cardiovascular-agents and moxonidine

Large drug trials have become very important to determine which drugs should be used in the treatment of patients with chronic heart failure (CHF). When these trials showed "positive" results, publication of the data soon followed, leading to a substantial impact on prescription patterns. In the case of "negative" results, many times they were not published, or were reported as an abstract or as short paper disclosing only the main findings. In this article we will discuss some of these trials that were conducted in the last 10 years, since we believe they may provide insight into the pathophysiology and treatment options in CHF.

Topics: Bosentan; Cardiovascular Agents; Deoxyepinephrine; Heart Failure; Humans; Imidazoles; Mibefradil; Pyrazines; Quinolines; Sulfonamides; Xamoterol

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.

Topics: Adrenergic alpha-Antagonists; Amino Acid Substitution; Animals; Binding, Competitive; Blood Pressure; Cardiovascular Agents; Cell Line; Clonidine; Consciousness; Dogs; Heart Rate; Humans; Imidazoles; In Vitro Techniques; Isoquinolines; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Mutation; Naphthyridines; Oxazoles; Quinolizines; Radioligand Assay; Receptors, Adrenergic, alpha-2; Recombinant Fusion Proteins; Rilmenidine; Saphenous Vein; Tritium