Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs.

The effects of congestive heart failure on the physiological and biochemical functions of the cardiac beta-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic beta-receptor density, measured by [3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the beta-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, beta-receptor down-regulation is chamber-specific, occurring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occurred in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by beta-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.