CENTRAL CARDIOVASCULAR ACTIONS OF AGMATINE, A PUTATIVE CLONIDINE-DISPLACING SUBSTANCE, IN CONSCIOUS RABBITS

Agmatine, an endogenous clonidine-displacing substance, has been shown to have an affinity for both alpha(2)-adrenoceptors and imidazoline r eceptors (IR). In conscious rabbits, we have examined the cardiovascul ar effects of agmatine and its interaction with clonidine, a presumed agonist and 2-methoxy-idazoxan, an antagonist at alpha(2)-adrenoceptor s. We have also examined the effect of agmatine on agents having high affinity for I-1-imidazoline receptors namely moxonidine (agonist) and efaroxan (antagonist). Initial dose-response studies showed that agma tine administered in low doses (0.01-10 mu g/kg) into the fourth ventr icle did not change mean arterial pressure but did produce a dose-depe ndent bradycardia (maximum -16 +/- 3 beats/min). A higher dose of 100 mu g/kg produced an adverse reaction in the conscious animals accompan ied by a marked increase in mean arterial pressure and a reversal of t he bradycardia. This is in contrast to the effects of fourth ventricul ar clonidine and moxonidine, which caused a dose-dependent fall in bot h mean arterial pressure and heart rate. Agmatine when administered at the highest well-tolerated dose of 10 mu g/kg did not further after t he clonidine-induced hypotension but produced a greater bradycardia (- 12 +/- 4 beats/min clonidine; -29 +/- 4 beats/min clonidine plus agmat ine; p < 0.05). Similarly, the hypotension induced by moxonidine was n ot altered by agmatine but heart rate was reduced after the addition o f agmatine (p < 0.01). Efaroxan and 2-methoxy-idazoxan, at doses which produced no effects when given alone, similarly reversed the fall in heart rate elicited by agmatine and caused a small but significant ris e in mean arterial pressure. We have previously shown that the doses o f these antagonists used in this study produce an equal reversal of th e bradycardia induced by fourth ventricular alpha-methyldopa (alpha(2) -adrenoceptor agonist) and clonidine and hence have similar alpha(2)-a drenoceptor blocking effects. Our results show that agmatine produces bradycardia as does moxonidine and clonidine but does not mimic or blo ck the hypotensive responses to these agents. These findings do not su pport the hypothesis that agmatine is an endogenous ligand for IR. How ever, the bradycardia induced by agmatine may be mediated via alpha(2) -adrenoceptors since it was equally blocked by efaroxan and 2-methoxy- idazoxan, Thus while alpha(2)-adrenoceptor actions of agmatine on hear t rate are evident at relatively low doses, the reason for the lack of alpha(2)-adrenoceptor mediated hypotension is not known. Copyright (C ) 1996 Elsevier Science Ltd.