Evidence for uncoupling of the beta receptor-adenylate cyclase complex.

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Abstract
To determine if cardiac tissue is capable of modulating its response to a stimulating hormone, desensitization to the positive inotropic effect of catecholamines on embryonic chick ventricular tissue was studied using a phase contrast microscope-video motion detector system and correlated the contractility findings with concurrent observations of .beta.-adrenergic receptor properties and adenylate cyclase activity. Incubation for 30 min with 1 .mu.M isoproterenol produced a diminution in the subsequent inotropic response to 0.1 .mu.M isoproterenol to 35 .+-. 8% (mean .+-. standard error of the mean) of the initial response. This desensitization to the positive inotropic effect of isoproterenol was catecholamine-specific and was not accompanied by alteration in the inotropic response to Ca2+. To investigate the mechanism of desensitization, properties of the .alpha.-adrenergic receptor in homogenates of chick embryo ventricle were studied using [H]dihydroalprenolol as a ligand. Thirty minutes of incubation with 1 .mu.M isoproterenol produced no change in .beta.-adrenergic receptor density (92.8 .+-. 5.1 f[femto]mol/mg protein) and only a small change in receptor affinity (KD = 5.2 .+-. 0.3 nM vs. 7.0 .+-. 0.3 nM; P < 0.01). Receptor affinity for isoproterenol, as judged by [3H]dihydroalprenolol displacement, was not changed significantly. The adenylate cyclase stimulation by isoproterenol in similarly prepared tissue was reduced to 29% of the control value after 30 min of exposure to 1 .mu.M isoproterenol. Adenylate cyclase sensitivity was restored by guanosine 5''-(.beta..sbd.imino) triphosphate. Desensitization of physiological responsiveness of ventricular tissue to a .beta.-adrenergic agonist was accompanied by little change in .beta.-adrenergic receptor properties but by marked diminution in adenylate cyclase responsiveness. Uncoupling of the .beta.-adrenergic receptor-adenylate cyclase complex may be the mechanism of short-term desensitization of ventricular muscle to the positive inotropic effects of isoproterenol.