Up-regulation of beta2-adrenergic receptors in previously transplanted, denervated nonfailing human hearts

Abstract

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 control 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. Beta1-receptor density was not in the left ventricles of the two group but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast, betah2-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 stimulate adenylyl cyclase primarily via beta2-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 forskolin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded similar degress of adenylyl cyclase stimulation in the two group, 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 beta2adrenergic receptors.