Medical Physiology, 3rd Edition

Short-Term Regulation of Arterial Pressure

Systemic mean arterial blood pressure is the principal variable that the cardiovascular system controls

Imagine that we must distribute city water to 1000 houses. We could decide in advance that each house uses 500 L/day and then pump this amount to each house at a constant rate. In other words, we would deliver ~20 L/hr, regardless of actual water usage. The cardiovascular equivalent of such a system would be a circulation in which the cardiac output and the delivery of blood to each tissue remain constant.

Alternatively, we could connect all the houses to a single large water tower that provides a constant pressure head. Because the height of the water level in the tower is fairly stable, all faucets in all houses see the same pressure at all times. This system offers several advantages. First, each house can regulate its water usage by opening faucets according to need. Second, heavy water usage in one house with all faucets open does not affect the pressure head in the other houses with only one faucet open. Third, the pressure head in the water tower guarantees that each house will receive sufficiently high pressure to send water to any upper floors. This water tower system is analogous to our own circulatory system, which provides the same flexibility for distribution of blood flow by, first and foremost, controlling the systemic mean arterial blood pressure.

The priority given to arterial pressure control is necessary because of the anatomy of the circulatory system. A network of branched arteries delivers to each organ a mean arterial pressure that approximates the mean aortic pressure. Thus, all organs, whether close to or distant from the heart, receive the same mean arterial pressure. Each organ, in turn, controls local blood flow by increasing or decreasing local arteriolar resistance. In Chapter 20, we described these local control mechanisms in a general way, and in Chapter 24, we will discuss specific vascular beds.

The system that we just introduced works because a change in blood flow in one vascular bed does not affect blood flow in other beds—as long as the heart can maintain the mean arterial pressure. However, the circulatory system must keep mean arterial pressure not only constant but also high enough for glomerular filtration to occur in the kidneys or to overcome high tissue pressures in organs such as the eye.

Since Chapter 17, we have regarded the heart as the generator of a constant driving pressure. The principles of the feedback loops that the body uses to control the circulation are similar to those involved in the regulation of many other physiological systems. The short-term regulation of arterial pressure—on a time scale of seconds to minutes—occurs via neural pathways and targets the heart, vessels, and adrenal medulla. This short-term regulation is the topic of the present discussion. The long-term regulation of arterial pressure—on a time scale of hours or days—occurs via pathways that target the blood vessels, as well as the kidneys, in their control of extracellular fluid (ECF) volume. This long-term regulation is the topic of the final portion of the chapter.

Neural reflexes mediate the short-term regulation of mean arterial blood pressure

The neural reflex systems that regulate mean arterial pressure operate as a series of negative-feedback loops. All such loops are composed of the following elements:

1. A detector. A sensor or receptor quantitates the controlled variable and transduces it into an electrical signal that is a measure of the controlled variable.

2. Afferent neural pathways. These convey the message away from the detector, to the central nervous system (CNS).

3. A coordinating center. A control center in the CNS compares the signal detected in the periphery to a set-point, generates an error signal, processes the information, and generates a message that encodes the appropriate response.

4. Efferent neural pathways. These convey the message from the coordinating center to the periphery.

5. Effectors. These elements execute the appropriate response and alter the controlled variable, thereby correcting its deviation from the set-point.

A dual system of sensors and neural reflexes controls mean arterial pressure. The primary sensors are baroreceptors, which are actually stretch receptors or mechanoreceptors that detect distention of the vascular walls. The secondary sensors are chemoreceptors that detect changes in blood imageimage, and pH. The control centers are located within the CNS, mostly in the medulla, but sites within the cerebral cortex and hypothalamus also exert control. The effectors include the pacemaker and muscle cells in the heart, the vascular smooth-muscle cells (VSMCs) in arteries and veins, and the adrenal medulla.

We all know from common experience that the CNS influences the circulation. Emotional stress can cause blushing of the skin or an increase in heart rate. Pain—or the stress of your first day in a gross anatomy laboratory—can elicit fainting because of a profound, generalized vasodilation and a decrease in heart rate (i.e., bradycardia).

Early physiologists, such as Claude Bernard, observed that stimulation of peripheral sympathetic nerves causes vasoconstriction and that interruption of the spinal cord in the lower cervical region drastically reduces blood pressure (i.e., produces hypotension). However, the first idea that a reflex might be involved in regulating the cardiovascular system came from experiments in which stimulating a particular sensory (i.e., afferent) nerve caused a change in heart rate and blood pressure. In 1866, Élie de Cyon and Carl Ludwig imageN23-1 studied the depressor nerve, a branch of the vagus nerve. After they transected this nerve, they found that stimulation of the central (i.e., cranial) end of the cut nerve slows down the heart and produces hypotension. Ewald Hering showed that stimulation of the central end of another cut nerve—the sinus nerve (nerve of Hering), which innervates the carotid sinus—also causes bradycardia and hypotension. These two experiments strongly suggested that the depressor and sinus nerves carry sensory information to the brain and that the brain in some fashion uses this information to control cardiovascular function.

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Élie de Cyon and Carl F. Ludwig

Contributed by Walter Boron

Élie de Cyon

Born into a Jewish community in Telsch, Lithuania (then a part of the Russian Empire), not far from the German border, Ila Faddevitch Tsion (1842–1910)—also known as Élie de Cyon (French) or Elias Cyon (English)—was a tragic figure. He studied medicine in Warsaw and Kiev before moving to Berlin, where he received his doctorate in medicine and surgery. After de Cyon joined the Medical-Surgical Academy in St. Petersburg and earned a second doctorate (in medicine) in 1865, the Ministry of Education in Russia sent him to Paris to study physiology, presumably with Claude Bernard. Afterward, de Cyon moved to Leipzig to work with Carl Ludwig. There, he developed the isolated, perfused, working frog heart and with Ludwig discovered the baroreflex. In 1866, de Cyon described the inhibitory effect of the vagus nerve on cardiac muscle. The branch of the vagus that innervates the heart is known as the nerve of Ludwig-Cyon. With his brother M. de Cyon, E. de Cyon in 1867 discovered the nerve that stimulates the heart. E. de Cyon observed, but did not document, the response of the heart to increased filling pressure, thereby anticipating by a few years the Frank-Starling mechanism.

In 1867, E. de Cyon again journeyed to St. Petersburg and was professor of physiology at St. Petersburg University from 1868 to 1872. During this time, he was a mentor of and had a major influence on I.P. Pavlov (1849–1936 imageN42-4), who mastered surgical techniques and began his studies of circulation and digestion with de Cyon. In 1974—against the will of the faculty— de Cyon was appointed professor and chair of physiology at the Medical-Surgical Academy of St. Petersburg. However, majority nihilist students demanded de Cyon's removal, chaos erupted, troops were called in, and the academy was closed. de Cyon requested and received a transfer to Leipzig but was dismissed from Russian service in 1875. He received an invitation from Claude Bernard to move to France, where de Cyon performed his research and obtained his third doctorate. However, after Bernard's death in 1878, de Cyon fell out of favor, left science, and became involved in a wide range of activities, including newspaper work and an effort to unite French and Russian interests against Germany. He moved in high social circles and died in Paris in 1919, never having returned to Russia.

Carl F. Ludwig

Carl F. Ludwig (1816–1895) was born in Witzenhausen, Germany, and obtained his doctorate in medicine in Marburg in 1839. In 1865 he became the inaugural professor of physiology at Leipzig, a position that he held until his death. Along with a few contemporaries—Helmholtz, Brücke, and Du Bois-Reymond—Ludwig rejected the view that special biological laws applied to animals, and instead he championed the view that the laws of physics and chemistry applied also to animals—a philosophy necessary for the further development of physiology as a science. Ludwig invented the kymograph for recording changes in blood pressure—the first graphical output in the field of physiology. His research touched many areas of physiology, his institute became a center of physiological research, and he trained a large number of investigators from across Europe. The papers from his institute usually bear only the name of his pupils!

References

 https://en.wikipedia.org/wiki/Elias_von_Cyon [Accessed September 4, 2015].

Shilinis IuA. I.P. Pavlov's teacher of physiology I.F. Tsion (1842–1912). Zh Vyssh Nerv Deiat Im I P Pavlova. 1999;49:576–588 [Article in Russian, abstract in English.].

Wikipedia. s.v. Carl Ludwig.  http://en.wikipedia.org/wiki/Carl_Ludwig [Accessed September 1, 2015].

High-pressure baroreceptors at the carotid sinus and aortic arch are stretch receptors that sense changes in arterial pressure

Corneille Heymans was the first to demonstrate that pressure receptors—called baroreceptors—are located in arteries and are part of a neural feedback mechanism that regulates mean arterial pressure. He found that injection of epinephrine—also known as adrenaline—into a dog raises blood pressure and, later, lowers heart rate. Heymans hypothesized that increased blood pressure stimulates arterial sensors, which send a neural signal to the brain, and that the brain in turn transmits a neural signal to the heart, resulting in bradycardia.

To demonstrate that the posited feedback loop did not depend on the blood-borne traffic of chemicals between the periphery and the CNS, Heymans cross-perfused two dogs so that only nerves connected the head of the dog to the rest of the animal's body. The dog's head received its blood flow from a second animal. (Today, one would use a heart-lung machine to perfuse the head of the first dog.) Heymans found that the vagus nerve carried both the upward and the downward traffic for the reflex arc and that agents carried in the blood played no role. He used a similar approach to demonstrate the role of the peripheral chemoreceptors in the control of respiration (see pp. 710–713). For his work on the neural control of respiration, Heymans received the Nobel Prize in Physiology or Medicine in 1938. imageN23-2

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Corneille Jean François Heymans

Contributed by Walter Boron

Corneille Jean François Heymans (1892–1968) was born in Ghent, Belgium. He obtained his doctorate in medicine at the University of Ghent in 1920. Afterward, he worked with E. Gley at the Collège de France in Paris, M. Arthus in Lausanne, H. Meyer in Vienna, EH. Starling in University College London, and Carl Wiggers imageN22-1 at Western Reserve University in Cleveland. In 1922, Heymans returned to Ghent to become a lecturer in pharmacodynamics, and in 1930 succeeded his father as professor of pharmacology.

For his work on the carotid and aortic bodies and their role in the regulation of respiration, he received the 1938 Nobel Prize in Physiology or Medicine.

Reference

The Nobel Prize in Physiology or Medicine 1938. Nobelprize.org website. Nobel Media AB: Stockholm; 2014 http://nobelprize.org/nobel_prizes/medicine/laureates/1938/ [Accessed September 2, 2015].

The entire control process, known as the baroreceptor control of arterial pressure (Fig. 23-1), consists of baroreceptors (i.e., the detectors), afferent neuronal pathways, control centers in the medulla, efferent neuronal pathways, and the heart and blood vessels (i.e., the effectors). The negative-feedback loop is designed so that increased mean arterial pressure causes vasodilation and bradycardia, whereas decreased mean arterial pressure causes vasoconstriction and tachycardia (i.e., increased heart rate).

image

FIGURE 23-1 Baroreceptor control of arterial pressure. In this example, we assume that an increase in mean arterial pressure (violet box) is the primary insult.

The sensor component consists of a set of mechanoreceptors located at strategic high-pressure sites within the cardiovascular system. As discussed below, the cardiovascular system also has low-pressure sensors that detect changes in venous pressure. The two most important high-pressure loci are the carotid sinus and the aortic arch. Stretching of the vessel walls at either of these sites causes vasodilation and bradycardia. The carotid sinus (Fig. 23-2A) is a very distensible portion of the wall of the internal carotid artery located just above the branching of the common carotid artery into the external and internal carotid arteries. The arterial wall at the carotid sinus contains thin lamellae of elastic fibers but very little collagen or smooth muscle. The aortic arch (see Fig. 23-2B) is also a highly compliant portion of the arterial tree that distends during each left ventricular ejection.

image

FIGURE 23-2 Afferent pathways of the high-pressure baroreceptors. In B, the chemoreceptors (i.e., aortic bodies) are located on the underside of the aortic arch as well as—on the right side of the body—at the bifurcation of the right brachiocephalic artery. On the left side of the body, aortic bodies, if present, are in a notch between the left common carotid artery and the left subclavian artery.

The baroreceptors in both the carotid sinus and the aortic arch are the branched and varicose (or coiled) terminals of myelinated and unmyelinated sensory nerve fibers, which are intermeshed within the elastic layers. The terminals express several nonselective cation channels in the TRP family: TRPC1, TRPC3, TRPC4, and TRPC5. TRPC channels may play a role both as primary electromechanical transducers and as modulators of transduction. An increase in the transmural pressure difference enlarges the vessel and thereby deforms the receptors. Baroreceptors are not really pressure sensitive but stretch sensitive. Indeed, TRPC1 is stretch sensitive. Direct stretching of the receptor results in increased firing of the baroreceptor's sensory nerve. The difference between stretch sensitivity and pressure sensitivity becomes apparent when one prevents the expansion of the vessel by surrounding the arterial wall with a plaster cast. When this is done, increase of the transmural pressure fails to increase the firing rate of the baroreceptor nerve. Removal of the cast restores the response. Other tissues surrounding the receptors act as a sort of mechanical filter, although much less so than the plaster cast.

As shown by the red records in the upper two panels of Figure 23-3A, a step increase in transmural pressure (i.e., stretch) produces an inward current that depolarizes the receptor, generating a receptor potential (see pp. 353–354). The pressure increase actually causes a biphasic response in the receptor voltage. Following a large initial depolarization (the dynamic component) is a more modest but steady depolarization (the static component). This receptor potential, unlike a regenerative action potential, is a graded response whose amplitude is proportional to the degree of stretch (compare red and purple records).

image

FIGURE 23-3 Afferent pathways of the high-pressure baroreceptors. In A, the records refer to hypothetical experiments on a baroreceptor in which one suddenly raises blood pressure to 75 mm Hg (purple) or to 125 mm Hg (red). In B, the records refer to results from the carotid sinus nerve. (Data from Chapleau MW, Abboud FM: Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs. Circ Res 61:648–658, 1987.)

These sensory neurons are bipolar neurons (see p. 259) whose cell bodies are located in ganglia near the brainstem. The central ends of these neurons project to the medulla. The cell bodies of the aortic baroreceptor neurons, which are located in the nodose ganglion (a sensory ganglion of the vagus nerve), express several TRPC channels. imageN23-3 Although these nonselective cation channels are stretch sensitive and blocked by Gd3+, they probably set only the sensitivity of the baroreceptor response. imageN23-3

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Receptor Potential of Baroreceptors

Contributed by Emile Boulpaep

As noted in the text, increased intraluminal pressure (actually an increase tension in the vessel wall) triggers an inward current that generates a depolarization (i.e., receptor potential). The inward current that underlies the receptor potential is not sensitive to blockers of voltage-gated Na+, K+, or Ca2+ channels, but is blocked by Gd3+. The channels inhibited by the Gd3+ may be the mechanoelectrical transducers in baroreceptor nerve endings. TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7 channels are present in the plasma membrane of the cell bodies of the aortic baroreceptor neurons in the nodose ganglion. Although these channels are stretch sensitive, the cell body presumably is not subject to stretch. On the other hand, TRPC1 and TRPC3 are present in the fine nerve endings of myelinated A-type fibers that are tonically active in the normal range of arterial blood pressures. Thus, these channels could be responsible for sensory transduction. An alternate view is that such TRPC channels may set the sensitivity of the baroreceptor.

On the other hand, several types of K+ channels modulate the sensitivity of the baroreceptor nerve endings to stretch. By patch-clamping the cell bodies of the aortic arch baroreceptor neurons, investigators have found that these K+ currents include Ca2+-activated K+ currents (KCa channels; see p. 196) and A currents (Kv channels sensitive to 4-aminopyridine; see pp. 193–196). The various types of K+ channels found at the cell bodies may also be functional at the peripheral sensory endings. Agents that block these K+ channels cause a sustained depolarization of the baroreceptor endings, decreasing the pressure sensitivity of the baroreceptors, presumably by inactivating other voltage-gated channels.

Reference

Glazebrook PA, Schilling WP, Kunze DL. TRPC channels as signal transducers. Pflugers Arch. 2005;451:125–130.

Increased arterial pressure raises the firing rate of afferent baroreceptor nerves

If, in the absence of a pressure step, we depolarize the baroreceptor nerve ending, the result is an increase in the frequency of action potentials in the sensory nerve. Therefore, it is not surprising that graded increases in pressure produce graded depolarizations, resulting in graded increases in the spike frequency (see Fig. 23-3A, lower two panels). Graded decreases in pressure gradually diminish receptor activity until the firing falls to vanishingly low frequencies at pressures around 40 to 60 mm Hg. Therefore, the baroreceptor encodes the mechanical response as a frequency-modulated signal.

A step increase in pressure generates a large initial depolarization, accompanied by a transient high-frequency discharge. The smaller steady depolarization is accompanied by a steady but lower spike frequency. Because baroreceptors have both a dynamic and a static response, they are sensitive to both the waveform and the amplitude of a pressure oscillation. Therefore, bursts of action potentials occurring in phase with the cardiac cycle encode information on the pulse pressure (i.e., difference between the peak systolic and lowest diastolic pressures). The static pressure-activity curve in Figure 23-3B—obtained on single units of the sinus nerve—shows that the spike frequency rises sigmoidally with increases in steady blood pressure. The pulsatile pressure-activity curve in Figure 23-3B shows that when the pressure is oscillating, the mean discharge frequency at low mean pressures is higher than when pressure is steady.

Not all arterial receptors have the same properties. As we gradually increase intravascular pressure, different single units in the isolated carotid sinus begin to fire at different static pressures. Thus, the overall baroreceptor response to a pressure increase includes both an increased firing rate of active units and the recruitment of more units, until a saturation level is reached at ~200 mm Hg. The carotid sinus in some individuals is unusually sensitive. When wearing a tight collar, such a person may faint just from turning the head because compression or stretching of the carotid sinus orders the medulla to lower blood pressure.

The responses of the receptors in the carotid sinus and the aortic arch are different. In a given individual, a change in the carotid sinus pressure has a greater effect on the systemic arterial pressure than does a change in the aortic pressure. Compared with the carotid sinus receptor, the aortic arch receptor

• has a higher threshold for activating the static response (~110 mm Hg versus ~50 mm Hg);

• has a higher threshold, likewise, for the dynamic response;

• continues responding to pressure increases at pressures at which the carotid baroreceptor has already saturated;

• is less sensitive to the rate of pressure change; and

• responds less effectively to a decrease in pressure than to an increase in pressure (over the same pressure range).

Once a change in the arterial pressure has produced a change in the firing rate of the sensory nerve, the signal travels to the medulla. The afferent pathway for the carotid sinus reflex is the sinus nerve, which then joins the glossopharyngeal trunk (cranial nerve [CN] IX; see Fig. 23-2A). The cell bodies of the carotid baroreceptors are located in the petrosal (or inferior) ganglion of the glossopharyngeal nerve (Fig. 23-4A). The afferent pathways for the aortic arch reflex are sensory fibers in the depressor branch of the vagus nerve (CN X; see Fig. 23-2B). After joining the superior laryngeal nerves, the sensory fibers run cranially to their cell bodies in the nodose (or inferior) ganglion of the vagus (see Fig. 23-4A).

image

FIGURE 23-4 Medullary control centers for the cardiovascular system. A, Relevant nuclei and cranial nerves are colorized and labeled in dark type. B, Hypothetical section through the medulla, showing projections of structures that do not necessarily coexist in a single cross section. Glu, etc., glutamate and other neurotransmitters (i.e., norepinephrine and peptides); NE, norepinephrine.

The medulla coordinates afferent baroreceptor signals

The entire complex of medullary nuclei involved in cardiovascular regulation is called the medullary cardiovascular center. Within this center, broad subdivisions can be distinguished, such as a vasomotor area and a cardioinhibitory area. The medullary cardiovascular center receives all important information from the baroreceptors and is the major coordinating center for cardiovascular homeostasis. imageN23-4

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Identifying the Medullary Cardiovascular Control Center

Contributed by Emile Boulpaep

Investigators have established the overall importance of the medullary cardiovascular center in cardiovascular control using a variety of technical approaches:

1. Successive transections of the brain and spinal cord. Transecting the brainstem at the level of the pons does not affect the maintenance of normal blood pressure. However, transecting the medulla below the level of the facial colliculus (see Fig. 23-4A) causes blood pressure to fall. Lower sections produce even deeper drops in pressure, all the way to ~40 mm Hg. The lowest pressures occur after transection at the level of the first cervical segment (i.e., spinal shock).

2. Stimulation of the bulbopontine region. Stimulating random cells in the medulla or pons can produce either pressor (i.e., increased blood pressure) or depressor responses. In general, the pressor areas extend more rostrally and more laterally than the depressor areas.

3. Recording from single neurons. Some neurons in medullary nuclei or other medullary areas exhibit electrical activity that is synchronous with the pulse. However, it is difficult to trace the activity of a specific neuron to a specific sensory input (e.g., a specific carotid baroreceptor) or to the control of a specific effector (e.g., the smooth muscle of a particular blood vessel). These recordings have not revealed any somatotopic organization (see pp. 400–401).

4. Labeling of pathways. Following the microinjection of radiolabeled amino acids into neurons of the NTS, the anterograde transport of the label allows tracking of the efferent pathway by autoradiography. Conversely, by exposing the cut central end of the carotid sinus nerve to horseradish peroxidase, it is possible—by exploiting the retrograde transport of the marker—to trace the course of the fibers to the NTS.

Most afferent fibers from the two high-pressure baroreceptors project to the nucleus tractus solitarii (NTS, from the Latin tractus solitarii [of the solitary tract]; see p. 348), one of which is located on each side of the dorsal medulla (see Fig. 23-4A and B). The neurotransmitter released by the baroreceptor afferents onto the NTS neurons is glutamate, which binds to the GluA2 subunits of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (see pp. 323–324 and Fig. 13-15C and D). Some neurons in the NTS (and also in the dorsal motor nucleus of the vagus; see below) have P2X purinoceptors that are activated by extracellular ATP.

Inhibitory interneurons project from the NTS onto the vasomotor area in the ventrolateral medulla (see Fig. 23-4B). This vasomotor area includes the A1 and C1 areas in the rostral ventrolateral medulla, imageN23-5 as well as the inferior olivary complex and other nuclei. Stimulation of the neurons in the C1 area produces a vasoconstrictor response. Unless inhibited by output from the NTS interneurons, neurons within the C1 area produce a tonic output that promotes vasoconstriction. Therefore, an increase in pressure stimulates baroreceptor firing, which, in turn, causes NTS interneurons to inhibit C1 neurons, resulting in vasodilation. This C1 pathway largely accounts for the vascular component of the baroreceptor reflex. The bursting pattern of C1 neurons is locked to the cardiac cycle.

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The Vasomotor Area

Contributed by Emile Boulpaep

The vasomotor area includes the A1 and C1 areas in the rostral ventrolateral medulla, as well as the inferior olivary complex and other nuclei (i.e., the nucleus gigantocellularis lateralis, lateral reticular nucleus, and medullary raphe).

The C1 area also includes some adrenergic neurons, identified by the presence of the enzyme phenylethanolamine-N-methyltransferase (see Fig. 13-8C), which converts norepinephrine to epinephrine. Multiple brainstem neurons synapse with C1-area neurons and release ACh, gamma-aminobutyric acid, enkephalin, and substance P. As we will see on page 544, the antihypertensive agent clonidine acts by binding to imidazole receptors on C1-area neurons.

Some of the baroreceptor afferent fibers project directly to the vasomotor area without interaction with the NTS.

Excitatory interneurons project from the NTS onto a cardioinhibitory area, which includes the nucleus ambiguus and the dorsal motor nucleus of the vagus (see p. 339). Neurons in the dorsal motor nucleus of the vagus largely account for the cardiac component of the baroreceptor reflex (i.e., bradycardia). Some inhibitory interneurons probably project from the NTS onto a cardioacceleratory area, also located in the dorsal medulla. Stimulation of neurons in this area causes heart rate and cardiac contractility to increase.

The efferent pathways of the baroreceptor response include both sympathetic and parasympathetic divisions of the autonomic nervous system

After the medullary cardiovascular center has processed the information from the afferent baroreceptor pathways and integrated it with data coming from other pathways, this center must send signals back to the periphery via efferent (i.e., motor) pathways. The baroreceptor response has two major efferent pathways: the sympathetic and parasympathetic divisions of the autonomic nervous system.

Sympathetic Efferents

As discussed above, increased baroreceptor activity instructs the NTS to inhibit the C1 (i.e., vasomotor) and cardioacceleratory areas of the medulla. Functionally diverse bulbospinal neurons in both areas send axons down the spinal cord to synapse on and to stimulate preganglionic sympathetic neurons in the intermediolateral column of the spinal cord. Thus, we can think of these bulbospinal neurons as being presympathetic or pre-preganglionic. The synapse can be adrenergic (in the case of the C1 neurons), peptidergic (e.g., neuropeptide Y), or glutamatergic. The glutamatergic synapses are the most important for the vasomotor response; the released glutamate acts on both NMDA (N-methyl-D-aspartate) and non-NMDA receptors on the preganglionic sympathetic neurons.

The cell bodies of the preganglionic sympathetic neurons are located in the intermediolateral gray matter of the spinal cord, between levels T1 and L3 (see Fig. 14-4). After considerable convergence and divergence, most of the axons from these preganglionic neurons synapse with postganglionic sympathetic neurons located within ganglia of the paravertebral sympathetic chain as well as within prevertebral ganglia (see Fig. 14-2). The neurotransmitter between the preganglionic and postganglionic sympathetic neurons is acetylcholine (ACh), which acts at N2 nicotinic acetylcholine receptors (nAChRs; p. 339). Because of the convergence and divergence, sympathetic output does not distribute according to dermatomes (see p. 339). Postganglionic sympathetic fibers control a wide range of functions (see Fig. 14-4). Those that control blood pressure run with the large blood vessels and innervate both muscular arteries and arterioles and veins.

Increased sympathetic activity produces vasoconstriction. Indeed, the baroreceptor reflex produces vasodilation because it inhibits the tonic stimulatory output of the vasomotor C1 neurons. Because the bulbospinal neurons synapse with preganglionic sympathetic neurons between T1 and L3, severing of the spinal cord above T1 causes a severe fall in blood pressure. Sectioning of the cord below L3 produces no fall in blood pressure.

Another important target of postganglionic neurons with a cardiovascular mission is the heart. Output from the middle cervical and stellate ganglia, along with that from several upper thoracic ganglia (see Fig. 14-4), ramifies and after extensive convergence and divergence forms the cardiac nerves. Thus, severing of the spinal cord above T1 would block the input to the preganglionic sympathetic fibers to the heart. In addition, some preganglionic fibers do not synapse in sympathetic ganglia at all but directly innervate the chromaffin cells of the adrenal medulla via the splanchnic nerve. These cells release epinephrine, which acts on the heart and blood vessels (see below).

Parasympathetic Efferents

As noted above, increased baroreceptor activity instructs the NTS to stimulate neurons in the nucleus ambiguus and the dorsal motor nucleus of the vagus (cardioinhibitory area). The target neurons in these two nuclei are preganglionic parasympathetic fibers of the vagus nerve (CN X) that project to the heart. These efferent vagal fibers follow the common carotid arteries, ultimately synapsing in small ganglia in the walls of the atria. There, they release ACh onto the N2-type nAChRs of the postganglionic parasympathetic neurons. The short postganglionic fibers then innervate the sinoatrial (SA) node, the atria, and the ventricles, where they act primarily to slow conduction through the heart (see below).

The principal effectors in the neural control of arterial pressure are the heart, the arteries, the veins, and the adrenal medulla

The cardiovascular system uses several effector organs to control systemic arterial pressure: the heart, arteries, veins, and adrenal medulla (Fig. 23-5).

image

FIGURE 23-5 Autonomic control of cardiovascular end organs.

Sympathetic Input to the Heart (Cardiac Nerves)

The sympathetic division of the autonomic nervous system influences the heart through the cardiac nerves, which form a plexus near the heart (see Fig. 23-2). The postganglionic fibers, which release norepinephrine, innervate the SA node, atria, and ventricles. Their effect is to increase both heart rate and contractility (Table 23-1). Because it dominates the innervation of the SA node (which is in the right atrium), sympathetic input from the right cardiac nerve has more effect on the heart rate than does input from the left cardiac nerve. On the other hand, sympathetic input from the left cardiac nerve has more effect on contractility. In general, the cardiac nerves do not exert a strong tonic cardioacceleratory influence on the heart. At rest, their firing rate is less than that of the vagus nerve.

TABLE 23-1

Effects of Sympathetic and Parasympathetic Pathways on the Cardiovascular System

EFFECTOR RESPONSE

ANATOMIC PATHWAY

NEUROTRANSMITTER

RECEPTOR

G PROTEIN

ENZYME OR PROTEIN

2nd Messenger

Tachycardia

Sympathetic

NE

β1 on cardiac pacemaker

s

↑ AC

↑ [cAMP]i

Bradycardia

Parasympathetic

ACh

M2 on cardiac pacemaker

Direct action of dimeric image

GIRK1 K+ channels

ΔVm

Increase cardiac contractility

Sympathetic

NE

β1 on cardiac myocyte

s
Direct action of Gαs on Cav1.2

↑ AC

↑ [cAMP]i

Decrease cardiac contractility

Parasympathetic

ACh

M2 on cardiac myocyte

i

↓ AC

↓ [cAMP]i

Presynaptic M2 receptor on noradrenergic neuron

i

↓ AC

↓ [cAMP]i in neuron

M3 receptor on cardiac myocyte

q

↑ PLC →
↑ [Ca2+]i →
↑ NOS →
↑ GC

↑ [cGMP]i →
↓ Cav1.2

Vasoconstriction in most blood vessels (e.g., skin)

Sympathetic

NE

α1 on VSMC

q

↑ PLC

↑ [Ca2+]i

Vasoconstriction in some blood vessels

Sympathetic

NE

α2 on VSMC

i/o

↓ AC

↓ [cAMP]i

Vasodilation in most blood vessels (e.g., muscle)

Adrenal medulla

Epi

β2 on VSMC

s

↑ AC

↑ [cAMP]i

Vasodilation in erectile blood vessels

Parasympathetic

ACh

Presynaptic M2 receptor on noradrenergic neurons

i

↓ AC

↓ [cAMP]i in neuron

ACh

M3 on endothelial cell

q

↑ PLC →
↑ [Ca2+]i →
↑ NOS

NO diffuses to VSMC

NO

NO receptor (i.e., GC) inside VSMC

↑ GC

↑ [cGMP]i

 

VIP

VIP receptor on VSMC

s

↑ AC

↑ [cAMP]i

Vasodilation in blood vessels of salivary gland

Parasympathetic

ACh

M3 receptor on gland cell

q

↑ Kallikrein

↑ Kinins

Vasodilation in blood vessels of muscle in fight-or-flight response

Sympathetic

ACh

Presynaptic M2 receptor on noradrenergic neurons

i

↓ AC

↓ [cAMP]i in neuron

NANC

Receptor on VSMC

     

AC, adenylyl cyclase; Epi, epinephrine; GC, guanylyl cyclase; NANC, nonadrenergic, noncholinergic; NE, norepinephrine; PLC, phospholipase C; VIP, vasoactive intestinal peptide; Vm, membrane potential.

Parasympathetic Input to the Heart (Vagus Nerve)

The vagus normally exerts an intense tonic, parasympathetic activity on the heart through ACh released by the postganglionic fibers. Severing of the vagus nerve or administration of atropine (which blocks the action of ACh) increases heart rate. Indeed, experiments on the effects of the vagus on the heart led to the discovery of the first neurohumoral transmitter identified, ACh (see p. 205). Vagal stimulation decreases heart rate by its effect on pacemaker activity (see p. 492). Just as the actions of the right and left cardiac nerves are somewhat different, the right vagus is a more effective inhibitor of the SA node than the left. The left vagus is a more effective inhibitor of conduction through the atrioventricular (AV) node. Vagal stimulation, to some extent, also reduces cardiac contractility.

Sympathetic Input to Blood Vessels (Vasoconstrictor Response)

The vasoconstrictor sympathetic fibers are disseminated widely throughout the blood vessels of the body. These fibers are most abundant in the kidney and the skin, relatively sparse in the coronary and cerebral vessels, and absent in the placenta. They release norepinephrine, which binds to adrenoceptors on the membrane of VSMCs. In most vascular beds, vasodilation is the result of a decrease in the tonic discharge of the vasoconstrictor sympathetic nerves.

Parasympathetic Input to Blood Vessels (Vasodilator Response)

Parasympathetic vasodilator fibers are far less common than sympathetic vasoconstrictor fibers. The parasympathetic vasodilator fibers supply the salivary and some gastrointestinal glands and are also crucial for vasodilation of erectile tissue in the external genitalia (see pp. 1105–1106 and 1127). Postganglionic parasympathetic fibers release ACh, which, as we shall see, indirectly causes vasodilation. In addition, these fibers produce vasodilation by releasing nitric oxide (NO) and vasoactive intestinal peptide (see pp. 346–347).

Sympathetic Input to Blood Vessels in Skeletal Muscle (Vasodilator Response)

In addition to the more widespread sympathetic vasoconstrictor fibers, skeletal muscle in nonprimates has a special system of sympathetic fibers that produce vasodilation (see pp. 342–343). imageN23-6 These special fibers innervate the large precapillary vessels in skeletal muscle. The origin of the sympathetic vasodilator pathway is very different from that of the vasoconstrictor pathway, which receives its instructions—ultimately—from the vasomotor area of the medulla. Instead, the sympathetic vasodilator fibers receive their instructions—ultimately—from neurons in the cerebral cortex, which synapse on other neurons in the hypothalamus or in the mesencephalon. The fibers from these second neurons (analogous to the bulbospinal neurons discussed above) transit through the medulla without interruption and reach the spinal cord. There, these fibers synapse on preganglionic sympathetic neurons in the intermediolateral column, just as do other descending neurons. The vasodilatory preganglionic fibers synapse in the sympathetic ganglia on postganglionic neurons that terminate on VSMCs surrounding skeletal muscle blood vessels. These postganglionic vasodilatory fibers release ACh and perhaps other transmitters.

N23-6

Cholinergic Sympathetic Neurons

Contributed by Emile Boulpaep, Walter Boron

From a macroscopic anatomical point of view, there is no doubt that the cholinergic sympathetic nerve endings of sudomotor nerves (i.e., the nerves that cause sweat secretion) and some vasomotor nerves are distal to the sympathetic ganglia. In this sense, these fibers are clearly “postganglionic.” Indeed, these rare cholinergic sympathetic fibers run together from the sympathetic ganglion to the target organ together with the majority adrenergic fibers.

From a physiological point of view, all of the sympathetic neurons that reach the adrenal medulla (see p. 343) are “preganglionic.” That is, these fibers derive from neuron cell bodies that lie in the intermediolateral cell column of the spinal cord. Their axons then transit through the paravertebral ganglia of the sympathetic trunk (see the left side of Fig. 14-4) without synapsing, and then follow along the splanchnic nerves. Most of these axons then go directly to the adrenal medulla, where they synapse on their targets, the chromaffin cells. However, some axons transit through the celiac ganglion—again without synapsing—before reaching their target chromaffin cells in the adrenal medulla. Thus, all sympathetic fibers that synapse on chromaffin cells are physiologically “preganglionic”: a single neuron carries information from the spinal cord to the target cell. However, the sympathetic neurons that traverse the celiac ganglion before reaching the adrenal medulla could—from a macroscopic anatomical point of view—be regarded as postganglionic.

Authors in the 1960s and 1970s suggested that cholinergic sympathetic fibers that innervate the sweat glands (see pp. 342 and 571) and some of the vascular smooth muscle in skeletal muscle (see p. 539) derive from neuronal cell bodies in the spinal cord. This situation would be analogous to that of the cholinergic sympathetic innervation of the adrenal medulla. If this were true, then one could regard these cholinergic sympathetic sudomotor/vasomotor fibers—physiologically—as being “preganglionic.” However, more recent experiments suggest that these cholinergic sympathetic fibers can arise from neuron cell bodies located in sympathetic ganglia and that these neurons develop from neural crest cells (see p. 539). Using antibodies directed against the vesicular ACh transporter (VAChT, which transports ACh from the cytoplasm of the nerve terminal into the synaptic vesicles), Schäfer and colleagues demonstrated that VAChT-positive “principal ganglionic cells” (i.e., postganglionic neurons) are present in paravertebral sympathetic ganglia at all levels of the thoracolumbar paravertebral chain. These observations are consistent with the idea that sudomotor nerve fibers and some vasomotor nerve fibers (e.g., skeletal microvasculature) are cholinergic postganglionic sympathetic neurons. These authors also demonstrated VAChT-positive principal ganglionic cells in two other sympathetic ganglia: the stellate and superior cervical ganglia.

Schäfer and colleagues also studied the developmental biology of postganglionic sympathetic neurons. They found that a small minority of sympathetic neurons have a cholinergic phenotype even during early embryonic development—before the neurons innervate sweat glands.

Thus, a true postganglionic sympathetic neuron—postganglionic in both the gross anatomical and the physiological sense of the word—can be cholinergic. In other words, a preganglionic sympathetic “first” neuron, with its cell body in the intermediolateral column, may synapse in a sympathetic ganglion with a postganglionic sympathetic “second” neuron that releases ACh at its nerve terminals. Thus, it is no longer necessary to assume that cholinergic sympathetic sudomotor/vasomotor neurons are, in fact, preganglionic fibers that traversed the sympathetic ganglion without synapsing.

References

Schäfer MK, Eiden LE, Weihe E. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system. Neuroscience. 1998;84:361–376.

Schäfer MK, Schutz B, Weihe E, Eiden LE. Target-independent cholinergic differentiation in the rat sympathetic nervous system. Proc Natl Acad Sci U S A. 1997;94:4149–4154.

Therefore, blood vessels within skeletal muscle receive both sympathetic adrenergic and sympathetic cholinergic innervation. The cholinergic system, acting directly via muscarinic receptors (see pp. 341–342), relaxes VSMCs and causes rapid vasodilation. This vasodilation in skeletal muscle occurs in the fight-or-flight response as well as perhaps during the anticipatory response in exercise (see pp. 349–350). In both cases, mobilization of the sympathetic vasodilator system is accompanied by extensive activation of the sympathetic division, including cardiac effects (i.e., increased heart rate and contractility) and generalized vasoconstriction of all vascular beds except those in skeletal muscle. (Little vasoconstriction occurs in cerebral and coronary beds, which have sparse sympathetic vasoconstrictor innervation.)

Adrenal Medulla

We have already mentioned that some preganglionic sympathetic fibers in the sympathetic splanchnic nerves also innervate the chromaffin cells in the adrenal medulla. Therefore, the adrenal medulla is the equivalent of a sympathetic ganglion. The synaptic terminals of the preganglionic fibers release ACh, which acts on nAChRs of the chromaffin cells of the adrenal medulla (see p. 1030). Chromaffin cells are thus modified postganglionic neurons that release their transmitters—epinephrine and, to a far lesser degree, norepinephrine—into the bloodstream rather than onto a specific end organ. Thus, the adrenal medulla participates as a global effector that through its release of epinephrine causes generalized effects on the circulation. As we will see in the next section, the epinephrine released by the adrenal medulla acts on both the heart and the blood vessels and thereby contributes to the control of the systemic arterial pressure.

The unique combination of agonists and receptors determines the end response in cardiac and vascular effector cells

Adrenergic Receptors in the Heart

The sympathetic output to the heart affects both heart rate and contractility. Norepinephrine, released by the postganglionic sympathetic neurons, acts on postsynaptic β1-adrenergic receptors of pacemaker cells in the SA node as well as on similar receptors of myocardial cells in the atria and ventricles. The β1 adrenoceptor, via the G protein Gs, acts via the cAMP–protein kinase A pathway (see p. 57) to phosphorylate multiple effector molecules in both pacemaker cells and cardiac myocytes (see Table 23-1).

In pacemaker cells,imageN23-7 β1 agonists stimulate (1) If, the diastolic Na+ current through HCN channels, and (2) ICa, a Ca2+ current through T-type and L-type Ca2+ channels. The net effect of these two changes is an increased rate of diastolic depolarization (i.e., phase 4 of the action potential; see Fig. 21-4A) and a negative shift in the threshold for the action potential (see pp. 492–493). Because diastole shortens, the heart rate increases.

N23-7

Action Potential of the Sinoatrial Node

Contributed by W. Jonathan Lederer

Figure 21-4A illustrates the phases of the SA node action potential and the underlying currents.

During phase 0 of the action potential, ICa activates regeneratively (see red record in bottom panel of Fig. 21-4A, specifically the rapid downstroke), producing a rapid upstroke of Vm. Underlying ICa are both T-type and L-type Ca2+ channels.

At the transition between phases 0 and 3, ICa then begins to inactivate, a feature that begins the repolarization process. Note that phases 1 and 2 are not seen in the SA node because the inactivation of ICacombines with the slow activation of IK to bring about the phase 3 repolarization of the action potential.

As Vm approaches the maximum diastolic potential at the beginning of phase 4, three slow changes in membrane current take place that underlie phase 4 pacemaker activity:

1. IK deactivates slowly with time (over hundreds of milliseconds), producing a decreasing outward current (see green record in middle panel of Fig. 21-4A, specifically the slow decline of outward current during phase 4).

2. ICa contributes inward (i.e., depolarizing) current in the following way. Even though Vm has become more negative at the end of phase 3, Vm is still positive enough to keep ICa partially activated (albeit to only a small extent) from the previous action potential. Additionally, at the end of phase 3, Vm is still negative enough to cause ICa to recover slowly from inactivation (remember that recovery from inactivation and activation of ICa are independent processes). Thus, as ICa recovers from inactivation over hundreds of milliseconds, there is a small, increasingly inward ICa that tends to depolarize the SA nodal cells during phase 4 (see red record in lower panel of Fig. 21-4A, specifically the slow downstroke of inward current during phase 4).

3. If slowly activates as Vm becomes sufficiently negative at the end of phase 3. The result is a slowly growing, inward (i.e., depolarizing) current (see blue record in middle panel of Fig. 21-4A, specifically the rather rapid downstroke of inward current during phase 4).

Thus, during phase 4, the sum of a decreasing outward current (IK) and two increasing inward currents (ICa and If) produces the slow pacemaker depolarization associated with the SA node.

As Vm rises from about −65 mV toward the threshold of about −55 mV during the pacemaker depolarization, ICa becomes increasingly activated and eventually becomes regenerative, producing the rapid upstroke of the action potential … which takes us back to the beginning of this discussion. Note that the turning off of If tends to oppose the rapid upstroke of Vm during phase 0. However, the activation of ICaoverwhelms the turning off of If.

In myocardial cells, β1 agonists exert several parallel positive inotropic effects via protein kinase A (Table 23-2). In addition, the activated αs subunit of the G protein can directly activate L-type Ca2+ channels. The net effects of these pathways are contractions that are both stronger (see p. 493) and briefer (see pp. 522–524).

TABLE 23-2

Effects of Activating the β1-Adrenergic Receptor in Ventricular Muscle*

*See Chapter 22 for a discussion of calstabin 2 (Box 22-4), Cav1.2 (p. 522 and Box 22-4), PLN (pp. 523–524 and Box 22-3), RYR2 (p. 522 and Box 22-4), SERCA2 (p. 523 and Box 22-3), TNNC1 (p. 522), and TNNI3 (p. 522)

imagePKA, protein kinase A; RYR2, ryanodine receptor type 2; SERCA2a, sarcoplasmic and endoplasmic reticulum Ca-ATPase type 2a; SR, sarcoplasmic reticulum.

Cholinergic Receptors in the Heart

Parasympathetic output to the heart affects heart rate and, to a much lesser extent, contractility. ACh released by postsynaptic parasympathetic neurons binds to M2 muscarinic (i.e., G protein–coupled) receptors on pacemaker cells of the SA node and on ventricular myocytes (see Table 23-1).

In pacemaker cells, ACh acts by three mechanisms. (1) ACh triggers a membrane-delimited signaling pathway mediated not by the G-protein α subunits but rather by the βγ heterodimers (see p. 56). The newly released βγ subunits directly open inward-rectifier K+ channels (GIRK1 or Kir3.1) in pacemaker cells (see pp. 197–198). The resulting elevation of the K+ conductance makes the maximum diastolic potential more negative during phase 4 of the action potential. (2) ACh also decreases If, thereby reducing the rate of diastolic depolarization. (3) ACh decreases ICa, thereby both reducing the rate of diastolic depolarization and making the threshold more positive (see p. 492). The net effect is a reduction in heart rate.

In myocardial cells, ACh has a minor negative inotropic effect, which could occur by two mechanisms: (1) Activation of the M2 receptor, via Gαi, inhibits adenylyl cyclase, reducing [cAMP]i and thereby counteracting the effects of adrenergic stimulation. (2) Activation of the M3 receptor, via Gαq, stimulates phospholipase C, raising [Ca2+]i and thus stimulating nitric oxide synthase (NOS; pp. 66–67). The newly formed NO stimulates guanylyl cyclase and increases [cGMP]i, which somehow inhibits L-type Ca2+ channels and decreases Ca2+ influx.

Adrenergic Receptors in Blood Vessels

The sympathetic division of the autonomic nervous system can modulate the tone of vascular smooth muscle in arteries, arterioles, and veins via two distinct routes—postganglionic sympathetic neurons and the adrenal medulla. Whether the net effect of sympathetic stimulation in a particular vessel is vasoconstriction (increased VSMC tone) or vasodilation (decreased VSMC tone) depends on four factors: (1) which agonist is released, (2) which adrenoceptors that agonist binds to, (3) whether receptor occupancy tends to cause vasoconstriction or vasodilation, and (4) which receptor subtypes happen to be present on a particular VSMC.

Which agonist is released is the most straightforward of the factors. Postganglionic sympathetic neurons release norepinephrine, and the adrenal medulla releases primarily epinephrine.

Which receptors the agonist binds to is more complex. Norepinephrine and epinephrine do not have exclusive affinity for a single type of adrenoceptor. The original α and β designations followed from the observation that norepinephrine appeared to have its greatest activity on α receptors, and epinephrine, on β receptors. However, although norepinephrine binds with a greater affinity to α receptors than to β receptors, it also can activate β receptors. Similarly, although epinephrine binds with a greater affinity to β receptors than to α receptors, it can also activate α receptors. Of course, synthetic agonists may be more specific and potent than either norepinephrine or epinephrine (e.g., the α agonist phenylephrine and β agonist isoproterenol). A finer pharmacological and molecular dissection reveals that both α and β receptors have subgroups (e.g., β1 and β2), and even the subgroups have subgroups (see pp. 342–343). Each of these many adrenoceptor types has a unique pharmacology. Thus, the β1 receptor has about the same affinity for epinephrine and norepinephrine, but the β2 receptor has a higher affinity for epinephrine than for norepinephrine.

Whether receptor occupancy tends to cause vasoconstriction or vasodilation is straightforward (see Table 23-1). The vasoconstriction elicited by catecholamines is an α effect, in particular, an α1 effect. Thus, norepinephrine released from nerve terminals acts on the α1 adrenoceptor, which is coupled to the G protein Gq. The resulting activation of phospholipase C (see pp. 53–56) and formation of inositol 1,4,5-trisphosphate (IP3) lead to a rise in [Ca2+]i and smooth-muscle contraction (see Table 20-7). In contrast, vasodilation, elicited by epinephrine released from the adrenal medulla, is a β2 effect. Occupancy of the β2adrenoceptor triggers the cAMP–protein kinase A pathway, leading to phosphorylation of myosin light-chain kinase (MLCK; p. 247); this reduces the sensitivity of MLCK to the Ca2+-calmodulin complex, resulting by default in smooth-muscle relaxation (see Table 20-7).

Which receptor subtypes happen to be present on a particular VSMC is a complex issue. Many blood vessels are populated with a mixture of α-receptor or β-receptor subtypes, each stimulated to varying degrees by norepinephrine and epinephrine. Therefore, the response of the cell depends on the relative dominance of the subtype of receptor present on the cell surface. Fortunately, the only two subtypes in blood vessels that matter clinically are α1 and β2.

The ultimate outcome in the target tissue (vasoconstriction versus vasodilation) depends on both the heterogeneous mixture of agonists (norepinephrine versus epinephrine) applied and the heterogeneous mixture of VSMC receptors (α1 and β2) present in tissues. As an example, consider blood vessels in the skin and heart. Because cutaneous blood vessels have only α1 receptors, they can only vasoconstrict, regardless of whether the agonist is norepinephrine or epinephrine. On the other hand, epinephrine causes coronary blood vessels to dilate because they have a greater number of β2 receptors than α1 receptors.

Cholinergic Receptors in or near Blood Vessels

The addition of ACh to an isolated VSMC causes contraction. Thus, in an artificial situation in which the nerve terminals release only ACh and in which no other tissues are present, ACh would lead to vasoconstriction. In real life, however, ACh dilates blood vessels by binding to muscarinic receptors on neighboring cells and generating other messengers that indirectly cause vasodilation (see Tables 23-1 and 20-7). For example, in skeletal muscle, ACh may bind to M2 receptors on the presynaptic membranes of postganglionic sympathetic neurons, decreasing [cAMP]i and inhibiting the release of norepinephrine. Thus, inhibition of vasoconstriction produces vasodilation.

In erectile tissue, ACh not only binds to presynaptic M2 receptors as before, but also binds to M3 receptors on vascular endothelial cells and, via the phospholipase C pathway, releases IP3 and raises [Ca2+]i (see Fig. 14-11). The Ca2+ stimulates NOS to produce NO (see pp. 66–67), which diffuses from the endothelial cell to the VSMC. Inside the VSMC, the NO activates soluble guanylyl cyclase, resulting in the production of cGMP and activation of protein kinase G. The subsequent phosphorylation of MLCK causes relaxation (see p. 477).

In salivary glands,imageN23-8 postganglionic parasympathetic neurons release ACh, which may stimulate gland cells to secrete kallikrein, an enzyme that cleaves kininogens to vasodilating kinins (e.g., bradykinin). A similar paracrine sequence of events may occur in the sweat glands of nonapical skin, where postganglionic sympathetic fibers release ACh, indirectly leading to local vasodilation (see p. 571).

N23-8

Vasodilation in Salivary and Sweat Glands

Contributed by Emile Boulpaep

1. Salivary glands. For a discussion of the physiology of vasodilator kinins see pages 553–554.

2. Sweat glands. See page 571 for a discussion of the mechanisms whereby cholinergic sympathetic neurons cause vasodilation in nonapical skin.

Nonadrenergic, Noncholinergic Receptors in Blood Vessels

Postganglionic parasympathetic nerve terminals may cause vasodilation by co-releasing neurotransmitters other than ACh (see Table 23-1), such as NO, neuropeptide Y, vasoactive intestinal peptide, and calcitonin gene–related peptide. NO of neuronal origin acts in the same way as endothelium-derived NO. Neuropeptide Y acts by lowering [cAMP]i; vasoactive intestinal peptide and presumably calcitonin gene–related peptide act by raising [cAMP]i (see Table 20-8).

The medullary cardiovascular center tonically maintains blood pressure and is under the control of higher brain centers

The medullary cardiovascular center normally exerts its tonic activity on the sympathetic preganglionic neurons, whose cell bodies lie in the thoracolumbar segments of the spinal cord. However, a variety of somatic and visceral afferents also make connections with this efferent pathway in the spinal cord, and such afferents are responsible for several reflexes that occur at the spinal level. The sympathetic preganglionic neurons are normally so dependent on medullary input that they are not very sensitive to local afferents. Rather, these somatic and visceral afferents exert their major effect by ascending to the medulla and synapsing in the NTS. Nevertheless, some spinal (i.e., segmental) cardiovascular reflexes do exist. For example, the skin blanches in response to both pain and inflammation. These spinal reflexes become most powerful after a spinal transverse lesion.

Neurons of the C1 area of the medulla (see Fig. 23-4) are responsible for maintaining a normal mean arterial pressure. In general, C1 neurons are tonically active and excite sympathetic preganglionic neurons to produce vasoconstriction (see p. 537). The presence of tonically active neurons in the C1 area raises the possibility that these neurons play a role in some forms of hypertension. Interestingly, clonidine, an antihypertensive agent, acts by binding to imidazole receptors on C1 area neurons.

Besides the afferents from the baroreceptors, the medullary cardiovascular center receives afferents from respiratory centers and from higher CNS centers, such as the hypothalamus and cerebral cortex (see Fig. 23-5). The hypothalamus integrates many cardiovascular responses. Indeed, one can use a microelectrode to stimulate particular sites in the hypothalamus to reproduce a variety of physiological responses. The dorsomedial hypothalamic nucleus in the hypothalamus acts on the rostral ventrolateral medulla (see p. 537) to mediate vasomotor and cardiac responses (e.g., during exercise and acute stress). The cerebral cortex influences the hypothalamic integration areas along both excitatory and inhibitory pathways. Thus, a strong emotion can lead to precipitous hypotension with syncope (i.e., fainting). Conditioned reflexes can also elicit cardiovascular responses. For example, it is possible, by reward conditioning, to train an animal to increase or to decrease its heart rate.

Secondary neural regulation of arterial blood pressure depends on chemoreceptors

Although baroreceptors are the primary sensors for blood pressure control, a second set of receptors, the peripheral chemoreceptors, also play a role. Whereas input from baroreceptors exerts a negative drive on the medullary vasomotor center, causing vasodilation, the peripheral chemoreceptors exert a positive drive on the vasomotor center, causing vasoconstriction (Fig. 23-6A). As far as the heart is concerned, inputs from both the baroreceptors and the peripheral chemoreceptors exert a positive drive on the cardioinhibitory center; that is, they both decrease heart rate (compare Figs. 23-1 and 23-6A).

image

FIGURE 23-6 Chemoreceptor control of the cardiovascular system. In this example, we assume that a decrease in image, an increase in image, or a decrease in pH is the primary insult (violet box). In A, the bradycardia occurs only when ventilation is fixed or prevented (e.g., breath-holding). In B, the effects of breathing overcome the intrinsic cardiovascular response, producing tachycardia.

The medullary respiratory centers—which include the areas that integrate the input from the peripheral chemoreceptors—strongly influence medullary cardiovascular centers. A fall in arterial image, a rise in image, or a fall in pH stimulates the peripheral chemoreceptors to increase the firing frequency of the afferent nerves to the medulla. In the absence of conflicting input, which we discuss next, the intrinsic response of the medulla to this peripheral chemoreceptor input is to direct efferent pathways to cause vasoconstriction and bradycardia (see Fig. 23-6A). Opposite changes in the imageimage, and pH have the opposite effects.

The peripheral chemoreceptors—whose primary role is to regulate ventilation (see pp. 710–713)—lie close to the baroreceptors. Just as there are two types of high-pressure baroreceptors (i.e., carotid sinus and aortic arch), there are also two types of peripheral chemoreceptors: the carotid bodies and the aortic bodies (compare the location of the baroreceptor and chemoreceptor systems in Fig. 23-2A, B).

Carotid Bodies

The carotid body—or glomus caroticum—is located between the external and internal carotid arteries. Although the human carotid body is small (i.e., ~1 mm3), it has an extraordinarily high blood flow per unit mass and a minuscule arteriovenous difference for imageimage, and pH—putting it in an excellent position to monitor the composition of the arterial blood. The chemosensitive cell in the carotid body is the glomus cell,imageN23-9 which synapses with nerve fibers that join the glossopharyngeal nerve (CN IX). A fall in arterial image, a rise in arterial image, or a fall in the pH increases the spike frequency in the sensory fibers of the afferent sinus nerve.

N23-9

Peripheral Chemoreceptors

Contributed by George Richerson, Emile Boulpaep, Walter Boron

Recent progress on the physiology of glomus cells has largely been a result of the ability to study glomus cells in culture and in the isolated carotid body in vitro.

Regarding the model in Figure 32-11, some controversy—which may reflect species differences—exists about which K+ channel is the target of hypoxia. Some evidence favors the charybdotoxin-sensitive Ca2+-activated K+ channel. Other data point to a Ca2+-insensitive voltage-gated K+ channel and a voltage-insensitive “resting” K+ channel.

Although one report (Williams et al, 2004) suggested that hemoxygenase-2 (HO-2) is a universal O2 sensor, the results of a later study (Ortega-Sáenz et al, 2006) showed that mice deficient in HO-2 have a normal ability to sense a decrease in [O2].

References

Hoshi T, Lahiri S. Oxygen sensing: It's a gas!. Science. 2004;306:2050–2051.

Ortega-Sáenz P, Pascual A, Gómez-Díaz R, López-Barneo J. Acute oxygen sensing in heme oxygenase-2 null mice. Proc J Gen Physiol. 2006;128:405–411.

Williams SEJ, Wootton P, Mason HS, et al. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science. 2004;306:2093–2097.

Aortic Bodies

The aortic bodies are situated immediately under the concavity of the aortic arch and in the angle between the right subclavian and carotid arteries. Aortic bodies may also be present at the angle between the left subclavian and common carotid arteries. The aortic glomus cells synapse with nerve fibers that are afferent pathways in the vagus nerve (CN X).

Afferent Fiber Input to the Medulla

The most important signal affecting the glomus cells is a low image, which triggers an increase in the firing rate of the sensory fibers. We will discuss ways in which this signal triggers neuronal firing on page 712. Like the afferent fibers from the baroreceptors, the afferent fibers from both the carotid body (CN IX) and the aortic bodies (CN X) project to the NTS in the medulla. Indeed, the responses to input from the peripheral chemoreceptors overlap with those to input from the baroreceptors.

Physiological Role of the Peripheral Chemoreceptors in Cardiovascular Control

The fluctuations in image that normally occur in humans are not large enough to affect the blood pressure or heart rate. For the cardiovascular system, the peripheral chemoreceptors play a role only during severe hypoxia (e.g., hemorrhagic hypotension). As already noted, the intrinsic cardiovascular effects of hypoxia on the peripheral chemoreceptors include vasoconstriction and bradycardia (see Fig. 23-6A). However, it is not easy to demonstrate this primary reflex bradycardia; indeed, it is observed only during forced apnea. Under real-life conditions, hypoxia causes tachycardia. Why? Hypoxia—via the peripheral chemoreceptors—normally stimulates the medullary respiratory centers, which in turn stimulate ventilation (see Fig. 23-6B). As discussed below, the high image that may accompany hypoxia stimulates the central chemoreceptors, and this independently stimulates ventilation. This increased ventilation has two effects. First, it stretches the lungs, which in turn stimulates pulmonary stretch receptors. Afferent impulses from these pulmonary stretch receptors ultimately inhibit the cardioinhibitory center, causing reflex tachycardia. Second, as discussed on pages 679–680, increased alveolar ventilation caused by hypoxia lowers systemic image, raising the pH of the brain ECF and inhibiting the cardioinhibitory center. Again, the net effect is tachycardia. Thus, the physiological response to hypoxia is tachycardia.

Central Chemoreceptors

In addition to peripheral chemoreceptors, central chemoreceptors are present in the medulla (see p. 713). However, in contrast to the peripheral chemoreceptors, which primarily sense a low image, the central chemoreceptors mainly sense a low brain pH, which generally reflects a high arterial image.

As already noted (see Fig. 23-4B), tonic baroreceptor input to the NTS in the medulla stimulates inhibitory interneurons that project onto the vasomotor area. This pathway exerts a considerable restraining influence on sympathetic output, which would otherwise cause vasoconstriction. Thus, cutting of these baroreceptor afferents causes vasoconstriction. The central chemoreceptor also influences the vasomotor area. Indeed, a high arterial image (i.e., low brain pH), which stimulates the central chemoreceptor, disinhibits the vasomotor area—just as cutting of baroreceptor afferents disinhibits the vasomotor area. The result is also the same: an increase in the sympathetic output and vasoconstriction.

In summary, a low image acting on the peripheral chemoreceptor and a high image acting on the central chemoreceptor act in concert to enhance vasoconstriction.