EXCEED THE SPACE PROVIDED. Coronary artery disease kills more Americans than any other disease. Coronary revascularization with either catheters (PTCA), surgery (CABG), or thrombolytic agent (TPA) has reduced morbidity and mortality from coronary occlusion. Yet there is always a delay between onset of symptoms in acute myocardial infarction and re-establishment of coronary flow. And delay translates into myocardial necrosis. Although it is critical to revascularize the heart if myocardium is to be salvaged, it has now become apparent that the very act of resuming flow after a period of ischemia causes its own form of damage, so-called reperfusion injury. There are many possible causes: free radicals, leukocyte damage and capillary plugging, shifts ofNa + and Ca ++, contracture, apoptosis. Histologic features and probably functional characteristics of reperfusion injury are distinct from those caused by ischemia. Treatment at reperfusion in an attempt to attenuate resulting inury has clinical potential. There is no consensus that treatment targeted at reperfusion injury in animal models has been effective. However, a novel adenosin( A1/A2 agonist AMP 579 has shown promise. Because of the still proprietary nature of this agent, I will examine properties and mechanisms of protection of NECA, another A]A 2 agonist. Oddly, A-2Areceptor blockade aborts protection, but it cannot be mimicked by A2A agonists. I will first define dosing requirements for NECA's protection against reperfusion injury and determine whether a combination of selective At and A2 agonists can mimic protection. I will explore NECA's signal transduction pathway leading to protection starting with the G s and phosphatidylinositol 3-kinase pathways, but also including G i and NO pathways. Because an AI/A 2 agonist can attenuate contracture in ischemia]reperfusion, I pl_ to see ifNECA interferes with accumulation of intracellular Ca ++. I will also determine whether NECA decreases intracellular osmolytes and attenuates swelling. Finally, I will see ifNECA's salvage of myocardium at reperfusion translates into rapid functional benefits. It is hoped that the potential of this new pharmacologic approach can be defined. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050688-10
Application #
6819233
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
1993-09-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
10
Fiscal Year
2005
Total Cost
$255,500
Indirect Cost
Name
University of South Alabama
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Tissier, Renaud; Chenoune, Mourad; Ghaleh, Bijan et al. (2010) The small chill: mild hypothermia for cardioprotection? Cardiovasc Res 88:406-14
Kuno, Atsushi; Solenkova, Nataliya V; Solodushko, Victoriya et al. (2008) Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C. Am J Physiol Heart Circ Physiol 295:H1288-H1295
Liu, Yanping; Yang, Xi-Ming; Iliodromitis, Efstathios K et al. (2008) Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. Basic Res Cardiol 103:54-9
Costa, Alexandre D T; Pierre, Sandrine V; Cohen, Michael V et al. (2008) cGMP signalling in pre- and post-conditioning: the role of mitochondria. Cardiovasc Res 77:344-52
Tissier, Renaud; Berdeaux, Alain; Ghaleh, Bijan et al. (2008) Making the heart resistant to infarction: how can we further decrease infarct size? Front Biosci 13:284-301
Kuno, Atsushi; Critz, Stuart D; Cui, Lin et al. (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion. J Mol Cell Cardiol 43:262-71
Cohen, Michael V; Philipp, Sebastian; Krieg, Thomas et al. (2007) Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways. J Mol Cell Cardiol 42:842-51
Kuno, Atsushi; Critz, Stuart D; Cohen, Michael V et al. (2007) Nicorandil opens mitochondrial K(ATP) channels not only directly but also through a NO-PKG-dependent pathway. Basic Res Cardiol 102:73-9
Cohen, Michael V; Yang, Xi-Ming; Downey, James M (2007) The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 115:1895-903
Tissier, Renaud; Hamanaka, Kazutoshi; Kuno, Atsushi et al. (2007) Total liquid ventilation provides ultra-fast cardioprotective cooling. J Am Coll Cardiol 49:601-5

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