The Autonomic Nervous System Affects the Cardiovascular SystemThrough 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.

Whether acting as neurotransmitters or as hormones, epi­nephrine, norepinephrine, and acetylcholine exert their cardio­vascular effects by activating membrane receptors on the cardiac muscle cells or on the endothelial cells or the smooth muscle cells of blood vessels. The receptors activated by epinephrine and norepinephrine are called adrenergic receptors (named after the adrenal gland). There are two major subtypes, alpha and beta: a-adrenergic receptors and β-adrenergic receptors. Each of these is subdivided into α∣, a₂, β∣, and β₂, and each of the four has important cardiovascular roles.

Acetylcholine activates cholinergic receptors. There are two major subtypes: muscarinic cholinergic receptors and nicotinic cholinergic receptors. The main cardiovascular effects of acetyl­choline are mediated through muscarinic cholinergic receptors. Of five known types of muscarinic receptors, the M₂ and M₃ receptors have the greatest cardiovascular importance.

Table 25-1 summarizes the main cardiovascular con­sequences of the activation of adrenergic and cholinergic receptors. Alpha-adrenergic receptors (both α₁ and α₂) are located on the cell membranes of the smooth muscle cells of the arterioles in all organs of the body as well as on the smooth muscle cells of the abdominal veins.

Arteriolar vasoconstriction increases the resistance and decreases the blood flow through an organ. If one or more major body organs are Vasoconstricted, the 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 the nonvasoconstricted organs. In this way, the sympathetic nervous system can use vasoconstriction in some organs to direct more blood flow to other, nonvasoconstricted 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, ventri­cular preload, and stroke volume. Venoconstriction in the abdominal organs is particularly important in the control of central blood volume and therefore central venous pressure. Venoconstriction causes only a small increase in the resistance to blood flow through an organ because the veins, whether constricted or dilated, offer much less resistance to blood flow than do the arterioles.

Sympathetic control of the heart is exerted through the β∣- adrenergic receptors, which are found on every cardiac muscle cell. These β-adrenergic 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 β>-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” situations because the dilation results in an anticipatory increase in blood flow to the heart and skeletal muscle. /Xppropriately for its role in emergency situations, β₂-adrenergic vasodilation can overpower α- adrenergic vasoconstriction in the coronary circulation and in skeletal muscles.

Cholinergic muscarinic receptors of the M₂ type are located in the cell membranes of cardiac muscle cells. The natural stimulus for the cardiac M₂ receptors is acetylcholine, released from postganglionic parasympathetic neurons. Cells of the sinoatrial and atrioventricular nodes are densely inner­vated by postganglionic parasympathetic neurons. Atrial cells also receive strong parasympathetic innervation. In the sino­atrial node, atria, and atrioventricular node, the activation of M₂ receptors has effects basically opposite to those of the acti­vation of β∣-adrenergic receptors. Parasympathetic activation powerfully slows the pacemaker rate, decreases the cell-to-cell conduction velocity, and increases the refractory period. By contrast, few ventricular muscle cells receive direct para­sympathetic innervation.

Cholinergic muscarinic receptors of the M₅ type arc found on the endothelial cells and on the smooth muscle cells of most arteries and arterioles. Activation of M₅ receptors on smooth muscle cells causes them to contract (and the blood vessels to constrict). However, this vasoconstrictor effect is usually overridden by the vasodilatory effect of activating the M₅ receptors on the vascular endothelial cells. In this strange arrangement, activation of M₅ 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 M₅ receptors on smooth muscle cells.

The M₅ receptors on vascular endothelial cells are innervated in three tissues. In the coronary circulation, parasympathetic neurons innervate vascular M₅ receptors and bring about vasodilation. This vasodilatory effect is minor, however, and the function of this innervation is unclear. In the external genital organs, parasympathetic neurons release both acetylcholine and nitric oxide.

To summarize, although arteries and arterioles through­out the body dilate when exposed to acetylcholine, only the arterioles of the heart, external genitalia, and (in some species) skeletal muscle are innervated by acetylcholine-releasing autonomic neurons. The functional significance of the M₃ receptors on 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 α∣- 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 activation of cardiac M₂ receptors.

FIGURE 25-1 ■ Arterial baroreceptors are located in the walls of the carotid sinuses and in the walls of the aortic arch and its major branches.The atrial volume receptors are located in the walls of the right and left atria. See text for a description of the neural pathways followed by the baroreceptor and volume receptor afferents.