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

1 We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha(2A)-adrenoceptor mice. The-in vitro pharmacology of these agonists was determined at recombinant (human) alpha(2)-adrenoceptors and at endogenous (dog) alpha(2A)-adrenoceptors. 2 In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 mu g kg(-1), i.v.) and clonidine (30, 100 and 300 mu g kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3 In D79N alpha(2A)-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. 4 In wild-type mice, responses to moxonidine (1 mg kg(-1), i.v.) were antagonized by the non-selective, non-imidazoline alpha(2)-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5 Affinity estimates (pK(i)) at human alpha(2A)-, alpha(2B)- and alpha(2C)-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 [S-35]-GTP gamma S incorporation assay, moxonidine and clonidine were alpha(2A)-adrenoceptor agonists (pEC(50)/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). 6 In dog saphenous vein, concentration-dependent contractions were observed (pEC(50)/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. 7 Thus, expression of alpha(2A)-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice, There was no evidence of I-1-imidazoline receptor-mediated effects. The ability of-these compounds to act as alpha(2A)-adrenoceptor agonists in vitro supports this conclusion.