Figure 1. Origin and distribution of somatic and autonomic nerves.^1,2 Somatic (voluntary) neurons exit all levels of the brain and spinal cord (CNS). They release acetylcholine (ACh) to activate nicotinic receptors (N_m) on skeletal muscle. Preganglionic parasympathetic neurons exit the brain and sacral spinal cord, where they synapse with ganglia near or within smooth muscle and heart. Here ACh is released and activates nicotinic receptors (N_n) on postganglionic neurons. These neurons also release ACh to activate muscarinic receptors (M) on the target tissues. Preganglionic sympathetic neurons exit the thoracic and lumbar levels (thoracolumbar) of the spinal cord and synapse with ganglia near the cord and, like the preganglionic parasympathetic fibers, release ACh to activate N_n receptors on postganglionic neurons. The most abundant of these distribute to smooth muscle and heart where they release norepinephrine (NE) to activate alpha and beta receptors (α, β). The adrenal medulla is functionally a postganglionic neuron that secrets mostly epinephrine (∼80% epinephrine and 20% norepinephrine), which arrives at the target tissues via the circulation. Also noteworthy is that some postganglionic sympathetic fibers distribute to sweat glands and release ACh where it activates muscarinic receptors (M).

Figure 2. Postganglionic parasympathetic synapse. A nerve impulse triggers release of acetylcholine (ACh), which subsequently binds to muscarinic receptors and initiates the parasympathetic response. Acetylcholine unbound in the synapse is hydrolyzed instantaneously by the enzyme acetylcholinesterase (AChE) to acetate (A) and choline (Ch). Muscarinic receptors (M) are also located on the nerve endings themselves and are referred to as prejunctional receptors. When activated by ACh, further release of the neurotransmitter is inhibited, providing a so-called negative-feedback loop.

Figure 3. The adrenergic synapse. The nerve impulse releases norepinephrine (NE), which binds to specific adrenergic receptors on the cell membranes of target tissue. (α₁, β₁, β₂). The neuronal endings contain α₂ prejunctional receptors. When activated by NE, further release of the neurotransmitter is inhibited. Adrenergic ligands also arrive at the synapse via the circulatory system. These include epinephrine (E) and norepinephrine (NE) secreted by the adrenal medulla or adrenergic drugs (D). The termination of norepinephrine (NE) is due primarily to reuptake into the nerve ending. Epinephrine (E) from the adrenal medulla and adrenergic drugs (D) are metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in local tissues or the liver following absorption. (See text for further explanation.)

Figure 4. Catecholamine synthesis. The molecular structure of catecholamines includes a catechol and an amine. During their termination, each of these moieties is a target for a specific enzyme, ie, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Catecholamine synthesis proceeds in a stepwise fashion, each step driven by a specific enzyme leading to a molecular change indicated by the asterisks. In the adrenal medulla the final step in the pathway results in the synthesis of epinephrine. Sympathetic neurons do not contain the methylating enzyme and therefore cannot synthesize epinephrine. All 3 neurotransmitters are found throughout the brain, but neurons within the basal ganglia release dopamine because they lack dopamine hydroxylase.

Figure 5. Cardiovascular effects of epinephrine and phenylephrine. Epinephrine increases heart rate (HR) by activating beta-1 receptors in the sinoatrial node, the heart's normal pacemaker. It also activates beta-1 receptors on myocardial cells, increasing their contractility and increasing systolic blood pressure (SBP). However, at low doses such as those provided in local anesthetic formulations, it activates beta-2 receptors on systemic arteries, producing vasodilation. This decline in arterial resistance produces a reduction in diastolic pressure (DBP). The sum of these effects results in little change of mean arterial pressure (MAP). In contrast, phenylephrine activates only alpha receptors, increasing arterial resistance and diastolic pressure. Systolic pressure also rises as the heart compensates for this increase in resistance by increasing its contractility and venoconstriction increases venous return (preload). The net effect is an increase in mean arterial pressure, which is sensed in baroreceptors, and a reflex slowing of heart rate supervenes. (Adapted from Westfall et al.¹¹)