Effects of beta-adrenoceptor blockade on beta-adrenergic signal transduction in cardiomyopathic hamster (BIO 8262) hearts.
In myopathic BIO 8262-hamsters beta1-adrenergic stimulation of cardiac adenylyl cyclase has been found to be markedly reduced compared to that of healthy controls. In order to test the hypothesis that the functional uncoupling of beta1-adrenoceptors in diseased hamster hearts is due to agonist-dependent desensitization, we investigated the effects of prolonged treatment with beta-adrenoceptor antagonists on cardiac beta-adrenergic signaling. Groups of hamsters aged 240 days received either drinking water, or drinking water containing metoprolol (10 or 100 mg/kg/day) or propranolol (4 or 40 mg/kg/day). After 4 weeks' treatment animals were killed and heart ventricles were prepared for determination of beta1- and beta2-adrenoceptor densities and their functional contribution to stimulation of adenylyl cyclase. Markers of myocardial hypertrophy, i.e. absolute and relative ventricular weight and 5-nucleotidase activity, were not affected by the different treatment regimens. Neither absolute densities nor relative proportions of beta-adrenoceptor subtypes differed between untreated and treated hamster groups. Metoprolol had no effects on the functional efficacy of beta1- and beta2-adrenoceptors. Hamsters treated with high dose propranolol showed unchanged beta1-adrenoceptor function but reduced beta2-adrenergic stimulation of adenylyl cyclase. The findings of the present study demonstrate that the disturbed coupling of cardiac beta1-adrenoceptors to adenylyl cyclase cannot be reversed by in vivo treatment with beta-adrenoceptor antagonists and, therefore, is unlikely to be due to agonist-dependent desensitization.
Witte
K
K
Institute of Pharmacology and Toxicology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany.
Kinzler
N
N
Schnecko
A
A
Olbrich
H G
HG
Lemmer
B
B
D015720:5'-Nucleotidase / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D006224:Cricetinae; D006352:Heart Ventricles / Q000473:pathology; D008647:Mesocricetus; D008790:Metoprolol / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size; D011433:Propranolol / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D015720:5'-Nucleotidase; D000262:Adenylyl Cyclases; D008790:Metoprolol