Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

Abstract

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, hi addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate tbe release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic α-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic aradrenoceptors that mediate the responses of certain organs and the presynaptic aradrenoceptors that modulate the NE release during nerve stimulation. Therefore, sub classification of α-adrenoceptors into a, and a, subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess β-adrenergic receptors, tbe stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinepbrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the Inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransraission and the sub classification of α-adrenoceptors to tbe treatment of hypertension is presented. Gonidtne, for example, appears to be a potent aradrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an a,-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic aradrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of a-methyldopa are related to tbe formation of a-methylnorepinephrine, a preferential aradrenoceptor agonist, which can stimulate peripheral presynaptic aradrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic aradrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via aradrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of β-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic fadlltatory β-adrenoceptors could be of significance in the antihypertensive action of these drugs. © 1980 American Heart Association, Inc.