Norepinephrine, released from sympathetic nerve terminals, has a key role in adjusting continuously the performance of the cardiovascular system. Although the amount of transmitter released depends primarily on the degree of activation of postganglionic sympathetic fibers, local metabolites and circulating vasoactive substances, in addition to affecting smooth-muscle cells directly, alter the amount of norepinephrine released. Thus, metabolic acidosis, an increase in potassium ions and in osmolality reduce the output of norepinephrine in the face of a constant frequency of stimulation of the postganglionic fibers. Many receptors have been identified on the prejunctional nerves which, when activated, can increase or decrease transmitter release. Those agonists which decrease it include adenosine and the adenine nucleotides, and norepinephrine, acetylcholine, histamine, and serotonin, acting on purinergic, alpha 2-adrenoceptors, muscarinic, H2-histaminergic and S1-serotoninergic receptors, respectively. Those that increase transmitter release include epinephrine (acting on beta 2-adrenoceptors) and angiotensin II. Part of the action of certain drugs is due to their prejunctional effects. Thus, cardiac glycosides cause a release of norepinephrine, and the antidepressant drug amitriptyline causes inhibition of prejunctional alpha-adrenoceptors and muscarinic receptors. Local changes in temperature also have complex actions on the neuroeffector junction and the vascular smooth muscle, which are of prime importance for cutaneous vessels.