Human heart failure is characterized by profound catecholamine desensitization, in vivo, accompanied by alterations in beta-adrenergic signaling, in vitro, e.g., decreases in cardiac beta-adrenergic receptors, increases in Gialpha, and reductions in adenylyl cyclase activity. Our recent studies in dogs with chronic ventricular denervation and heart failure demonstrate marked attenuation of catecholamine desensitization. The first hypothesis to be tested is that in the absence of cardiac nerves, beta-adrenergic receptor signaling is present during the development of heart failure, e.g., by suppressing beta-adrenergic receptor kinase levels or maintaining the catalytic unit of adenylyl cyclase. This will be studied in dogs with and without selective ventricular denervation with chronic rapid ventricular pacing-induced heart failure. The first goal of this proposal is to define the cellular mechanisms responsible for the preserved catecholamine responsiveness. In vitro, the adrenergic receptor-G-protein-adenylyl cyclase signal transduction system will be studied. The second hypothesis to be tested is that differences in beta-adrenergic signaling in animals with ventricular denervation and heart failure may be affected by hemodynamics and cardiac geometry. To address this, isolated myocytes will be studied, first in terms of contraction and relaxation in both endo- and epicardial layers in response to isoproterenol, norepinephrine, forskolin and calcium. Secondly, studies of beta-adrenergic receptors, adenylyl cyclase and G-proteins will be examined in sarcolemmal preparations from the isolated myocytes. Thus, the current proposal contains two unique features. This proposal will provide the first data on altered catecholamine desensitization mechanisms in heart failure due to interruption of cardiac nerves. This part of the proposal has obvious significance not only for patients with transplanted hearts, which are denervated, but also for understanding basic mechanisms involved in autonomic regulation in heart failure. This becomes particularly important in view of recent clinical studies showing beneficial effects in patients in heart failure. Secondly, no study has systematically examined catecholamine desensitization mechanisms using a combination of in vivo studies and isolated myocytes for transmural physiology, biochemistry and molecular biology.
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