Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild‐type and D79N α2A‐adrenoceptor transgenic mice

We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N α2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) α2-adrenoceptors and at endogenous (dog) α2A-adrenoceptors. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 μg kg−1, i.v.) and clonidine (30, 100 and 300 μg kg−1, i.v.) dose-dependently decreased blood pressure and heart rate. In D79N α2A-adrenoceptor mice, responses to rilmenidine and moxonidine did not differ from vehicle control. Clonidine-induced hypotension was absent, but dose-dependent hypertension and bradycardia were observed. In wild-type mice, responses to moxonidine (1 mg kg−1, i.v.) were antagonized by the non-selective, non-imidazoline α2-adrenoceptor antagonist, RS-79948-197 (1 mg kg−1, i.v.). Affinity estimates (pKi) at human α2A-, α2B- and α2C-adrenoceptors, respectively, were: rilmenidine (5.80, 5.76 and 5.33), moxonidine (5.37, <5 and <5) and clonidine (7.21, 7.16 and 6.87). In a [35S]-GTPγS incorporation assay, moxonidine and clonidine were α2A-adrenoceptor agonists (pEC50/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). In dog saphenous vein, concentration-dependent contractions were observed (pEC50/intrinsic activity relative to noradrenaline): rilmenidine (5.83/0.70), moxonidine (6.48/0.98) and clonidine (7.22/0.83). Agonist-independent affinities were obtained with RS-79948-197. Thus, expression of α2A-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice. There was no evidence of I1-imidazoline receptor-mediated effects. The ability of these compounds to act as α2A-adrenoceptor agonists in vitro supports this conclusion. British Journal of Pharmacology (1999) 126, 1522–1530; doi:10.1038/sj.bjp.0702429