β-Adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts

Abstract

To test the hypothesis that there is up-regulation of β-adrenergic receptor density or supersensitivity of β-adrenergic receptor-stimulated adenylate cyclase in the denervated transplanted human heart, we studied myocardium from transplanted, normal, and failing hearts. Myocardium was obtained from 10 patients 9 ± 3 months after cardiac transplantation, from 10 patients without cardiac disease, and from eight patients with symptomatic congestive heart failure due to idiopathic cardiomyopathy. β-Adrenergic receptor density in transplanted myocardium (15 ± 3 fmol/mg protein, 1.20 ± 0.14 fmol/mg DNA) was not different from that in normal myocardium (22 ± 3 fmol/mg protein, 1.46 ± 0.13 fmol/mg DNA; p = NS for both). In myocardium from cardiomyopathic hearts, β-adrenergic receptor density was markedly reduced (8 ± 2 fmol/mg protein, 0.84 ± 0.13 fmol/mg DNA; p < 0.05 and p < 0.01 vs. normal myocardium, respectively). Likewise, the response of adenylate cyclase to isoproterenol in transplanted myocardium was not significantly different from that in normal myocardium, but the response was markedly depressed in cardiomyopathic myocardium. Although forskolin-stimulated adenylate cyclase activity was similar in all three groups, guanine nucleotide-stimulated adenylate cyclase activity was markedly reduced in transplanted myocardium (20 ± 17 vs. 78 ± 13 pmol/mg/min for normal myocardium, p < 0.01) and to a lesser degree in cardiomyopathic myocardium (39 ± 14 pmol/mg/min, p < 0.03 vs. normal myocardium). Thus, there is no evidence of β-adrenergic receptor up-regulation or supersensitivity in denervated transplanted human myocardium. Moreover, the depressed adenylate cyclase response to guanine nucleotide stimulation in transplanted and cardiomyopathic myocardium indicates that in these conditions there may be an alteration in the expression or function of one or more guanine nucleotide regulatory proteins.