RILMENIDINE-INDUCED HYPOTENSION IN CONSCIOUS RABBITS INVOLVES IMIDAZOLINE-PREFERRING RECEPTORS

The relative contributions of imidazoline-preferring receptors (IPR) and alpha(2)-adrenoceptors to hypotensive and bradycardic effects of intracisternal (i.c.) rilmenidine were investigated in conscious rabbits. We compared the antagonist potencies of two alpha(2)-adrenoceptor antagonists, 2-methoxy-idazoxan (0.001-10 mu g/kg i.c.), which has very low affinity for IPR, and idazoxan (0.003-30 mu g/kg i.c.), which has high affinity for blocking IPR. We also compared the i.c. effects of the antagonists on responses to alpha-methyldopa (alpha-MD), a drug with centrally acting alpha(2)-adrenoceptor agonist metabolites that have no affinity for IPR. Rilmenidine (22 mu g/kg i.c.) and alpha-MD (400 mu g/kg i.c.) produced similar decreases in mean arterial pressure (MAP) (Delta MAP=-23+/-2 and -24+/-2%, respectively) and in heart rate (HR) (Delta HR=-11+/-1 and -9+/-2%, respectively, n=30). The hypotension and bradycardia produced by alpha-MD and rilmenidine were completely reversed by 2-methoxy-idazoxan, but 2-methoxy-idazoxan was 16 and 9 times more potent at restoring MAP and HR, respectively, after alpha-MD than after rilmenidine. In contrast, idazoxan was more potent in reversing the hypotension elicited by i.c. injections of rilmenidine than that elicited by alpha-MD. Idazoxan, however, had no effect on rilmenidine-induced bradycardia, but did dose-dependently reverse the decrease in HR produced by alpha-MD. In separate experiments, we observed that the doses of each antagonist drug in themselves did not modify MAP nor HR significantly, but a 10-fold higher dose of idazoxan (300 mu g/kg) caused immediate although brief hypertension and tachycardia. Thus, at ''therapeutically relevant'' doses, the preferential reversal of rilmenidine's hypotension by idazoxan as compared with 2-methoxy-idazoxan supports a more important contribution of IPR than of alpha(2)-adrenoceptors in the central cardiovascular effects of rilmenidine. Furthermore, since 2-methoxy-idazoxan at a high dose (10 mu g/kg) completely reversed rilmenidine-induced hypotension suggests that the two receptor systems are likely to be in series along the same cardiovascular autonomic pathways in the brainstem.