Cardiac failure is the leading cause of morbidity and mortality among aged individuals in Westernized societies. While acute decompensation is treated with combined vascular unloading via nitrates and beta-adrenergic stimulation, this interaction can be antagonistic. We recently discovered that nitroxyl anion (HNO/NO-), the one-electron reduced form of NO, induces marked vasodilation and marked positive inotropic and lusitropic cardiac effects. Intriguingly, and opposite to NO donors and nitrates, these cardiac effects are additive to beta-stimulation, largely unaffected by beta-blockade, and similar in normal and failing hearts. While initial in vivo studies suggested a role of calcitonin gene-related peptide (CGRP) release, newer data indicates this is not the sole mechanism, and that direct, potent myocyte action occurs. The guiding hypothesis of this proposal is that HNO/NO- donors directly and substantially enhance myocyte contractility, that unlike NO, this is linked to elevation of cAMP and PKA activation, and is similarly active in myocytes from normal and failing hearts. Studies will test this hypothesis, determine basic mechanisms by which HNO NO- effects excitation-contraction coupling and redox modulation, directly test a link to cAMP and PKA, and define interactions of HNO/NO- with adrenergic receptor signaling. Clarification of the mechanism of action of HNO/NO- will greatly advance our understanding and potential use of this agent as a potential and novel heart failure therapy. The three aims are to test whether and how HNO/NO- influences excitation-contraction coupling, directly test the link to cAMP and PKA, define redox modulation, and interactions of HNO/NO- with adrenergic receptor signaling. Studies are largely conducted in isolated myocytes, employing fluorescent methods to define cAMP signaling and localization, and pharmacologic and genetic engineering approaches to dissect key pathways. These studies will provide key ground work clarifying a novel nitroxyl/cAMP/PKA paradigm, and its potential to develop into a therapy for cardiac failure.
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