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The cardiovascular effects of MPV 295 [4(5)-2-(2,6-dimethylphenyl)ethylimidazole], a new antihypertensive agent with α2-adrenoceptor agonistic properties

Research paper by H. Ruskoaho, J. -M. Savola, S. Kaipiainen, J. Puurunen, N. Kärki

Indexed on: 01 May '83Published on: 01 May '83Published in: Naunyn-Schmiedeberg's Archives of Pharmacology



Abstract

The cardiovascular effects of a new compound MPV 295 [4(5)-2-(2,6-dimethylphenyl)ethylimidazole] were studied in both normotensive and spontaneously hypertensive rats (SHR) and in normotensive cats. Intravenous (i.v.) administration of MPV 295 to anaesthetized cats and rats produced an initial increase in blood pressure followed by a long-lasting hypotension and bradycardia. The compound was also effective when administered intracerebroventricularly (i.c.v.) in rats in a dose range 10–100 μg/rat. The antagonism of the hypotensive effect of i.v. injected MPV 295 by i.c.v. administered α-adrenoceptor blocking drugs yohimbine (10 and 30 μg/rat), prazosin (0.5 μg/rat) and 170150 [(imidazolinyl-2)-2-benzodioxane 1–4] (10 μg/rat) suggests that a stimulation of central α-adrenoceptors may be involved in antihypertensive effect of MPV 295. Oral administration of MPV 295 (3 mg/kg) to conscious, chronically cannulated SHR induced a fall in both mean blood pressure (max. 20%) and heart rate (max. 20%). The antihypertensive effect of MPV 295 persisted for longer than 4 h.The pharmacological profile of MPV 295 was compared to that of clonidine also with respect to the agonistic effect on cardiac presynaptic α2-adrenoceptors and on vascular post-synaptic α1- and α2-adrenoceptors in the intact circulatory system of the pithed rat. Clonidine and MPV 295 dose-dependently diminished the increase in heart rate produced by dependently diminished the increase in heart rate produced by electrical stimulation of the spinal cardioaccelerator sympathetic nerve fibers. The doses which caused 50% inhibition of stimulated-tachycardia were for clonidine and MPV 295, 7.0 μg/kg and 53.0 μg/kg respectively. Treatment with yohimbine caused parallel shifts to the right of the log dose-response curves of both clonidine and MPV 295. In pithed rats, the vasopressor effects of clonidine were antagonized both by yohimbine (1.0 mg/kg i.v.) and prazosin (0.1 mg/kg i.v.), whereas the increase in mean blood pressure brought about by an i.v. injection of MPV 295 was antagonized by yohimbine but not by prazosin. These findings demonstrate that MPV 295 preferentially stimulates α1-adrenoceptors in the cardiovascular system of the pithed rat.These results indicate that MPV 295 has clear antihypertensive effects in anaesthetized and conscious animals. The antihypertensive effect of MPV 295 may be mediated by stimulation of central α-adrenoceptors. Further, MPV 295 can be classified as a selective agonist of cardiac presynaptic and vascular postsynaptic α2-adrenoceptors based on experiments in pithed rats.