On minimum cyclic AMP formation rates associated with positive inotropic effects mediated through ?1-adrenoceptors in kitten myocardium

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Abstract
The agonist (−)-denopamine was used as a tool to study relationships between pharmacological effects and adenylate cyclase stimulation mediated through β1-adrenoceptors. (−)-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 β2-adrenoceptors. β1-Adrenoceptors mediated all effects of (−)-denopamine in atria and effects of low (−)-denopamine concentrations in papillary muscles and tracheae, as assessed with β1-selective antagonists. High (−)-denopamine concentrations caused positive inotropic effects in papillary muscles and tracheorelaxant effects that were resistant to blockade by β1-, β2- and α-adrenoceptor antagonists (non-adrenergic effects). (−)-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 β1- and β2-adrenoceptors to cyclase stimulation was assessed by selective blockade. Cyclase stimulation through β2-adrenoceptors by (−)-denopamine was 12% in ventricle and 82% in trachea but is not associated with positive inotropic effects and tracheal relaxation. (−)-Denopamine exhibited only a 2- to 5-fold selectivity for β1-adrenoceptors compared to β2-adrenoceptors, as estimated consistently from binding assays and blockade of cyclase stimulation in myocardial and tracheal cell membranes. Desensitization of kitten ventricular tissues, caused by a 3 h exposure to 30 μmol/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. 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 β-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. Alternatively, there may exist a critical threshold of cyclic AMP production required to elicit inotropic effects. An analysis of the present data and published data of ventricular myocardium shows that threshold and maximum possible positive inotropic effects of agonists appear between 8% and 25% of maximum possible stimulation of adenylate cyclase, respectively, mediated through β1-adrenoceptors. This range of cyclase stimulation represents a lower approximation to the ability of cyclic AMP to amplify the β1-adrenoceptor-agonist interaction that leads to increases in myocardial force.

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