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 r eceptor signal transduction in denervated, previously transplanted hum an ventricular myocardium. Background. In model systems, surgical dene rvation typically results in both presynaptic and postsynaptic superse nsitivity in beta adrenergic receptor pathways and alteration in G pro tein-mediated signal transduction. Methods. We examined beta adrenergi c receptor signal transduction in the left and right ventricles remove d from nine subjects with a previous transplant and surgical denervati on 25 +/- 4 months after their first transplantation. Twenty-six heart s removed from organ donors served as central hearts. Results. Total b eta-adrenergic receptor density and stimulation of muscle contraction in isolated right ventricular trabeculae by the nonselective agonist i soproterenol were similar in the transplant and donor groups. Beta(1)- receptor density was not different in the left ventricles of the two g roups but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast,beta(2)-receptor density was higher in transpl ant left and right ventricles relative to the respective values in don or ventricles by 33% in left ventricles and 97% in right ventricles (b oth p < 0.05). Isoproterenol, which in particulate fractions of human heart stimulates adenylyl cyclase primarily via beta, receptors, produ ced a greater increase in cyclic adenosine monophosphate generation in membranes prepared from transplant left ventricles and right ventricl es compared with donors. In contrast, guanosine 5'-[beta,gamma-imido]t riphosphate, sodium fluoride and forsko- Iin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded s imilar 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. Conclu sions. These data indicate that the transplanted human heart exhibits an up-regulation of functional beta(2)-adrenergic receptors.