The transplanted human heart demonstrates abnormalities in autonomic responsiveness, the mechanism of which remains unknown. The long-term objectives of these studies are to understand the mechanisms by which sympathetic and parasympathetic innervation affect the regulation of autonomic responses of the human myocardium. Adrenergic and muscarinic responses of mammalian myocardium are coupled to intracellular functions via guanine nucleotide binding proteins. Recent studies in chick,, rat and human myocardium have suggested that innervation of the heart may play a role in regulating the responsiveness of the heart to autonomic stimuli via changes in receptors and G-protein-effector interactions. We plan to utilize three model systems to investigate the role of innervation and drug therapy in regulating autonomic balance in the transplanted myocardium. Endomyocardial biopsy specimens from human hearts following orthotopic cardiac transplantation, will be used to test the hypotheses that denervation leads to alteration in autonomic response by inducing changes in levels of adrenergic and muscarinic receptors,, changes in levels of G-proteins and their coupling to adenylate cyclase activity and that these alterations are associated with changes in the levels of the messenger RNA (mRNA) coding for these receptors and G-proteins. Since it will be impossible to evaluate the role of immunosuppressive agents in mediating the changes in autonomic responsiveness seen in the transplanted human myocardium, we will use a model of heterotopic cardiac transplantation in the Lewis rat to investigate the effects of denervation, with and without immunosuppressive agents on autonomic receptor-effector coupling. In order to determine the role of innervation in modulating the autonomic responsiveness of the heart, we will utilize a co-culture system of neonatal rat myocytes and sympathetic ganglia. We will conduct these studies to determine if innervation alters the levels of receptors and their coupling via G-proteins to adenylate cyclase activity and whether these changes represent a reversal of the effects observed in denervated myocardium. These studies should enhance our understanding of the basis of autonomic responsiveness of the heart, and the role that innervation and denervation may play in regulating autonomic balance of the heart.
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