Systems Pharmacology

Sympathetic Nervous System

In the course of phylogeny an ef cient control system evolved that enabled the functions of individual organs to be orchestrated in increasingly complex life forms and permitted rapid adaptation to changing environmental conditions. This regulatory system consists of the central nervous system (CNS) (brain plus spinal cord) and two separate pathways for two-way communication with peripheral organs, namely, the somatic and the autonomic nervous systems. The somatic nervous system, comprising exteroceptive andinteroceptive afferents,special sense organs, and motor efferents, serves to perceive external states and to target appropriate body movement (sensory perception: threat † response: flight or attack). The autonomic (vegetative) nervous system

(ANS) together with the endocrine system controls the milieu interieur. It adjusts internal organ functions to the changing needs of the organism. Neural control permits very quick adaptation, whereas the endocrine system provides for a long-term regulation of functionalstates. The ANS operateslargely beyond voluntary control: it functions autonomously. Itscentralcomponentsreside in the hypothalamus, brainstem, and spinal cord. The ANS also participates in the regulation of endocrine functions.

The ANS has sympathetic and parasympathetic (p.102) branches. Both are made up of centrifugal (efferent) and centripetal (afferent)nerves. In manyorgansinnervated by both branches, respective activation of the sympathetic and parasympathetic input evokes opposing responses.

In various disease states (organ malfunctions), drugs are employed with the intention of normalizing susceptible organ functions. To understand the biological effects of substances capable of inhibiting or exciting sympathetic or parasympathetic nerves, one must first envisage the functions subserved by the sympathetic and parasympathetic divisions (A, Response to sympathetic activa-

tion). In simplistic terms, activation of the sympathetic division can be considered a means by which the body achieves a state of maximal work capacity as required in fight-or-flight situations.

In both cases, there is a need for vigorous activity of skeletal musculature. To ensure adequate supply of oxygen and nutrients, blood flow in skeletal muscle is increased; cardiac rate and contractility are enhanced, resulting in a larger blood volume being pumped into the circulation. Narrowing of splanchnic blood vessels diverts blood into vascular beds in muscle.

Because digestion of food in the intestinal tract is dispensable and essentially counterproductive, the propulsion of intestinal contents is slowed to the extent that peristalsis diminishes and sphincters are narrowed. However, in order to increase nutrient supply to heart and musculature, glucose from the liver and free fatty acids from adipose tissue must be released into the blood. The bronchi are dilated, enabling tidal volume and alveolar oxygen uptake to be increased.

Sweat glands are also innervated by sympathetic fibers (wet palms due to excitement); however, these are exceptional as regards their neurotransmitter (ACh, p.110).

The lifestyles of modern humans are different from those of our hominid ancestors, but biological functions have remained the same: a “stress”-induced state of maximal work capacity, albeit without energy-con- suming muscle activity.

Structure of the Sympathetic Nervous System

The sympathetic preganglionic neurons (first neurons) project from the intermediolateral column of the spinal gray matter to the paired paravertebral ganglionic chain lying alongside the vertebral column and to unpaired prevertebral ganglia. These ganglia represent sites of synaptic contact between preganglionic axons (1st neurons) and nerve cells (2nd neurons or sympathocytes) that emit axons terminating at postganglionic synapses (or contacts) on cells in various end organs. In addition, there are preganglionic neurons that project either to peripheral ganglia in end organs or to the adrenal medulla.

Sympathetic transmitter substances.

Whereas acetylcholine (see p.104) serves as the chemical transmitter at ganglionic synapses between first and second neurons, norepinephrine (noradrenaline) is the mediator at synapses of the second neuron (B). This second neuron does not synapse with only a single cell in the effector organ; rather it branches out, each branch making en passant contacts with several cells. At these junctions the nerve axons form enlargements (varicosities) resembling beads on a string. Thus, excitation of the neuron leads to activation of a larger aggregate of effector cells, although the action of released norepinephrine may be confined to the region of each junction. Excitation of preganglionic neurons innervating the adrenal medulla causes liberation of acetylcholine. This, in turn, elicits secretion of epinephrine (adrenaline) into the blood, by which it is distributed to body tissues as a hormone (A).

Adrenergic Synapse

Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05–0.2 µm in diameter). In the

axoplasm, norepinephrine is formed by stepwise enzymatic synthesis from L-tyrosine, which is converted by tyrosine hydroxylase to L-Dopa (see p.188). L-Dopa in turn is decarboxylated to dopamine, which is taken up into storage vesicles by the vesicular monoamine transporter (VMAT). In the vesicle, dopamine is converted to norepinephrine by dopamine β-hydroxylase. In the adrenal medulla, the major portion of norepinephrine undergoes enzymatic methylation to epinephrine.

When stimulated electrically, the sympathetic nerve discharges the contents of part of its vesicles, including norepinephrine, into the extracellular space. Liberated norepinephrine reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of pre-syn- aptic α2-receptors inhibits norepinephrine release. Through this negative feedback, release can be regulated.

The effect of released norepinephrine wanes quickly, because ~ 90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells).

The liver is richly endowed with COMT and MAO; it therefore contributes significantly to the degradation of circulating norepinephrine and epinephrine. The end product of the combined actions of MAO and COMT is vanillylmandelic acid.