On minimum cyclic AMP formation rates associated with positive inotropic effects mediated through beta 1-adrenoceptors in kitten myocardium. Beta 1-specific and non-adrenergic stimulant effects of denopamine

Abstract

The agonist (-)-denopamine was used as a tool to study relationships between pharmacological effects and adenylate cyclase stimulation mediated through beta 1-adrenoceptors. 1. (-)-Denopamine was a full agonist in kitten papillary muscles (force), kitten left atria (force) and kitten and guinea-pig atria (sinoatrial frequency). (-)-Denopamine was a strong partial agonist in guinea-pig tracheae (relaxation). None of these effects was influenced by blockade of beta 2-adrenoceptors. beta 1-Adrenoceptors mediated all effects of (-)-denopamine in atria and effects of low (-)-denopamine concentrations in papillary muscles and tracheae, as assessed with beta 1-selective antagonists. 2. High (-)-denopamine concentrations caused positive inotropic effects in papillary muscles and tracheorelaxant effects that were resistant to blockade by beta 1-, beta 2- and alpha-adrenoceptor antagonists (non-adrenergic effects). 3. (-)-Denopamine stimulated the adenylate cyclase of membranes derived from kitten ventricle and calf tracheal cells with an intrinsic activity of 0.3 and 0.2, respectively, compared to catecholamines. The contribution of beta 1- and beta 2-adrenoceptors to cyclase stimulation was assessed by selective blockade. Cyclase stimulation through beta 2-adrenoceptors by (-)-denopamine was 12% in ventricle and 82% in trachea but is not associated with positive inotropic effects and tracheal relaxation. 4. (-)-Denopamine exhibited only a 2- to 5-fold selectivity for beta 1-adrenoceptors compared to beta 2-adrenoceptors, as estimated consistently from binding assays and blockade of cyclase stimulation in myocardial and tracheal cell membranes. 5. Desensitization of kitten ventricular tissues, caused by a 3 h exposure to 30 mumol/l (-)-isoprenaline followed by 5 h washout, reduced the inotropic sensitivity of papillary muscles without decreasing the maximum inotropic effects of (-)-denopamine. In desensitized tissues, the nonadrenergic effect contributed by 30% to the maximum inotropic effect of (-)-denopamine. 6. In membranes, derived from desensitized tissues, the maximum adenylate cyclase stimulation induced by (-)-isoprenaline, (-)-denopamine and xamoterol was reduced to 1/2 of the corresponding stimulations observed in membranes from sham desensitized tissues. The density of beta-adrenoceptors, assessed with 3H-(-)-CGP 12,177, was not changed by the desensitization procedure suggesting that part of the receptors was uncoupled from the adenylate cyclase. The partial inotropic agonist xamoterol, which has an intrinsic activity of 0.5 in non-desensitized tissues, failed to cause positive inotropic effects in desensitized papillary muscles suggesting that not all cyclic AMP possesses inotropic relevance.(ABSTRACT TRUNCATED AT 400 WORDS)