UNIQUE PRESYNAPTIC ALPHA-2-RECEPTOR SELECTIVITY AND SPECIFICITY OF THE ANTIHYPERTENSIVE AGENT MOXONIDINE

Abstract

The characteristics of the .alpha.-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic .alpha.1- and .alpha.2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic .alpha.2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at .alpha.1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for .alpha.2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for .alpha.2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both .alpha.-receptor subtypes, but moxonidine consistently showed greater .alpha.2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 .mu.mol/l in the isolated papillary muscle.