EFFECTS OF CHRONIC APPLICATION OF PROPRANOLOL ON BETA-ADRENERGIC SIGNAL-TRANSDUCTION IN HEART VENTRICLES FROM MYOPATHIC BIO TO2 AND CONTROLHAMSTERS

1 In human congestive heart failure beta-adrenoceptor antagonists impr ove exercise tolerance and cardiac contractility. These beneficial eff ects are thought to reflect an up-regulation of cardiac beta-adrenocep tors, involving mainly the beta(1)-subtype. In the present study we ev aluated the functional contribution of beta-adrenoceptor subtypes to s timulation of adenylyl cyclase in an animal model of dilated cardiomyo pathy, and compared the effects of treatment with propranolol on cardi ac B-adrenergic signal transduction in myopathic and control hamsters. 2 Cardiomyopathic BIO TO2 hamsters and BIO FIB controls aged 270 days were used. In the treatment study, hamsters received drinking water w ith or without propranolol 40 mg kg(-1) d(-1) for 4 weeks prior to sac rifice. Density and subtype distribution of beta-adrenoceptors were de termined in radioligand binding studies. Functional contributions of b eta-adrenoceptors were evaluated by subtype-selective stimulation of a denylyl cyclase. Cardiac G-protein content was determined by immunoblo tting. 3 Compared to BIO FIB controls, myopathic hamsters showed incre ases in cardiac total beta- and beta(2)-adrenoceptor density, G(s)alph a and G(i)alpha content. In BIO TO2 ventricles, beta(1)-adrenoceptors were almost completely uncoupled from adenylyl cyclase stimulation des pite an unchanged density. Treatment of hamsters with propranolol resu lted in increased density of beta(1)-adrenoceptors in both strains, bu t had no effect on their functional efficacy. Moreover, beta(2)-adrene rgic stimulation of adenylyl cyclase was even reduced in propranolol-t reated animals, which could not be explained by changes in cardiac G-p rotein content. 4 Cardiomyopathic BIO TO2 hamsters showed functional u ncoupling of cardiac beta(1)-adrenoceptors, which could not be normali zed by propranolol and, therefore, is unlikely to be solely due to ago nist-dependent desensitization. The paradoxical reduction in beta(2)-a drenergic efficiency in propranolol-treated myopathic and control hams ters deserves further investigation.