Anatomy

The sympathetic nervous system (SNS) is widely distributed throughout the body. Although afferent pathways exist and are important in relaying visceral sensory information to the central nervous system, the most clearly defined portions of the SNS are the efferent preganglionic and postganglionic fibers and their associated paravertebral ganglia. The cell bodies that give rise to the preganglionic fibers of the SNS lie in the intermediolateral columns of the thoracolumbar spinal cord from T1 to L2 or L3 (hence, the SNS is sometimes referred to as the thoracolumbar nervous system).

The short myelinated preganglionic fibers leave the spinal cord in the anterior nerve roots, form white rami, and synapse in sympathetic ganglia lying in three locations outside the cerebrospinal axis. The gray rami arise from the ganglia and carry postganglionic fibers back to the spinal nerves for distribution to the sweat glands, pilomotor muscles, and blood vessels of the skin and skeletal muscle (Figure 40-1). The 22 sets of paravertebral ganglia are paired on either side of the vertebral column, connected to the spinal nerves by the white and gray rami communicans, and interconnected by nerve trunks to form the lateral chains. They include the upper and middle cervical ganglia, the stellate ganglia (fusion of inferior cervical and T1 ganglia), and the ganglia of the thoracic, abdominal, and pelvic sympathetic trunks. Unpaired prevertebral ganglia are found in the abdomen and pelvis near the ventral surface of the vertebral column. They are named according to the major branches of the aorta: for example, celiac, renal, and superior and inferior mesenteric ganglia. The terminal ganglia lie near the innervated organs (cervical ganglia in the neck, rectum, and bladder).

The cells of the adrenal medulla are analogous to sympathetic ganglia, except that the postganglionic cells have lost their axons and secrete norepinephrine, epinephrine, and dopamine directly into the bloodstream. Preganglionic fibers may pass through several paravertebral ganglia and synapse with multiple neurons in a ganglion, a characteristic that leads to a diffused output. Postganglionic fibers arising from the sympathetic ganglia may receive input from several preganglionic fibers and innervate visceral structures in the head, neck, thorax, and abdomen. They may pass to target organs through a nerve network along blood vessels or rejoin a mixed peripheral nerve.

Acetylcholine is the neurotransmitter of all preganglionic sympathetic fibers, including those that innervate the cells of the adrenal medulla. Norepinephrine is released by nearly all sympathetic postganglionic nerve endings; exceptions are the postganglionic cholinergic fibers that innervate sweat glands (sudomotor) and blood vessels in skeletal muscles (vasomotor). Increasing evidence indicates that neurons in the peripheral nervous system release two or more transmitters from individual nerve terminals when stimulated. Substances released with norepinephrine, such as adenosine triphosphate, may function as cotransmitters or neuromodulators of the response to norepinephrine.

Synthesis, storage, release, and inactivation of norepinephrine

The main site of norepinephrine synthesis is in the postganglionic nerve terminal. Tyrosine is transported actively into the axoplasm and converted to dihydroxyphenylalanine (rate-limiting step) and then to dopamine by cytoplasmic enzymes. Dopamine is transported into storage vesicles, where it is converted to norepinephrine (Figure 40-2). Exocytosis of norepinephrine is triggered by the increased intracellular calcium that accompanies an action potential. Active reuptake (uptake 1) of norepinephrine into the presynaptic terminal terminates the effect of norepinephrine at the effector site. This process accounts for nearly all of the released norepinephrine, which is then stored in vesicles for reuse. Monoamine oxidase is responsible for metabolism of the small amount of norepinephrine that enters the cytoplasm after neuronal reuptake without being taken up into vesicles. Monoamine oxidase and catechol-O-methyltransferase are responsible for metabolism of norepinephrine that is not reabsorbed into neurons.

β-Phenylethylamine can be considered the parent compound. Compounds with hydroxyl groups at positions 3 and 4 of the benzene ring are called catechols; catecholamines are catechols with an ethylamine side chain. Many directly acting sympathomimetic amines stimulate both α and β receptors (Table 40-1). The ratio of activities varies among agonists along a spectrum from predominantly α (phenylephrine) to predominantly β (isoproterenol). β-Receptor selectivity is enhanced by substitution of the amine group. Table 40-2 lists the antagonists of the adrenergic receptors, and Table 40-3 lists drugs that have a unique mechanism of action within the SNS.