Regulation of the Heartbeat

Parasympathetic Pathways

Cardiac parasympathetic fibers originate in the medulla oblongata, in cells that lie in the dorsal motor nucleus of the vagus or in the nucleus ambiguus. The precise location varies from species to species. Efferent vagal fibers pass inferiorly through the neck as the cervical vagus nerves ( Fig. 5.2 ), which lie close to the common carotid arteries. They then pass through the mediastinum to synapse with postganglionic cells on the epicardial surface or within the walls of the heart itself. Most of the cardiac ganglion cells are found in plexuses and are located near the SA node and atrioventricular (AV) conduction tissue.

The right and left vagi are distributed differentially to the various cardiac structures. The right vagus nerve affects the SA node predominantly; its stimulation slows SA nodal firing or may even stop it for several seconds. The left vagus nerve mainly inhibits AV conduction tissue to produce various degrees of AV block. However, the distributions of the efferent vagal fibers overlap, such that left vagal stimulation also depresses the SA node and right vagal stimulation impedes AV conduction.

The SA and AV nodes are rich in cholinesterase . Hence the effects of any given vagal impulse are brief because cholinesterase rapidly hydrolyzes the neurally released acetylcholine . The effects of vagal activity on SA and AV nodal function also display a very short latency (about 50 to 100 milliseconds), because the released acetylcholine activates special K ⁺ channels (I _K,ACh , an inwardly rectifying potassium channel) in the cardiac cells. The opening of these channels is so prompt because it does not require the operation of a second messenger, such as cyclic adenosine monophosphate (cAMP) .

When the vagus nerves are stimulated at a constant frequency for several seconds, the HR decreases abruptly and attains a steady-state value within one or two cardiac cycles ( Fig. 5.3A ). Also, when stimulation is discontinued, the HR returns very quickly to its basal level. The combination of the brief latency and rapid decay of the response (because of the abundance of cholinesterase) allows the vagus nerves to exert a beat-by-beat control of SA and AV nodal function.

Parasympathetic influences dominate sympathetic effects at the SA node, as shown in Fig. 5.4 . This vagal dominance in the regulation of HR is mediated mainly by suppression of the release of norepinephrine from the sympathetic nerve endings by the acetylcholine released from neighboring vagus nerve endings. This nerve–nerve interaction between the two divisions of the autonomic nervous system is discussed more fully in association with Fig. 5.5 .

Sympathetic Pathways

The cardiac sympathetic fibers originate in the intermediolateral columns of the upper five or six thoracic and lower one or two cervical segments of the spinal cord. They emerge from the spinal column through the white communicating branches and enter the paravertebral chains of ganglia. Preganglionic and postganglionic neurons synapse mainly in the stellate and middle cervical ganglia (see Fig. 5.2 ). The middle cervical ganglia lie close to the vagus nerves in the superior portion of the mediastinum. Postganglionic sympathetic and preganglionic parasympathetic fibers then form a plexus of mixed efferent nerves to the heart (see Fig. 5.2 ).

Postganglionic cardiac sympathetic fibers approach the base of the heart along the adventitial surface of the great vessels. On reaching the base of the heart, these fibers are distributed to the various chambers as an extensive epicardial plexus. They then penetrate the myocardium, usually along the coronary vessels. The majority of adrenergic receptors in the nodal regions and in the myocardium are β -adrenergic receptors ; that is, they are activated by β-adrenergic agonists, such as isoproterenol , and are inhibited by β-adrenergic blocking agents, such as propranolol .

Like the vagus nerves, the left and right sympathetic fibers are distributed differentially. In the dog, for example, fibers on the left side have more pronounced effects on myocardial contractility than do fibers on the right side, whereas the fibers on the left side have much less effect on HR than do the fibers on the right side ( Fig. 5.6 ). In some dogs, left cardiac sympathetic nerve stimulation may not affect the HR at all. This bilateral asymmetry probably also exists in humans. In one group of patients, block of the right stellate ganglion caused a mean reduction in HR of 14 beats/min, whereas left-sided blockade decreased HR by only 2 beats/min.

Figs. 5.3B and 5.6 show that the effects of sympathetic stimulation decay very gradually after the cessation of stimulation, in contrast to the abrupt termination of the response after vagal activity (see Fig. 5.3A ). Most of the norepinephrine released during sympathetic stimulation is taken up again by the nerve terminals, and much of the remainder is carried away by the bloodstream. These processes are relatively slow. Furthermore, at the beginning of sympathetic stimulation, the facilitatory effects on the heart attain steady-state values much more slowly than do the inhibitory effects of vagal stimulation (see Fig. 5.3 ).

At least two factors are responsible for the more gradual onset of the HR response to sympathetic activity than to vagal activity. First, the response to sympathetic activity depends mainly on the intracellular production of second messengers, mainly cAMP, in the automatic cells in the SA node (see Fig. 5.5 ). This is slower than the response to vagal activity. The muscarinic receptors that respond to the acetylcholine released from the vagal terminals are coupled directly to the acetylcholine-regulated K ⁺ channels by a G protein; this direct coupling allows a prompt response. Second, the postganglionic nerve endings of each of the two autonomic divisions release neurotransmitters at different rates. Intense vagal activity releases enough acetylcholine during a brief period (e.g., 1 s) to arrest the heartbeat. Conversely, even during intense sympathetic activity, enough norepinephrine is released during each cardiac cycle to change cardiac behavior by only a small increment. Thus the vagus nerves are able to exert beat-by-beat control of HR, whereas the sympathetic nerves cannot alter cardiac function very much within one cardiac cycle.

The dominance of parasympathetic over sympathetic effects on SA and AV node activities depends on the nature of their interactions. There are prejunctional (nerve–nerve) and postjunctional (within the cardiac cell) interactions between vagal and sympathetic neurons (see Fig. 5.5 ). Within the terminal autonomic innervation, parasympathetic and sympathetic fibers are interlaced within microns of each other.

The experiment illustrated in Fig. 5.7 demonstrates that stimulation of the cardiac sympathetic nerves results in the overflow of substantial norepinephrine into the coronary sinus blood. The amount of norepinephrine that overflows into the coronary sinus blood parallels the amount of norepinephrine released at cardiac sympathetic terminals. Concomitant vagal stimulation reduces the overflow of norepinephrine by about 30%. The sympathetic adrenergic terminal membrane has muscarinic receptors activated by acetylcholine that causes inhibition of norepinephrine release. Thus vagal activity decreases cardiac frequency (see Fig. 5.4 ) and contractility (see Fig. 5.31 ) partly by antagonizing the facilitatory effects of any concomitant sympathetic activity. Physiologically, neuropeptide Y (NPY) , a cotransmitter with norepinephrine in sympathetic adrenergic nerves, can inhibit acetylcholine from neighboring vagal fibers (see Fig. 5.5 ).

Postjunctional interaction of parasympathetic and sympathetic transmitter occurs largely, but not exclusively, through regulation of cAMP formation (see Fig. 5.5 ). Postjunctional targeting of transmitter action begins at guanine nucleotide–coupled receptors (GPCRs), namely muscarinic and β-adrenergic receptors. Inhibitory G proteins (G _i ) for muscarinic receptor and stimulatory G proteins (G _s ) for β-adrenergic receptors provide another means of targeting transmitter action. Fig. 5.8 illustrates the general features of postjunctional action of a transmitter. Transmitter occupancy of its GPCR facilitates the exchange of GTP for GDP and the G protein α subunit dissociates from the βγ subunits. The α subunit regulates adenylyl cyclase activity (inhibition via G _i , stimulatory via G _a ) and thereby the concentration of cAMP. In the case of G _i , the βγ subunits serve as a transducer to activate I _K,ACh channels that cause membrane hyperpolarization in SA (see Fig. 3.5 ) and AV (see Fig. 3.10 ) nodes. Cyclic AMP is a water-soluble substance whose message is targeted by intracellular compartments of its synthetic enzyme, adenylyl cyclase, its hydrolytic enzymes, phosphodiesterases, and its anchoring peptides, cAMP-dependent protein kinase anchoring proteins (AKAPs). Thus norepinephrine raises intracellular cAMP, which interacts with its cognate protein kinase to regulate cardiac function by phosphorylating strategic proteins (troponin I, phospholamban, various ionic channels, glycolytic enzymes). Acetylcholine, by reducing cAMP formation, exerts the opposite actions on these intracellular effectors. Thus the postjunctional interaction between these autonomic transmitters adds another level of integration to their regulation of heart function (see Fig. 5.8 ).

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Higher Centers Also Influence Cardiac Performance

Stimulation of various regions of the brain induces dramatic alterations in cardiac rate, rhythm, and contractility. In the cerebral cortex, the centers that regulate cardiac function are mostly in the anterior half of the brain—principally in the frontal lobe, the orbital cortex, the motor and premotor cortex, the anterior part of the temporal lobe, the insula, and the cingulate gyrus. In the thalamus, tachycardia may be induced by stimulation of the midline, ventral, and medial groups of nuclei. Variations in HR also may be evoked by stimulating the posterior and posterolateral regions of the hypothalamus.

Stimuli applied to field H2 of Forel in the diencephalon elicit various cardiovascular responses, including tachycardia; such changes closely resemble those observed during muscular exercise. Undoubtedly the cortical and diencephalic centers are responsible for initiating the cardiac reactions that occur during excitement, anxiety, and other emotional states. Hypothalamic centers are also involved in the cardiac response to alterations in environmental temperature. Localized temperature changes in the preoptic anterior hypothalamus alter HR and peripheral resistance.

Stimulation of the parahypoglossal area of the medulla activates cardiac sympathetic and inhibits cardiac parasympathetic pathways. In certain dorsal regions of the medulla, distinct cardiac accelerator and augmentor sites have been detected in animals with transected vagi. Stimulation of accelerator sites raises HR, whereas stimulation of augmentor sites increases cardiac contractility. The accelerator regions were more abundant on the right, and the augmentor sites more prevalent on the left. A similar distribution also exists in the hypothalamus. Therefore it appears that for the most part the sympathetic fibers descend ipsilaterally from the brainstem.

Heart Rate Can Be Regulated via the Baroreceptor Reflex

Acute changes in arterial blood pressure reflexly elicit inverse changes in HR ( Fig. 5.9 ) via the baroreceptors located in the aortic arch and carotid sinuses (see also Chapter 9 ). The inverse relation between HR and arterial blood pressure is usually most pronounced over an intermediate range of arterial blood pressures. In the experiment shown in Fig. 5.9 , this range varied between about 70 and 160 mm Hg. Below the intermediate range of pressures, the HR maintains a constant, high value, whereas above this pressure range, it maintains a constant, low value.

The effects of changes in carotid sinus pressure on the activity in the cardiac autonomic nerves of an anesthetized dog are shown in Fig. 5.10 . Alterations in HR are achieved by reciprocal changes in vagal and sympathetic neural activity over an intermediate range of arterial pressures (from about 100 to 200 mm Hg). Below this range of arterial blood pressures, the high HR is achieved by intense sympathetic activity and the virtual absence of vagal activity. Conversely, above the intermediate range of arterial blood pressures, the low HR is achieved by intense vagal activity and a constant low level of sympathetic activity.

The Bainbridge Reflex and Atrial Receptors Regulate Heart Rate

In 1915 Bainbridge reported that infusions of blood or saline accelerated the HR in dogs. This increase in HR occurred whether arterial blood pressure did or did not rise. Tachycardia was observed whenever central venous pressure rose sufficiently to distend the right side of the heart, and the effect was abolished by bilateral transection of the vagi.

The magnitude and direction of the HR changes evoked by the Bainbridge reflex depend on the prevailing HR. When the HR is slow, intravenous infusions usually accelerate the heart. At more rapid HRs, however, infusions ordinarily slow the heart. Increases in blood volume not only evoke the Bainbridge reflex but also activate other reflexes (notably the baroreceptor reflex) that tend to change the HR in the opposite direction. The actual change in HR evoked by an alteration of blood volume is therefore the result of these antagonistic reflex effects ( Fig. 5.11 ).

In unanesthetized dogs, infusions of blood increased HR and CO proportionately ( Fig. 5.12 ); consequently, SV varied little. Conversely, reductions in blood volume diminished the CO but increased HR. Undoubtedly, the Bainbridge reflex prevailed over the baroreceptor reflex when the blood volume was raised, but the baroreceptor reflex prevailed over the Bainbridge reflex when the blood volume was diminished.

Both atria have receptors that influence HR. They are located principally in the venoatrial junctions—in the right atrium at its junctions with the venae cavae and in the left atrium at its junctions with the pulmonary veins. Distention of these atrial receptors sends impulses centrally in the vagi. The efferent impulses are carried by fibers from both autonomic divisions to the SA node. The cardiac response is highly selective. Even when the reflex increase in HR is large, changes in ventricular contractility are negligible. Furthermore, the increase in sympathetic activity is restricted to the HR; there is no increase of sympathetic activity to the peripheral arterioles.

Stimulation of the atrial receptors also increases urine volume. Reduced activity in the renal sympathetic nerve fibers might be partially responsible for this diuresis. However, the principal mechanism appears to be a neurally mediated reduction in the secretion of vasopressin (antidiuretic hormone) by the posterior pituitary gland.

Atrial natriuretic peptide (ANP) is released from storage granules within atrial myocytes in response to increases in blood volume by virtue of the resulting stretch of the atrial walls. ANP, a 28–amino acid peptide, has potent diuretic and natriuretic effects on the kidneys, and it dilates the resistance and capacitance of blood vessels. Thus ANP is an important regulator of blood volume and blood pressure.

Respiration Induces a Common Cardiac Dysrhythmia

Rhythmic variations in HR, occurring at the frequency of respiration, are detectable in most individuals and tend to be more pronounced in children. Typically, the cardiac rate accelerates during inspiration and decelerates during expiration ( Fig. 5.13 ).

Recordings from cardiac autonomic nerves reveal that activity increases in the sympathetic nerve fibers during inspiration, whereas activity in the vagal nerve fibers increases during expiration ( Fig. 5.14 ). Acetylcholine released at the vagal endings is hydrolyzed so rapidly that the rhythmic changes in activity are able to elicit rhythmic variations in HR. Conversely, norepinephrine released at the sympathetic endings is removed more slowly, thus damping out the effects of rhythmic variations in norepinephrine release on HR. Hence rhythmic changes in HR arise almost entirely from oscillations in vagal activity. Respiratory sinus dysrhythmia is exaggerated when vagal tone is enhanced.

Both reflex and central factors contribute to the genesis of the respiratory cardiac dysrhythmia ( Fig. 5.15 ). During inspiration, intrathoracic pressure decreases, and therefore venous return to the right side of the heart is accelerated and right atrial pressure increases (see also Chapter 10 ) and elicits the Bainbridge reflex (see Fig. 5.15 ). After the time delay required for the increased venous return to reach the left side of the heart, left ventricular output increases and raises arterial blood pressure. This greater pressure, in turn, reduces HR reflexly through baroreceptor stimulation (see Fig. 5.15 ).

Fluctuations in sympathetic activity to the arterioles cause peripheral resistance to vary at the respiratory frequency. Consequently, arterial blood pressure fluctuates rhythmically, affecting HR via the baroreceptor reflex. Stretch receptors in the lungs may also affect HR (see Fig. 5.15 ). Moderate pulmonary inflation may increase HR reflexly. The afferent and efferent limbs of this reflex are located in the vagus nerves.

Central factors are also responsible for respiratory cardiac dysrhythmia (see Fig. 5.15 ). The medullary respiratory center influences cardiac autonomic centers. In heart–lung bypass experiments conducted on animals, the chest is opened, the lungs are collapsed, venous return is diverted to a pump-oxygenator, and arterial blood pressure is maintained at a constant level. In such experiments, rhythmic movements of the rib cage attest to the activity of the medullary respiratory centers, and the movements of the rib cage are often accompanied by rhythmic changes in HR at the respiratory frequency. This respiratory cardiac dysrhythmia is almost certainly induced by an interaction between the respiratory and cardiac centers in the medulla (see Fig. 5.15 ).

Activation of the Chemoreceptor Reflex Affects Heart Rate

The cardiac response to peripheral (or arterial) chemoreceptor stimulation merits special consideration because it illustrates the complexity that may be introduced when one stimulus excites two organ systems simultaneously. In intact animals, stimulation of the arterial chemoreceptors consistently increases ventilatory rate and depth, but HR usually changes only slightly. The directional change in HR evoked by the peripheral chemoreceptors is related to the enhancement of pulmonary ventilation ( Fig. 5.16 ). When respiratory stimulation is mild, HR usually diminishes; when the increase in pulmonary ventilation is more pronounced, HR usually accelerates.

The cardiac response to arterial chemoreceptor stimulation is the result of primary and secondary reflex mechanisms ( Fig. 5.17 ). The primary reflex effect of arterial chemoreceptor excitation is to stimulate the medullary vagal center and thereby decrease HR. Secondary effects are mediated by the respiratory system. Respiratory stimulation by the arterial chemoreceptors tends to inhibit the medullary vagal center. This inhibitory effect varies with concomitant stimulation of respiration.

An example of the primary inhibitory influence of arterial chemoreceptor stimulation is displayed in Fig. 5.18 . In this experiment, the lungs were completely collapsed, and an artificial oxygenator was used to maintain blood oxygen levels. When the carotid chemoreceptors were stimulated, an intense bradycardia and some degree of AV block ensued. These effects are mediated primarily by efferent vagal fibers.

The hyperventilation that is ordinarily evoked by carotid chemoreceptor stimulation influences HR secondarily, both by initiating more pronounced pulmonary inflation reflexes and by producing hypocapnia (see Fig. 5.17 ). Each of these influences tends to depress the primary cardiac response to chemoreceptor stimulation and thereby to accelerate the heart. Hence, when pulmonary hyperventilation is not prevented, the primary and secondary effects tend to neutralize each other, and carotid chemoreceptor stimulation affects HR only minimally. FLOAT NOT FOUND

Clinical Box

The identical primary vagal inhibitory effect also operates in humans. The electrocardiogram shown in Fig. 5.19 was recorded from a quadriplegic patient who could not breathe spontaneously and required tracheal intubation and artificial respiration. When the tracheal catheter was briefly disconnected to permit nursing care, profound bradycardia quickly developed. The heart rate was 65 beats/min just before the tracheal catheter was disconnected. In less than 10 s after cessation of artificial respiration, the heart rate fell to about 20 beats/min. This bradycardia could be prevented by blocking of the effects of efferent vagal activity with atropine, and its onset could be delayed considerably by hyperventilation of the patient before disconnection of the tracheal catheter.

Ventricular Receptor Reflexes Play a Minor Role in the Regulation of Heart Rate

Sensory receptors near the endocardial surfaces of the ventricular walls initiate reflexes similar to those elicited by the arterial baroreceptors. Excitation of these endocardial receptors diminishes HR and peripheral resistance. Other sensory receptors have been identified in the epicardial regions of the ventricles. Ventricular receptors are excited by a variety of mechanical and chemical stimuli, but their physiological functions are not clear.

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