AUTONOMIC RECEPTOR FUNCTION IN LV HYPERTROPHY & FAILURE

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The goal of this grant is to investigate mechanisms distal to the beta- adrenergic receptor mediating altered beta-adrenergic receptor-cyclase coupling in heart failure and catecholamine desensitization. It is planned to focus on two models, i.e., pacing-induced heart failure and catecholamine desensitization with or without cardiac denervation. These models are particularly powerful for three reasons: 1) they allow the study of biochemical and molecular mechanisms in larger animal models in which the physiology can be characterized in the conscious state, 2) they allow the study of serial changes during progression of the disease state from initial changes to more chronic states characterized by decompensation, and 3) the disease states are reversible. Four hypotheses will be tested. The first hypothesis is that abnormalities in the coupling of the beta-adrenergic receptor to adenylyl cyclase occur prior to the development of left ventricular (LV) decompensation and that these abnormalities reflect either uncoupling of the receptor from the guanine nucleotide stimulatory protein (Gs), changes in proportions of beta1 and beta2 receptors, or to a defect in the adenylyl cyclase catalytic unit. The second hypothesis is that in the pacing-induced model of heart failure and in the catecholamine desensitization model where the inotropic response to catecholamines is profoundly depressed, Gs activity is maintained, but Gi is enhanced and contributes to impaired generation of adenylyl cyclase in response to sympathetic stimulation. The third hypothesis is that cardiac neural impairment, e.g., denervation, is required for downregulation of cell surface beta-adrenergic receptors in heart failure or catecholamine desensitization. The fourth hypothesis is that in the failing heart, beta-adrenergic receptor occupancy is higher than in the normal heart resulting in maintenance of cyclic AMP levels despite the impairment in the beta-adrenergic stimulatory pathway. Thus, by examination of these hypotheses in models of heart failure and desensitization, it will be possible to better understand biochemical and molecular mechanisms responsible for depressed physiological responses to sympathetic stimulation in vivo.