UP-REGULATION OF BETA(2)-ADRENERGIC RECEPTORS IN PREVIOUSLY TRANSPLANTED, DENERVATED NONFAILING HUMAN HEARTS

Objectives. The purpose of this study was to examine beta-adrenergic receptor signal transduction in denervated, previously transplanted human ventricular myocardium. Background. In model systems, surgical denervation typically results in both presynaptic and postsynaptic supersensitivity in beta adrenergic receptor pathways and alteration in G protein-mediated signal transduction. Methods. We examined beta adrenergic receptor signal transduction in the left and right ventricles removed from nine subjects with a previous transplant and surgical denervation 25 +/- 4 months after their first transplantation. Twenty-six hearts removed from organ donors served as central hearts. Results. Total beta-adrenergic receptor density and stimulation of muscle contraction in isolated right ventricular trabeculae by the nonselective agonist isoproterenol were similar in the transplant and donor groups. Beta(1)-receptor density was not different in the left ventricles of the two groups but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast,beta(2)-receptor density was higher in transplant left and right ventricles relative to the respective values in donor ventricles by 33% in left ventricles and 97% in right ventricles (both p < 0.05). Isoproterenol, which in particulate fractions of human heart stimulates adenylyl cyclase primarily via beta, receptors, produced a greater increase in cyclic adenosine monophosphate generation in membranes prepared from transplant left ventricles and right ventricles compared with donors. In contrast, guanosine 5'-[beta,gamma-imido]triphosphate, sodium fluoride and forsko- Iin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded similar degrees of adenylyl cyclase stimulation in the two groups, and both pertussis toxin and cholera toxin-catalyzed adenosine diphosphate ribosylation were not altered in transplanted left ventricles. Conclusions. These data indicate that the transplanted human heart exhibits an up-regulation of functional beta(2)-adrenergic receptors.