(Verbatim from the application): Heart failure is often the lethal consequence of a variety of cardiovascular disorders, such as myocardial infarction, hypertension, and coronary artery dysfunction. Although agents that elevate cAMP are commonly used to treat heart failure, knowledge of the cellular/molecular basis of how these drugs act is limited. The long-term goal of the proposed study is to understand how cAMP-dependent vasodilators reduce morbidity and mortality of cardiovascular disorders, and thereby suggest new approaches for the treatment of heart failure. Preliminary studies indicate that cAMP-dependent vasodilators relax coronary arteries in vitro by an endothelium-independent mechanism that involves K efflux. Subsequent patch-clamp studies suggest that cAMP opens the large-conductance, calcium- and voltage-activated potassium (BKCa) channel by stimulating the cGMP-dependent protein kinase (PKG) instead of PKA. Preliminary biochemical studies have confirmed this cross-activation. Furthermore, the effects of cAMP can be reversed by agents that inhibit the activity of phosphoprotein phosphatases. Therefore, the hypothesis of the proposed studies is that cAMP-producing agents relax coronary arteries by opening BKCa channels in coronary smooth muscle by stimulating the activity of PKG (but not PKA) and phosphoprotein phoshatase 2A (PP2A). This hypothesis will be tested by employing state-of-the-art techniques of electrophysiology and biochemistry / molecular biology to determine 1) the effect of cAMP-dependent vasodilators on coronary arteries in vitro; 2) the effect of cAMP-stimulating agents on whole-cell and single-channel K currents from single myocytes isolated from coronary arteries; 3) cAMP-dependent 'cross-activation' of PKG; and 4) a potential role of phosphates activity in mediating the response to cAMP in coronary arteries and whether there is a direct interaction between the BKCa channel and PP2A. It is hoped that these studies will lead to the development of novel therapeutic agents that will help reduce the morbidity and mortality associated with heart failure and other cardiovascular diseases (e.g. agents that target BKCa channels of phosphoprotein phosphatases).
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