Myocardial adrenergic denervation supersensitivity depends on a postreceptor mechanism not linked with increased cAMP production.

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Abstract
BACKGROUND: Two major hypotheses have been proposed to explain catecholamine supersensitivity after myocardial denervation, but neither sufficiently explains certain features of the phenomenon. In addition, a nonsurgical method for long-term myocardial adrenergic denervation is desirable but has not been accomplished or described with respect to catecholamine supersensitivity. METHODS AND RESULTS: We have accomplished chronic myocardial adrenergic denervation by using 6-hydroxydopamine (6-OHDA). Sixteen weeks after 6-OHDA administration to newborn pigs, we found substantial myocardial adrenergic denervation associated with beta-adrenergic receptor (beta AR) downregulation. Despite decreased beta AR number, the dose of isoproterenol yielding 50% maximal heart rate change (ED50) was decreased, and heart rates during exercise showed increased responsiveness despite decreased circulating catecholamines. Thus, stimulation of fewer receptors yielded an increased response, implying improved signal transduction efficiency. Competitive binding studies with isoproterenol showed an increased proportion of beta AR with high-affinity binding in myocardial membranes from 6-OHDA pigs, suggesting that interaction between beta AR and cardiac G, may contribute to improved signal transduction efficiency. However, measures of adenylyl cyclase activity indicated marked reduction in beta AR-dependent and G2-dependent cAMP production in myocardial membranes from denervated animals despite a normal amount of cardiac Gs and decreased Gi. CONCLUSIONS: We have demonstrated that substantial, long-term myocardial adrenergic denervation is possible using 6-OHDA. Denervation supersensitivity in this model does not depend on enhanced cAMP stimulation but rather depends on postreceptor elements in the beta AR-responsive pathway that may be independent of Gs-activated adenylyl cyclase activity. In this model of adrenergic denervation supersensitivity, beta-receptors, through Gs, may be linked to an alternative effector that drives heart rate responsiveness.