and heart rate. At perfusion pressures above 150 mm Hg there is no further increase in response, presumably because the rate of baroreceptor discharge and the degree of inhibition of sympathetic nerve activity are maximal.
FIGURE 32–6 Fall in systemic blood pressure produced by raising the pressure in the isolated carotid sinus to various values. Solid line: Response in a normal monkey. Dashed line: Response in a hypertensive monkey, demonstrating baroreceptor resetting (arrow).
From the foregoing discussion, it is apparent that the baroreceptors on the arterial side of the circulation, their afferent connections to the medullary cardiovascular areas, and the efferent pathways from these areas constitute a reflex feedback mechanism that operates to stabilize blood pressure and heart rate. Any drop in systemic arterial pressure decreases the discharge in the buffer nerves, and there is a compensatory rise in blood pressure and cardiac output. Any rise in pressure produces dilation of the arterioles and decreases cardiac output until the blood pressure returns to its previous baseline level.
In chronic hypertension, the baroreceptor reflex mechanism is “reset” to maintain an elevated rather than a normal blood pressure. In perfusion studies on hypertensive experimental animals, raising the pressure in the isolated carotid sinus lowers the elevated systemic pressure, and decreasing the perfusion pressure raises the elevated pressure (Figure 32–6). Little is known about how and why this occurs, but resetting occurs rapidly in experimental animals. It is also rapidly reversible, both in experimental animals and in clinical situations.
ROLE OF BARORECEPTORS IN SHORT-TERM CONTROL OF BLOOD PRESSURE
The changes in pulse rate and blood pressure that occur in humans on standing up or lying down are due for the most part to baroreceptor reflexes. The function of the receptors can be tested by monitoring changes in heart rate as a function of increasing arterial pressure during infusion of the α-adrenoceptor agonist phenylephrine. A normal response is shown in Figure 32–7; from a systolic pressure of about 120–150 mm Hg, there is a linear relation between pressure and lowering of the heart rate (longer RR interval). Baroreceptors are very important in short-term control of arterial pressure. Activation of the reflex allows for rapid adjustments in blood pressure in response to abrupt changes in posture, blood volume, cardiac output, or peripheral resistance during exercise.
FIGURE 32–7 Baroreflex-mediated lowering of the heart rate during infusion of phenylephrine in a human subject. Note that the values for the RR interval of the electrocardiogram, which are plotted on the vertical axis, are inversely proportional to the heart rate. (Reproduced with permission from Kotrly K, et al: Effects of fentanyl-diazepam-nitrous oxide anaesthesia on arterial baroreflex control of heart rate in man. Br J Anaesth 1986;58:406.)
Blood pressure initially rises dramatically after bilateral section of baroreceptor nerves or bilateral lesions of the NTS. However, after a period of time, mean blood pressure returns to near control levels, but there are large fluctuations in pressure during the course of a day. Removal of the baroreceptor reflex prevents an individual from adjusting their blood pressure in response to stimuli that cause abrupt changes in blood volume, cardiac output, or peripheral resistance, including exercise and postural changes. A long-term change in blood pressure resulting from loss of baroreceptor reflex control is called neurogenic hypertension.
ATRIAL STRETCH AND CARDIOPULMONARY RECEPTORS
The stretch receptors in the atria are of two types: those that discharge primarily during atrial systole (type A), and those that discharge primarily late in diastole, at the time of peak atrial filling (type B). The discharge of type B baroreceptors is increased when venous return is increased and decreased by positive-pressure breathing, indicating that these baroreceptors respond primarily to distention of the atrial walls. The reflex circulatory adjustments initiated by increased discharge from most if not all of these receptors include vasodilation and a fall in blood pressure. However, the heart rate is increased rather than decreased.
Receptors in the endocardial surfaces of the ventricles are activated during ventricular distention. The response is a vagal bradycardia and hypotension, comparable to a baroreceptor reflex. Left ventricular stretch receptors may play a role in the maintenance of vagal tone that keeps the heart rate low at rest. Various chemicals are known to elicit reflexes due to activation of cardiopulmonary chemoreceptors and may play a role in various cardiovascular disorders (see Clinical Box 32–2).
CLINICAL BOX 32–2
Cardiopulmonary Chemosensitive Receptors
For nearly 150 years, it has been known that activation of chemosensitive vagal C fibers in the cardiopulmonary region (eg, juxtacapillary region of alveoli, ventricles, atria, great veins, and pulmonary artery) causes profound bradycardia, hypotension, and a brief period of apnea followed by rapid shallow breathing. This response pattern is called the Bezold-Jarisch reflex and was named after the individuals who first reported these findings. This reflex can be elicited by a variety of substances including capsaicin, serotonin, phenylbiguanide, and veratridine. Although originally viewed as a pharmacologic curiosity, there is a growing body of evidence supporting the view that the Bezold-Jarisch reflex is activated during certain pathophysiologic conditions. For example, this reflex may be activated during myocardial ischemia and reperfusion as a result of increased production of oxygen radicals and by agents used as radio-contrast for coronary angiography. This can contribute to the hypotension that is frequently a stubborn complication of heart disease. Activation of cardiopulmonary chemosensitive receptors may also be part of a defense mechanism protecting individuals from toxic chemical hazards. Activation of cardiopulmonary reflexes may help reduce the amount of inspired pollutants that gets absorbed into the blood, protecting vital organs from potential toxicity of these pollutants, and facilitating their elimination. Finally, the syndrome of cardiac slowing with hypotension (vasovagal syncope) has also been attributed to activation of the Bezold-Jarisch reflex. Vasovagal syncope can occur after prolonged upright posture that results in pooling of blood in the lower extremities and diminished intracardiac blood volume (also called postural syncope). This phenomenon is exaggerated if combined with dehydration. The resultant arterial hypotension is sensed in the carotid sinus baroreceptors, and afferent fibers from these receptors trigger autonomic signals that increase cardiac rate and contractility. However, pressure receptors in the wall of the left ventricle respond by sending signals that trigger paradoxical bradycardia and decreased contractility, resulting in sudden marked hypotension. The individual also feels lightheaded and may experience a brief episode of loss of consciousness.
The most critical intervention for individuals who experience episodes of neurogenic syncope is to avoid dehydration and to avoid situations that trigger the adverse event. Episodes of syncope may be reduced or prevented by an increased dietary salt intake or administration of mineralocorticoids. Vasovagal syncope has been treated with the use of β-adrenoceptor antagonists and disopyramide, an antiarrhythmic agent that blocks Na+ channels. Cardiac pacemakers have also been used to stabilize the heart rate during episodes that normally trigger bradycardia.
The function of the receptors can also be tested by monitoring the changes in pulse and blood pressure that occur in response to brief periods of straining (forced expiration against a closed glottis: the Valsalva maneuver). Valsalva maneuvers occur regularly during coughing, defecation, and heavy lifting. The blood pressure rises at the onset of straining (Figure 32–8) because the increase in intrathoracic pressure is added to the pressure of the blood in the aorta. It then falls because the high intrathoracic pressure compresses the veins, decreasing venous return and cardiac output. The decreases in arterial pressure and pulse pressure inhibit the baroreceptors, causing tachycardia and a rise in peripheral resistance. When the glottis is opened and the intrathoracic pressure returns to normal, cardiac output is restored but the peripheral vessels are constricted. The blood pressure therefore rises above normal, and this stimulates the baroreceptors, causing bradycardia and a drop in pressure to normal levels.
FIGURE 32–8 Diagram of the response to straining (the Valsalva maneuver) in a normal man, recorded with a needle in the brachial artery. Blood pressure rises at the onset of straining because increased intrathoracic pressure is added to the pressure of the blood in the aorta. It then falls because the high intrathoracic pressure compresses veins, decreasing venous return and cardiac output. (Courtesy of M Mcllroy.)
In patients whose sympathetic nervous system is not functional, heart rate changes still occur because the baroreceptors and the vagi are intact. However, in patients with autonomic insufficiency, a syndrome in which autonomic function is widely disrupted, the heart rate changes are absent. For reasons that are still obscure, patients with primary hyperaldosteronism also fail to show the heart rate changes and the blood pressure rise when the intrathoracic pressure returns to normal. Their response to the Valsalva maneuver returns to normal after removal of the aldosterone-secreting tumor.
PERIPHERAL CHEMORECEPTOR REFLEX
Peripheral arterial chemoreceptors in the carotid and aortic bodies have very high rates of blood flow. These receptors are primarily activated by a reduction in partial pressure of oxygen (PaO2), but they also respond to an increase in the partial pressure of carbon dioxide (PaCO2) and pH. Chemoreceptors exert their main effects on respiration; however, their activation also leads to vasoconstriction. Heart rate changes are variable and depend on various factors, including changes in respiration. A direct effect of chemoreceptor activation is to increase vagal nerve activity. However, hypoxia also produces hyperpnea and increased catecholamine secretion from the adrenal medulla, both of which produce tachycardia and an increase in cardiac output. Hemorrhage that produces hypotension leads to chemoreceptor stimulation due to decreased blood flow to the chemoreceptors and consequent stagnant anoxia of these organs. Chemoreceptor discharge may also contribute to the production of Mayer waves. These should not be confused with Traube–Hering waves, which are fluctuations in blood pressure synchronized with respiration. The Mayer waves are slow, regular oscillations in arterial pressure that occur at the rate of about one per 20–40 s during hypotension. Under these conditions, hypoxia stimulates the chemoreceptors. The stimulation raises the blood pressure, which improves the blood flow in the receptor organs and eliminates the stimulus to the chemoreceptors, so that the pressure falls and a new cycle is initiated.
When intracranial pressure is increased, the blood supply to RVLM neurons is compromised, and the local hypoxia and hypercapnia increase their discharge. This activates a central chemoreceptors located on the ventrolateral surface of the medulla. The resultant rise in systemic arterial pressure (Cushing reflex) tends to restore the blood flow to the medulla. Over a considerable range, the blood pressure rise is proportional to the increase in intracranial pressure. The rise in blood pressure causes a reflex decrease in heart rate via the arterial baroreceptors. This is why bradycardia rather than tachycardia is characteristically seen in patients with increased intracranial pressure.
A rise in arterial Pco2 stimulates the RVLM, but the direct peripheral effect of hypercapnia is vasodilation. Therefore, the peripheral and central actions tend to cancel each other out. Moderate hyperventilation, which significantly lowers the CO2 tension of the blood, causes cutaneous and cerebral vasoconstriction in humans, but there is little change in blood pressure. Exposure to high concentrations of CO2 is associated with marked cutaneous and cerebral vasodilation, but vasoconstriction occurs elsewhere and usually there is a slow rise in blood pressure.
The capacity of tissues to regulate their own blood flow is referred to as autoregulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relatively constant. This capacity is well developed in the kidneys (see Chapter 37), but it has also been observed in the mesentery, skeletal muscle, brain, liver, and myocardium. It is probably due in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibers that surround the vessels contract. If it is postulated that the muscle responds to the tension in the vessel wall, this theory could explain the greater degree of contraction at higher pressures; the wall tension is proportional to the distending pressure times the radius of the vessel (law of Laplace; see Chapter 31), and the maintenance of a given wall tension as the pressure rises would require a decrease in radius. Vasodilator substances tend to accumulate in active tissues, and these “metabolites” also contribute to auto-regulation (metabolic theory of autoregulation). When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away.
The metabolic changes that produce vasodilation include, in most tissues, decreases in O2 tension and pH. These changes cause relaxation of the arterioles and precapillary sphincters. A local fall in O2 tension, in particular, can initiate a program of vasodilatory gene expression secondary to production of hypoxia-inducible factor-1α (HIF-1α), a transcription factor with multiple targets. Increases in CO2 tension and osmolality also dilate the vessels. The direct dilator action of CO2 is most pronounced in the skin and brain. The neurally mediated vasoconstrictor effects of systemic as opposed to local hypoxia and hypercapnia have been discussed above. A rise in temperature exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to the vasodilation. K+ is another substance that accumulates locally, and has demonstrated dilator activity secondary to the hyperpolarization of vascular smooth muscle cells. Lactate may also contribute to the dilation. In injured tissues, histamine released from damaged cells increases capillary permeability. Thus, it is probably responsible for some of the swelling in areas of inflammation. Adenosine may play a vasodilator role in cardiac muscle but not in skeletal muscle. It also inhibits the release of norepinephrine.
Injured arteries and arterioles constrict strongly. The constriction appears to be due in part to the local liberation of serotonin from platelets that stick to the vessel wall in the injured area. Injured veins also constrict.
A drop in tissue temperature causes vasoconstriction, and this local response to cold plays a part in temperature regulation (see Chapter 17).
SUBSTANCES SECRETED BY THE ENDOTHELIUM
As noted in Chapter 31, the endothelial cells constitute a large and important tissue. They secrete many growth factors and vasoactive substances. The vasoactive substances include prostaglandins and thromboxanes, nitric oxide (NO), and endothelins.
PROSTACYCLIN & THROMBOXANE A2
Prostacyclin is produced by endothelial cells and thromboxane A2 by platelets from their common precursor arachidonic acid via the cyclooxygenase pathway. Thromboxane A2 promotes platelet aggregation and vasoconstriction, whereas prostacyclin inhibits platelet aggregation and promotes vasodilation. The balance between platelet thromboxane A2 and prostacyclin fosters localized platelet aggregation and consequent clot formation (see Chapter 31) while preventing excessive extension of the clot and maintaining blood flow around it.
The thromboxane A2–prostacyclin balance can be shifted toward prostacyclin by administration of low doses of aspirin. Aspirin produces irreversible inhibition of cyclooxygenase by acetylating a serine residue in its active site. Obviously, this reduces production of both thromboxane A2 and prostacyclin. However, endothelial cells produce new cyclooxygenase in a matter of hours, whereas platelets cannot manufacture the enzyme, and the level rises only as new platelets enter the circulation. This is a slow process because platelets have a half-life of about 4 days. Therefore, administration of small amounts of aspirin for prolonged periods reduces clot formation and has been shown to be of value in preventing myocardial infarctions, unstable angina, transient ischemic attacks, and stroke.
A chance observation two decades ago led to the discovery that the endothelium plays a key role in vasodilation. Many different stimuli act on the endothelial cells to produce endothelium-derived relaxing factor (EDRF), a substance that is now known to be nitric oxide (NO). NO is synthesized from arginine (Figure 32–9) in a reaction catalyzed by nitric oxide synthase (NO synthase, NOS). Three isoforms of NOS have been identified: NOS 1, found in the nervous system; NOS 2, found in macrophages and other immune cells; and NOS 3, found in endothelial cells. NOS 1 and NOS 3 are activated by agents that increase intracellular Ca2+ concentrations, including the vasodilators acetylcholine and bradykinin. The NOS in immune cells is not activated by Ca2+ but is induced by cytokines. The NO that is formed in the endothelium diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase, producing cyclic 3,5-guanosine monophosphate (cGMP; see Figure 32–9), which in turn mediates the relaxation of vascular smooth muscle. NO is inactivated by hemoglobin.
FIGURE 32–9 Synthesis of NO from arginine in endothelial cells and its action via stimulation of soluble guanylyl cyclase and generation of cGMP to produce relaxation in vascular smooth muscle cells. The endothelial form of nitric oxide synthase (NOS) is activated by increased intracellular Ca2+ concentration (top), and an increase is produced by acetylcholine (Ach), bradykinin, or shear stress acting on the cell membrane. Thiol, tetrahydrobiopterin, FAD, and FMN are requisite cofactors. NO then diffuses to adjacent smooth muscle cells in the wall of the vessel (bottom), diffuses across the plasma membrane, and activates soluble guanylyl cyclase to evoke an increase in cellular cGMP and smooth muscle relaxation.
Adenosine, atrial natriuretic peptide (ANP), and histamine via H2 receptors produce relaxation of vascular smooth muscle that is independent of the endothelium. However, acetylcholine, histamine via H1 receptors, bradykinin, vasoactive intestinal peptide (VIP), substance P, and some other polypeptides act via the endothelium, and various vasoconstrictors that act directly on vascular smooth muscle would produce much greater constriction if their effects were not limited by their ability simultaneously to cause release of NO. When flow to a tissue is suddenly increased by arteriolar dilation, the large arteries to the tissue also dilate. This flow-induced dilation is due to local release of NO. Products of platelet aggregation also cause release of NO, and the resulting vasodilation helps keep blood vessels with an intact endothelium patent. This is in contrast to injured blood vessels, where the endothelium is damaged at the site of injury and platelets therefore aggregate and produce vasoconstriction (see Chapter 31).
Further evidence for a physiologic role of NO is the observation that mice lacking NOS 3 are hypertensive. This suggests that tonic release of NO is necessary to maintain normal blood pressure.
NO is also involved in vascular remodeling and angiogenesis, and NO may be involved in the pathogenesis of atherosclerosis. It is interesting in this regard that some patients with heart transplants develop an accelerated form of atherosclerosis in the vessels of the transplant, and there is reason to believe that this is triggered by endothelial damage. Nitroglycerin and other nitrovasodilators that are of great value in the treatment of angina act by stimulating guanylyl cyclase in the same manner as NO.
Penile erection is also produced by release of NO, with consequent vasodilation and engorgement of the corpora cavernosa (see Chapter 23). This accounts for the efficacy of drugs such as Viagra, which slow the breakdown of cGMP.
OTHER FUNCTIONS OF NO
NO is present in the brain and, acting via cGMP, it is important in brain function (see Chapter 7). NO is also necessary for the antimicrobial and cytotoxic activity of various inflammatory cells, although the net effect of NO in inflammation and tissue injury depends on the amount and kinetics of release, which in turn may depend on the specific NOS isoform involved. In the gastrointestinal tract, NO is important in the relaxation of smooth muscle. Other functions of NO are mentioned in other parts of this book.
The production of carbon monoxide (CO) from heme is shown in Figure 28–4. HO2, the enzyme that catalyzes the reaction, is also present in cardiovascular tissues, and there is growing evidence that CO as well as NO produces local dilation in blood vessels. Interestingly, hydrogen sulfide is likewise emerging as a third gaseotransmitter that regulates vascular tone, although the relative roles of NO, CO, and H2S have yet to be established.
Endothelial cells also produce endothelin-1, one of the most potent vasoconstrictor agents yet isolated. Endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are the members of a family of three similar 21-amino-acid polypeptides. Each is encoded by a different gene. The unique structure of the endothelins resembles that of the sarafotoxins, polypeptides found in the venom of a snake, the Israeli burrowing asp.
In endothelial cells, the product of the endothelin-1 gene is processed to a 39-amino-acid prohormone, big endothelin-1, which has about 1% of the activity of endothelin-1. The prohormone is cleaved at a tryptophan-valine (Trp-Val) bond to form endothelin-1 by endothelin-converting enzyme. Small amounts of big endothelin-1 and endothelin-1 are secreted into the blood, but for the most part, they are secreted locally and act in a paracrine fashion.
Two different endothelin receptors have been cloned, both of which are coupled via G proteins to phospholipase C (see Chapter 2). The ETA receptor, which is specific for endothelin-1, is found in many tissues and mediates the vasoconstriction produced by endothelin-1. The ETB receptor responds to all three endothelins, and is coupled to Gi. It may mediate vasodilation, and it appears to mediate the developmental effects of the endothelins (see below).
REGULATION OF SECRETION
Endothelin-1 is not stored in secretory granules, and most regulatory factors alter the transcription of its gene, with changes in secretion occurring promptly thereafter. Factors activating and inhibiting the gene are summarized in Table 32–4.
TABLE 32–4 Regulation of endothelin-1 secretion via transcription of its gene.
As noted above, endothelin-1 appears to be primarily a paracrine regulator of vascular tone. However, endothelin-1 is not increased in hypertension, and in mice in which one allele of the endothelin-1 gene is knocked out, blood pressure is actually elevated rather than reduced. The concentration of circulating endothelin-1 is, however, elevated in congestive heart failure and after myocardial infarction, so it may play a role in the pathophysiology of these diseases.
OTHER FUNCTIONS OF ENDOTHELINS
Endothelin-1 is found in the brain and kidneys as well as the endothelial cells. Endothelin-2 is produced primarily in the kidneys and intestine. Endothelin-3 is present in the blood and is found in high concentrations in the brain. It is also found in the kidneys and gastrointestinal tract. In the brain, endothelins are abundant and, in early life, are produced by both astrocytes and neurons. They are found in the dorsal root ganglia, ventral horn cells, the cortex, the hypothalamus, and cerebellar Purkinje cells. They also play a role in regulating transport across the blood–brain barrier. There are endothelin receptors on mesangial cells (see Chapter 37), and the polypeptide participates in tubuloglomerular feedback.
Mice that have both alleles of the endothelin-1 gene deleted have severe craniofacial abnormalities and die of respiratory failure at birth. They also have megacolon (Hirschsprung disease), apparently because the cells that normally form the myenteric plexus fail to migrate to the distal colon (see Chapter 27). In addition, endothelins play a role in closing the ductus arteriosus at birth.
SYSTEMIC REGULATION BY NUEROHUMORAL AGENTS
Many circulating substances affect the vascular system. The vasodilator regulators include kinins, VIP, and ANP. Circulating vasoconstrictor hormones include vasopressin, norepinephrine, epinephrine, and angiotensin II.
Two related vasodilator peptides called kinins are found in the body. One is the nonapeptide bradykinin, and the other is the decapeptide lysylbradykinin, also known as kallidin (Figure 32–10). Lysylbradykinin can be converted to bradykinin by aminopeptidase. Both peptides are metabolized to inactive fragments by kininase I, a carboxypeptidase that removes the carboxyl terminal arginine (Arg). In addition, the dipeptidylcarboxypeptidase kininase IIinactivates bradykinin and lysylbradykinin by removing phenylalanine-arginine (Phe-Arg) from the carboxyl terminal. Kininase II is the same enzyme as angiotensin-converting enzyme, which removes histidine-leucine (His-Leu) from the carboxyl terminal end of angiotensin I.
FIGURE 32–10 Kinins. Lysylbradykinin (top) can be converted to bradykinin (bottom) by aminopeptidase. The peptides are inactivated by kininase I (KI) or kininase II (KII) at the sites indicated by the short arrows.
Bradykinin and lysylbradykinin are formed from two precursor proteins: high-molecular-weight kininogen and low-molecular-weight kininogen (Figure 32–11). They are formed by alternative splicing of a single gene located on chromosome 3. Proteases called kallikreins release the peptides from their precursors. They are produced in humans by a family of three genes located on chromosome 19. There are two types of kallikreins: plasma kallikrein,which circulates in an inactive form, and tissue kallikrein, which appears to be located primarily on the apical membranes of cells concerned with transcellular electrolyte transport. Tissue kallikrein is found in many tissues, including sweat and salivary glands, the pancreas, the prostate, the intestine, and the kidneys. Tissue kallikrein acts on high-molecular-weight kininogen to form bradykinin and low-molecular-weight kininogen to form lysylbradykinin. When activated, plasma kallikrein acts on high-molecular-weight kininogen to form bradykinin.
FIGURE 32–11 Formation of kinins from high-molecular-weight (HMW) and low-molecular-weight (LMW) kininogens.
Inactive plasma kallikrein (prekallikrein) is converted to the active form, kallikrein, by active factor XII, the factor that initiates the intrinsic blood clotting cascade. Kallikrein also activates factor XII in a positive feedback loop, and high-molecular-weight kininogen has a factor XII-activating action (see Figure 31–12).
The actions of both kinins resemble those of histamine. They are primarily paracrines, although small amounts are also found in the circulating blood. They cause contraction of visceral smooth muscle, but they relax vascular smooth muscle via NO, lowering blood pressure. They also increase capillary permeability, attract leukocytes, and cause pain upon injection under the skin. They are formed during active secretion in sweat glands, salivary glands, and the exocrine portion of the pancreas, and they are probably responsible for the increase in blood flow when these tissues are actively secreting their products.
Two bradykinin receptors, B1 and B2, have been identified. Their amino acid residues are 36% identical, and both are coupled to G proteins. The B1 receptor may mediate the pain-producing effects of the kinins, but little is known about its distribution and function. The B2 receptor has strong homology to the H2 receptor and is found in many different tissues.
There is a family of natriuretic peptides involved in vascular regulation, including ANP secreted by the heart, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They are released in response to hypervolemia. ANP and BNP circulate, whereas CNP acts predominantly in a paracrine fashion. In general, these peptides antagonize the action of various vasoconstrictor agents and lower blood pressure. ANP and BNP also serve to coordinate the control of vascular tone with fluid and electrolyte homeostasis via actions on the kidney.
Vasopressin is a potent vasoconstrictor, but when it is injected in normal individuals, there is a compensating decrease in cardiac output, so that there is little change in blood pressure. Its role in blood pressure regulation is discussed in Chapter 17.
Norepinephrine has a generalized vasoconstrictor action, whereas epinephrine dilates the vessels in skeletal muscle and the liver. The relative unimportance of circulating norepinephrine, as opposed to norepinephrine released from vasomotor nerves, is pointed out in Chapter 20, where the cardiovascular actions of catecholamines are discussed in detail.
Angiotensin II has a generalized vasoconstrictor action. It is formed by the action of angiotensin converting enzyme (ACE) on angiotensin I, which itself is liberated by the action of renin from the kidney on circulating angiotensinogen (see Chapter 38). Renin secretion, in turn, is increased when the blood pressure falls or extracellular fluid (ECF) volume is reduced, and angiotensin II therefore helps to maintain blood pressure. Angiotensin II also increases water intake and stimulates aldosterone secretion, and increased formation of angiotensin II is part of a homeostatic mechanism that operates to maintain ECF volume (see Chapter 20). In addition, there are renin–angiotensin systems in many different organs, and there may be one in the walls of blood vessels. Angiotensin II produced in blood vessel walls could be important in some forms of clinical hypertension. The role of angiotensin II in cardiovascular regulation is also amply demonstrated in the widespread use of ACE inhibitors as antihypertensive medications.
Urotensin-II, a polypeptide first isolated from the spinal cord of fish, is present in human cardiac and vascular tissue. It is one of the most potent mammalian vasoconstrictors known, and is being explored for its role in a large range of different human disease states. For example, levels of both urotensin-II and its receptor have been shown to be elevated in hypertension and heart failure, and may be markers of disease in these and other conditions.
RVLM neurons project to the thoracolumbar IML and release glutamate on preganglionic sympathetic neurons that innervate the heart and vasculature.
The NTS is the major excitatory input to cardiac vagal motor neurons in the nucleus ambiguus.
Carotid sinus and aortic depressor baroreceptors are innervated by branches of the ninth and tenth cranial nerves, respectively (glossopharyngeal and aortic depressor nerves). These receptors are most sensitive to changes in pulse pressure but also respond to changes in mean arterial pressure.
Baroreceptor nerves terminate in the NTS and release glutamate. NTS neurons project to the CVLM and nucleus ambiguus and release glutamate. CVLM neurons project to RVLM and release GABA. This leads to a reduction in sympathetic activity and an increase in vagal activity (ie, the baroreceptor reflex).
Activation of peripheral chemoreceptors in the carotid and aortic bodies by a reduction in PaO2 or an increase in PaCO2 leads to an increase in vasoconstriction. Heart rate changes are variable and depend on a number of factors including changes in respiration.
In addition to various neural inputs, RVLM neurons are directly activated by hypoxia and hypercapnia.
Most vascular beds have an intrinsic capacity to respond to changes in blood pressure within a certain range by altering vascular resistance to maintain stable blood flow. This property is known as autoregulation.
Local factors such as oxygen tension, pH, temperature, and metabolic products contribute to vascular regulation; many produce vasodilation to restore blood flow.
The endothelium is an important source of vasoactive mediators that act to either contract or relax vascular smooth muscle.
Three gaseous mediators—NO, CO, and H2S—are important regulators of vasodilation.
Endothelins and angiotensin II induce vasoconstriction and may be involved in the pathogenesis of some forms of hypertension.
For all questions, select the single best answer unless otherwise directed.
1. When a pheochromocytoma (tumor of the adrenal medulla) suddenly discharges a large amount of epinephrine into the circulation, the patient’s heart rate would be expected to
A. increase, because the increase in blood pressure stimulates the carotid and aortic baroreceptors.
B. increase, because epinephrine has a direct chronotropic effect on the heart.
C. increase, because of increased tonic parasympathetic discharge to the heart.
D. decrease, because the increase in blood pressure stimulates the carotid and aortic chemoreceptors.
E. decrease, because of increased tonic parasympathetic discharge to the heart.
2. A 65-year-old male had been experiencing frequent episodes of syncope as he got out of bed in the mornings. He was diagnosed with orthostatic hypotension due to a malfunction in his baroreceptor reflex. Activation of the baroreceptor reflex
A. is primarily involved in short-term regulation of systemic blood pressure.
B. leads to an increase in heart rate because of inhibition of the vagal cardiac motor neurons.
C. inhibits neurons in the CVLM.
D. excites neurons in the RVLM.
E. occurs only under situations in which blood pressure is markedly elevated.
3. A 45-year-old female had a blood pressure of 155/95 when she was at her physician’s office for a physical. It was her first time to see this physician and her first physical in over 10 years. The doctor suggested that she begin monitoring her pressure at home. Sympathetic nerve activity would be expected to increase
A. if glutamate receptors were activated in the NTS.
B. if GABA receptors were activated in the RVLM.
C. if glutamate receptors were activated in the CVLM.
D. during stress.
E. when one transitions from an erect to a supine posture.
4. Which of the following neurotransmitters are correctly matched with an autonomic pathway?
A. GABA is released by NTS neurons projecting to the RVLM.
B. Glutamate is released by CVLM neurons projecting to the IML.
C. GABA is released by NTS neurons projecting to the nucleus ambiguus.
D. GABA is released by CVLM neurons projecting to the RVLM.
E. Glutamate is released by CVLM neurons projecting to the NTS.
5. A 53-year-old woman with chronic lung disease was experiencing difficulty breathing. Her arterial PO2 and Pco2 were 50 and 60 mm Hg, respectively. Which one of the following statements about chemoreceptors is correct?
A. Peripheral chemoreceptors are very sensitive to small increases in arterial Pco2.
B. Activation of arterial chemoreceptors leads to a fall in arterial pressure.
C. Peripheral chemoreceptors are located in the NTS.
D. Central chemoreceptors can be activated by an increase in intracranial pressure that compromises blood flow in the medulla.
E. Central chemoreceptors are activated by increases in tissue pH.
6. A 55-year-old man comes to his primary care physician complaining of erectile dysfunction. He is given a prescription for Viagra, and on follow-up, reports that his ability to sustain an erection has been improved markedly by this treatment. The action of which of the following vasoactive mediators would primarily be increased in this patient?
D. Nitric oxide
E. Atrial natriuretic peptide
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