EFFECTS OF BETA-ADRENOCEPTOR BLOCKADE ON BETA-ADRENERGIC SIGNAL-TRANSDUCTION IN CARDIOMYOPATHIC HAMSTER (BIO-8262) HEARTS

In myopathic BIO 8262-hamsters beta(1)-adrenergic stimulation of cardi ac adenylyl cyclase has been found to be markedly reduced compared to that of healthy controls. In order to test the hypothesis that the fun ctional uncoupling of beta(1)-adrenoceptors in diseased hamster hearts is due to agonist-dependent desensitization, we investigated the effe cts of prolonged treatment with beta-adrenoceptor antagonists on cardi ac beta-adrenergic signaling. Groups of hamsters aged 240 days receive d either drinking water, or drinking water containing metoprolol (10 o r 100 mg/kg/day) or propranolol (4 or 40 mg/kg/day). After 4 weeks' tr eatment animals were killed and heart ventricles were prepared for det ermination of beta(1)- and beta(2)-adrenoceptor densities and their fu nctional contribution to stimulation of adenylyl cyclase. Markers of m yocardial hypertrophy, i.e. absolute and relative ventricular weight a nd 5-nucleotidase activity, were not affected by the different treatme nt regimens. Neither absolute densities nor relative proportions of be ta-adrenoceptor subtypes differed between untreated and treated hamste r groups. Metoprolol had no effects on the functional efficacy of beta (1)- and beta(2)-adrenoceptors. Hamsters treated with high dose propra nolol showed unchanged beta(1)-adrenoceptor function but reduced beta( 2)-adrenergic stimulation of adenylyl cyclase. The findings of the pre sent study demonstrate that the disturbed coupling of cardiac beta(1)- adrenoceptors to adenylyl cyclase cannot be reversed by in vivo treatm ent with beta-adrenoceptor antagonists and, therefore, is unlikely to be due to agonist-dependent desensitization. (C) 1997 Elsevier Science B.V.