Modulation of peripheral sympathetic nerve transmission

The past 15 years have been witness to a remarkable growth in knowledge regarding the modulation of "sympathetic traffic" to neuroeffector organs, including vascular tissue. The release of norepinephrine from peripheral sympathetic neurons is now known to be under both negative and positive feedback control. Norepinephrine, when released from peripheral neurons, acts on presynaptic alpha₂-receptors to inhibit further neurotransmission. Vascular postsynaptic alpha₂-receptors, sensitive to circulating catecholamines, subserve vasoconstriction. The antihypertensive agents clonidine, guanabenz and guanfacin likely reduce blood pressure by acting centrally on alpha₂ postsynaptic neurons to limit sympathetic transmission to blood vessels. Clonidine can produce venoconstriction and thereby improve orthostatic hypotension by activating venous alpha₂-receptors. Additional presynaptic dopaminergic receptors (DA₂), muscarinic receptors (acetylcholine), opioid receptors, prostaglandin receptors, adenosine receptors (A₁) and histamine (H₂) receptors are present on sympathetic nerve membranes and, when engaged with the appropriate ligand, can limit the exocytotic process. Gamma-aminobutyric acid and serotonin demonstrate similar roles in reducing sympathetic nerve activity. In contrast to these inhibitory presynaptic mechanisms, facilitation of norepinephrine release appears to occur by way of neuronal angiotensin II receptor activation and perhaps through stimulation of sympathetic nerve membrane beta₂-receptors. An appreciation of these inhibitory and facilitator mechanisms is useful in the treatment of a variety of clinical conditions, including hypertension, heart failure, orthostatic hypotension, septic shock and a number of common withdrawal syndromes.