title: Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice.
abstract: 1. We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) alpha2-adrenoceptors and at endogenous (dog) alpha2A-adrenoceptors. 2. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 microg kg(-1), i.v.) and clonidine (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3. In D79N alpha2A-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 alpha2-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5. Affinity estimates (pKi) at human alpha2A-, alpha2B- and alpha2C-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]-GTPgammaS incorporation assay, moxonidine and clonidine were alpha2A-adrenoceptor agonists (pEC50/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 (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. 7. Thus, expression of alpha2A-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 alpha2A-adrenoceptor agonists in vitro supports this conclusion.
authors.affiliation: Center for Biological Research, Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304, USA.
authors.forename: Q M
authors.initials: QM
authors.lastname: Zhu
authors.forename: J D
authors.initials: JD
authors.lastname: Lesnick
authors.forename: J R
authors.initials: JR
authors.lastname: Jasper
authors.forename: S J
authors.initials: SJ
authors.lastname: MacLennan
authors.forename: M P
authors.initials: MP
authors.lastname: Dillon
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: D R
authors.initials: DR
authors.lastname: Blue
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology; D003243:Consciousness; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D009287:Naphthyridines / Q000378:metabolism / Q000494:pharmacology; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology; D011807:Quinolizines; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000077769:Rilmenidine; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
chemical_list: C547768:ADRA2A protein, human; C547769:Adra2a protein, mouse; D000317:Adrenergic alpha-Antagonists; D002317:Cardiovascular Agents; D007093:Imidazoles; D007546:Isoquinolines; D009287:Naphthyridines; D010080:Oxazoles; D011807:Quinolizines; C104875:RS 79948-197; D018341:Receptors, Adrenergic, alpha-2; D011993:Recombinant Fusion Proteins; D014316:Tritium; C054290:L 657743; C043482:moxonidine; D003000:Clonidine; D000077769:Rilmenidine