Beta-adrenoceptors and adenylate cyclase activity in hypertrophied and failing rabbit left ventricle

Abstract

Beta-adrenoceptor density and affinity, studied by H3-CGP 12177 binding, and adenylate cyclase activity were measured in 12 left ventricles of rabbits with heart failure and compared to 13 left ventricles of control (C) rabbits. Heart failure (HF) was induced by a double volume (aortic insufficiency) plus pressure (aortic stenosis 14 days later) overload. Left ventricular mass was increased in HF by 67% above C. Saturation curves with CGP 12177 showed a 36% decrease in beta-adrenoceptor density (C = 61.5 +/- 5.4 fmol/mg prot., P less than 0.05) but competition curves with isoproterenol were not different in HF and C. Basal and Gpp(NH)p stimulated adenylate cyclase activity were decreased by 36% and 22% respectively in rabbits with heart failure as compared with control animals and cAMP production was significantly smaller in failing left ventricles than in control left ventricles both after NaF stimulation (C: 161.3 +/- 24.9 pmols/mg/min; HF: 98.8 +/- 7.0 pmols/mg/min; P less than 0.05) and even more after forskolin stimulation (C: 159.1 +/- 23.9 and HF: 60.8 +/- 7.3 pmols/mg/min; P less than 0.01). Although isoproterenol stimulated ACA was smaller in HF than in C, EC50 was similar in both groups (1.6 x 10(-7) M). We conclude that in the early stage of heart failure in the rabbit, although adrenoceptor density is decreased, there are no changes of affinity of beta-adrenoceptors for isoproterenol and the major alteration of cAMP production appears to lie down-stream the receptor level with a markedly impaired stimulation of adenylate cyclase activity by forskolin.