Neurohumoral Mechanisms Regulate Blood Pressure and Blood Volume to Ensure Adequate Blood Flow for All Body Organs

The influences of the nervous system and hormones on the cardiovascular system are referred to collectively as the neurohumoral mechanisms of cardiovascular control. The neurohumoral mechanisms are also called extrinsic control mechanisms because they act on organs from the outside. As described in Chapter 24, the mechanisms of cardiovascular control that act locally, within individual tissues, are referred to as intrinsic control mechanisms. The local, or intrinsic, mechanisms predominate over extrinsic mechanisms in the control of blood flow to the “critical” organs, which include the heart (i.e., coronary circulation), brain, and working (exercising) skeletal muscle. In contrast, neurohumoral, or extrinsic, control mechanisms predominate over the intrinsic mechanisms in the control of blood flow to the “noncritical” organs, which include the kidneys, the splanchnic organs, and resting skeletal muscle. The noncritical organs are those that can withstand temporary reductions in blood flow (and metabolism) to make extra blood flow available for the critical organs, whose optimal function on a moment-to-moment basis may be necessary for survival (e.g., in a life-threatening situation involving “fight or flight”).

Neurohumoral mechanisms also control the heart rate and cardiac contractility. This allows cardiac output to be adjusted to provide adequate blood flow for all the systemic organs, or at least for the critical organs. An important distinction is that cardiac muscle is under neurohumoral control, whereas the coronary blood vessels are primarily under local control. When neurohumoral mechanisms increase the heart rate and cardiac contractility, the cardiac metabolic rate also increases. The increased metabolic rate acts via local metabolic control mechanisms to dilate coronary arterioles, which increases coronary blood flow.

To appreciate the importance of neurohumoral control mechanisms, consider what would happen in their absence. For example, what would occur during exercise if all the body organs relied on local control mechanisms to adjust their blood flow? At the onset of exercise, metabolic control mechanisms would cause vasodilation in the exercising skeletal muscles. Vascular resistance would decrease in the exercising muscles, and the blood flow through the muscles would increase. However, decreasing the vascular resistance in skeletal muscles would lower the total peripheral resistance (TPR). As a consequence, arterial blood pressure would decrease. This would decrease the perfusion pressure for all the systemic organs, and blood flow would therefore decrease below normal levels in the brain, kidneys, splanchnic organs, and so forth. The decreased blood flow in these organs would trigger autoregulatory responses, and these organs would vasodilate. However, the vasodilation would lower the TPR even further, which would reduce arterial pressure even more. This in turn would limit the increase in skeletal muscle blood flow. The end result would be some increase in blood flow in the exercising muscle and decreased blood flow elsewhere, but none of the organs (including skeletal muscle) would be receiving sufficient blood flow to meet their metabolic needs. Arterial pressure would be dangerously low, and the animal would exhibit profound exercise intolerance.

Neurohumoral control mechanisms allow an animal to avoid these complications. First, cardiac output is increased sufficiently to meet the increased need for blood flow in the exercising muscle (and in the coronary circulation) while keeping all the other organs supplied with a normal blood flow. If cardiac output cannot be increased sufficiently to meet all these needs, the control mechanisms take the additional step of temporarily reducing blood flow in the noncritical organs and making this extra flow available to the critical organs.

How do the neurohumoral control systems “know” when cardiac output is sufficiently high to meet the needs of all the organs and when to initiate vasoconstriction in the noncritical organs? An indirect strategy is used: cardiac output is increased enough to keep arterial pressure at a normal level. As long as arterial pressure is maintained at the normal level, local metabolic control mechanisms can successfully match blood flow to metabolic need in each individual organ. If cardiac output cannot be sufficiently increased to keep arterial pressure from falling, neurohumoral mechanisms initiate vasoconstriction in the noncritical organs. Thus, neurohumoral control mechanisms will deprive noncritical organs of an ideal level of blood flow if the critical organs are in need of more blood flow than can be supplied by the heart.

There are many important neurohumoral control mechanisms, but four are emphasized in the following presentation. The first two of these are cardiovascular reflexes. The arterial baroreceptor reflex works to regulate arterial pressure through the continual adjustment of cardiac output and vascular resistance (in the noncritical organs). The atrial volume receptor reflex works in conjunction with the arterial baroreceptor reflex to regulate arterial pressure and to adjust cardiac preload. The other two neurohumoral mechanisms described in this chapter are the defense-alarm reaction (the “fight or flight response”) and vasovagal syncope (the “playing dead” reaction). These responses exemplify psychogenic influences on the cardiovascular system.

The Autonomic Nervous System Affects the Cardiovascular System Through the Release of Epinephrine, Norepinephrine, and Acetylcholine

The autonomic nervous system is the “neuro” arm of neurohumoral control. Sympathetic and parasympathetic neurons influence the cardiovascular system through the release of the neurotransmitters norepinephrine and acetylcholine. In addition, sympathetic nerves affect the cardiovascular system by stimulating the release of epinephrine and norepinephrine from the adrenal medulla. The adrenal secretions enter the bloodstream as hormones and circulate throughout the body. Chapter 13 contains additional, basic information about the autonomic nervous system.

Whether acting as neurotransmitters or as hormones, epinephrine, norepinephrine, and acetylcholine exert their cardiovascular effects by activating receptor proteins located in the membranes of cardiac muscle cells or of the smooth muscle cells (or in some cases the endothelial cells) in the walls of blood vessels. The receptors activated by epinephrine and norepinephrine are called adrenergic receptors (named after the adrenal gland). There are two major types: α-adrenergic receptors and β-adrenergic receptors. The α-adrenergic receptors are subdivided into α₁ and α₂. There are three subtypes of β-receptors: β₁, β₂, and β₃, with the first two of these being important in cardiovascular control.

Acetylcholine activates cholinergic receptors. There are two major types: muscarinic cholinergic receptors and nicotinic cholinergic receptors. The main cardiovascular effects of acetylcholine are mediated through muscarinic cholinergic receptors located on cardiac, smooth muscle, or endothelial cells. Of five subtypes of muscarinic receptors, the M₂ and M₃ receptor subtypes have the greatest cardiovascular importance.

Table 25-1 summarizes the main cardiovascular consequences of the activation of adrenergic and cholinergic receptors. α-Adrenergic receptors (both α₁ and α₂) are located in the cell membranes of the smooth muscle cells of the arterioles in all organs and in the smooth muscle cells of the abdominal veins. These adrenergic receptors are innervated by postganglionic sympathetic neurons, which release the neurotransmitter norepinephrine. Circulating epinephrine or norepinephrine can also activate the adrenergic receptors. Activation of these α-adrenergic receptors leads to constriction of the arterioles or the veins.

Arteriolar vasoconstriction increases the resistance and decreases the blood flow through an organ. If one or more major body organs are vasoconstricted, the total peripheral resistance (TPR) increases. TPR (along with cardiac output) determines arterial blood pressure, so widespread α-adrenergic vasoconstriction in the body leads to an increase in arterial blood pressure. The increase in arterial pressure increases the driving force for blood flow in all organs of the systemic circulation. In effect, the sympathetic nervous system can vasoconstrict some organs and thereby direct more blood flow to other, non-vasoconstricted organs.

The major role of veins is to act as reservoirs for blood. Venoconstriction displaces venous blood toward the central circulation, which increases central venous pressure, right ventricular preload, and (by the Starling mechanism) stroke volume. Venoconstriction in the abdominal organs is particularly effective in increasing central venous pressure. Venoconstriction causes a relatively small increase in the resistance to blood flow through an organ because the veins, whether dilated or constricted, offer much less resistance to blood flow than do the arterioles.

Sympathetic control of the heart is exerted through the β₁-adrenergic receptors, which are found on every cardiac muscle cell. These beta receptors are activated by norepinephrine or epinephrine. Chapters 19 and 21 discuss the effects of activation of the cardiac β-adrenergic receptors. In brief, pacemaker rate increases, cell-to-cell conduction velocity increases, and refractory period decreases. In addition, contractility is increased, so the cardiac contractions are quicker and stronger. The overall effect is increased heart rate and increased stroke volume.

β₂-Adrenergic receptors are found on the arterioles, particularly in the coronary circulation and in skeletal muscles. The activation of arteriolar β₂-adrenergic receptors causes relaxation of the vascular smooth muscle and dilation of the arterioles. However, these β₂-adrenergic receptors are not innervated by the sympathetic nervous system, so they are not activated directly by sympathetic nerves. Instead, they respond to circulating epinephrine and norepinephrine (released from the adrenal medulla). The adrenal medulla releases epinephrine and norepinephrine in situations that involve trauma, fear, or anxiety. Dilation of arterioles in the coronary circulation and in skeletal muscles is appropriate in such “fear, fight, or flight” response situations because the dilation results in an anticipatory increase in blood flow to the heart and skeletal muscle. Appropriately for its role in emergency situations, β₂-adrenergic vasodilation can overpower α-adrenergic vasoconstriction in the coronary circulation and in skeletal muscles.

Parasympathetic effects on the heart are mediated via the neurotransmitter acetylcholine, which activates cholinergic muscarinic receptors of the M₂ type. Cardiac muscle cells of the sinoatrial and atrioventricular nodes are densely innervated by postganglionic parasympathetic neurons. Atrial cells also receive strong parasympathetic innervation. In these parts of the heart, activation of cardiac M₂ receptors has effects basically opposite to those of the activation of β₁-adrenergic receptors. Parasympathetic activation powerfully slows the cardiac pacemakers, decreases cell-to-cell conduction velocity, and increases refractory period. Curiously, ventricular muscle cells receive very little direct parasympathetic innervation. Therefore, parasympathetic activation has only a minor, direct effect on ventricular contractility. However, parasympathetic neurons do exert an interesting, indirect effect on ventricular muscle cells. Most parasympathetic neurons in the ventricles release their acetylcholine onto sympathetic neuron terminals, rather than directly onto ventricular muscle cells. This acetylcholine activates muscarinic cholinergic receptors on the sympathetic neuron terminals, which inhibits the release of norepinephrine from the terminals and thus weakens the effects of sympathetic activity on ventricular cells. By decreasing heart rate and by opposing sympathetic effects on ventricular contractility, parasympathetic activation can profoundly decrease cardiac output.

Cholinergic muscarinic receptors of the M₃ type are found on the endothelial cells and also on the smooth muscle cells of most arteries and arterioles. Activation of M₃ receptors on smooth muscle cells causes them to contract. However, this vasoconstrictor effect is usually overridden by a vasodilatory effect of activating the M₃ receptors on the vascular endothelial cells. In this strange arrangement, activation of M₃ receptors on endothelial cells causes the synthesis of nitric oxide, which then diffuses out of the endothelial cells and into the nearby smooth muscle cells, where it causes vasodilation. The vasodilatory effect of stimulating the M₃ receptors on endothelial cells is stronger than the vasoconstrictor effect of stimulating the M₃ receptors on smooth muscle cells.

The M₃ receptors on vascular endothelial cells are innervated in three organs. Parasympathetic neurons innervate vascular M₃ receptors in the coronary circulation, where the effect of parasympathetic activation is vasodilation. This vasodilatory effect is minor, however, and the function of this innervation is unclear. In the blood vessels of the external genital organs, parasympathetic neurons release both acetylcholine and nitric oxide. The acetylcholine activates M₃ receptors on the endothelial cells to stimulate the release of additional nitric oxide from endothelial cells. The nitric oxide relaxes vascular smooth muscle, which causes vasodilation, engorgement of the organs with blood, and therefore erection. The third tissue in which vascular M₃ receptors are innervated is skeletal muscle. In some species (e.g., cats and dogs) but not in others (e.g., primates), the M₃ receptors of skeletal muscle blood vessels are innervated by special postganglionic sympathetic neurons that release acetylcholine as a neurotransmitter (rather than the usual, norepinephrine). These sympathetic cholinergic neurons appear to be activated specifically in anticipation of muscular exercise and during the “fear, fight, or flight” (defense-alarm) reaction. The resulting vasodilation increases blood flow through the skeletal muscle just before and during the initiation of exercise. Although primates do not have sympathetic cholinergic vasodilatory nerves, they can bring about an anticipatory vasodilation of skeletal muscle arterioles through activation of β₁-adrenergic receptors by circulating epinephrine and norepinephrine, as mentioned earlier.

To summarize, arteries and arterioles throughout the body have M₃ adrenergic receptors, and these blood vessels dilate when exposed to acetylcholine (with nitric oxide serving as the mediator). But acetylcholine-releasing autonomic neurons only innervate the blood vessels in the heart, the external genitalia, and (in some species) skeletal muscle. The functional significance of the M₃ receptors on arteries and arterioles in other organs is unclear because no neurons (either sympathetic or parasympathetic) appear to innervate them, and neither acetylcholine nor any other muscarinic receptor agonist normally circulates in the bloodstream.

Of all the autonomic influences on the cardiovascular system just mentioned, three stand out as most important. The first is α₁– and α₂-adrenergic vasoconstriction in the arterioles of all body organs, which is brought about by the sympathetic nervous system. The second is β₁-adrenergic excitation of cardiac muscle, which is brought about by the sympathetic nervous system and results in an increased heart rate and stroke volume. The third is the decrease in heart rate brought about by parasympathetic activation of cardiac M₂ receptors.