The goal of this research proposal is to investigate the role of purine in myocardial injury and protection in normal and failing hearts, and to determine whether the failing hear could tolerate stunning and cold be is chemically or pharmacologically preconditioned. A common factor often shared by cardiac surgeons is a prolonged recovery period (stunned myocardium) during which the myocardium is susceptible to pump failure or arrhythmia. Metabolic interventions capable of shortening this period of vulnerability have obvious clinical importance. Prolonged delay in metabolic recovery following ischemic injury is related to availability of essential precursors, i.e. adenosine, which have been lost upon reperfusion. The phenomenon of ischemic preconditioning is an intrinsic protective mechanisms by which the briefly ischemic myocardium can tolerate subsequent lethal ischemic injury. The mechanism(s) by which myocardial ATP is spared during prolonged ischemia is not known, Adenosine receptor and ATP-sensitive potassium channels are believed to mediated preconditioning . Although, cardioprotection of exogenous of endogenous adenosine in myocardial stunning and preconditioning in normal and isolated cardiomyopathic hearts. We have clearly demonstrated that pharmacologic interventions that selectively entrap endogenous adenosine and inosine in the ischemic segment of the myocardium are cardioprotective. A combination of selective nucleoside transport blocked (NBMPR) and adenosine deaminase inhibitor (EHNA) will be used to manipulate endogenous adenosine formation, transport and metabolism. Preliminary results suggest that this strategy is associate with excellent functional recovery and ATP repletion, suggesting that adenosine is entrapped in compartment where adenosine in incorporated into ATP. We thought to investigate whether similar strategy of protection could be beneficial to the dilated heart. Therefore, the specific aims of this research proposal are as follow: 1) To elucidate the mechanism(s) by which preconditioning preserves ATP during prolonged ischemia in normal and dilated hearts; 2) TO determine the role of purine in myocardial stunning and preconditioning in previously normal and failing hearts; and 3) To determine whether substrate and energy enhancement of the failing heart increase myocardial tolerance to global or regional stunning and preconditioning. To achieve our goals, we will utilize subcellular fractions, isolated cardiomyocytes, isolated perfused and in vivo small animal models. To determine functional and metabolic correlates, large animal models will be used. Compartmentalization of endogenous adenosine will be determine using two different classes of nucleoside transport blockers in isolated cardiomyocyte. Results form this proposed research will ultimately lead to he development of new strategies to manipulate endogenous adenosine formation thus maximize its cardioprotective effects especially in the failing heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051090-04
Application #
2028992
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1993-12-01
Project End
1999-05-31
Budget Start
1996-12-01
Budget End
1999-05-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Abd-Elfattah, Anwar Saad; Tuchy, Gert E; Jessen, Michael E et al. (2013) Hot shot induction and reperfusion with a specific blocker of the es-ENT1 nucleoside transporter before and after hypothermic cardioplegia abolishes myocardial stunning in acutely ischemic hearts despite metabolic derangement: hot shot drug delivery befor J Thorac Cardiovasc Surg 146:961-970.e3
Abd-Elfattah, Anwar Saad; Aly, Hamdy; Hanan, Scott et al. (2012) Myocardial protection in beating heart cardiac surgery: I: pre- or postconditioning with inhibition of es-ENT1 nucleoside transporter and adenosine deaminase attenuates post-MI reperfusion-mediated ventricular fibrillation and regional contractile dysfunc J Thorac Cardiovasc Surg 144:250-5
Abd-Elfattah, Anwar Saad; Ding, Mai; Jessen, Michael E et al. (2012) On-pump inhibition of es-ENT1 nucleoside transporter and adenosine deaminase during aortic crossclamping entraps intracellular adenosine and protects against reperfusion injury: role of adenosine A1 receptor. J Thorac Cardiovasc Surg 144:243-9
Mahgoub, M A; Guo, J H; Gao, S P et al. (1999) Hyperdynamic circulation of arteriovenous fistula preconditions the heart and limits infarct size. Ann Thorac Surg 68:22-8
Abd-Elfattah, A S; Hoehner, J; Wechsler, A S (1998) Identification of nucleoside transport binding sites in the human myocardium. Mol Cell Biochem 180:105-10
Abd-Elfattah, A S; Maddox, R P; Jessen, M E et al. (1998) Role of nucleoside transport and purine release in a rabbit model of myocardial stunning. Mol Cell Biochem 180:145-51
Abd-Elfattah, A S; Ding, M; Wechsler, A S (1995) Intermittent aortic crossclamping prevents cumulative adenosine triphosphate depletion, ventricular fibrillation, and dysfunction (stunning): is it preconditioning? J Thorac Cardiovasc Surg 110:328-39
Abd-Elfattah, A S; Wechsler, A S (1995) Myocardial preconditioning: a model or a phenomenon? J Card Surg 10:381-8