(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).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064779-03
Application #
6537793
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Balshaw, David M
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$219,000
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
White, Richard E; Gerrity, Ross; Barman, Scott A et al. (2010) Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women. Steroids 75:788-93
Zhu, Shu; Browning, Darren D; White, Richard E et al. (2009) Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells. Am J Physiol Lung Cell Mol Physiol 297:L758-66
Zhu, Shu; White, Richard E; Barman, Scott A (2006) Effect of PKC isozyme inhibition on forskolin-induced activation of BKCa channels in rat pulmonary arterial smooth muscle. Lung 184:89-97
White, Richard E; Han, Guichun; Dimitropoulou, Christiana et al. (2005) Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle. Am J Physiol Heart Circ Physiol 289:H1468-75
Barman, Scott A; Zhu, Shu; White, Richard E (2005) Hypoxia modulates cyclic AMP activation of BkCa channels in rat pulmonary arterial smooth muscle. Lung 183:353-61
Dimitropoulou, Christiana; White, Richard E; Ownby, Dennis R et al. (2005) Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels. Am J Respir Cell Mol Biol 32:239-47
Barman, Scott A; Zhu, Shu; White, Richard E (2004) PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 286:L1275-81
Barman, Scott A; Zhu, Shu; White, Richard E (2004) Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 286:L149-55
Barman, Scott A; Zhu, Shu; Han, Guichan et al. (2003) cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 284:L1004-11
White, Richard E (2002) Estrogen and vascular function. Vascul Pharmacol 38:73-80

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