Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts.
To identify the role of the myocardial beta-adrenergic pathway in congestive heart failure, we examined beta-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in beta-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P less than 0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P less than 0.05). We conclude that in failing human hearts a decrease in beta-receptor density leads to subsensitivity of the beta-adrenergic pathway and decreased beta-agonist-stimulated muscle contraction. Regulation of beta-adrenergic receptors may be an important variable in cardiac failure.
D000262:Adenylyl Cyclases / Q000032:analysis; D000293:Adolescent; D000328:Adult; D002395:Catecholamines / Q000494:pharmacology*; D003285:Contractile Proteins / Q000032:analysis; D003402:Creatine Kinase / Q000032:analysis; D004082:Dihydroalprenolol / Q000378:metabolism; D005260:Female; D005459:Fluorides / Q000494:pharmacology; D006333:Heart Failure / Q000503:physiopathology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000032:analysis*; D011869:Radioligand Assay; D011941:Receptors, Adrenergic / Q000032:analysis*; D011943:Receptors, Adrenergic, beta / Q000032:analysis*; D014316:Tritium
D002395:Catecholamines; D003285:Contractile Proteins; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D014316:Tritium; D004082:Dihydroalprenolol; D006632:Histamine; D003402:Creatine Kinase; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005459:Fluorides; D006909:Hydroxyproline