Diabetes is one of the leading causes of cardiovascular death and disability in the United States and despite the treatment with insulin, patients with diabetes still have severe coronary vascular disease and altered cardiac metabolism. The goal of our studies is to better understand the mechanism responsible for diabetic cardiac disease especially the consequences of reduced production of NO on cardiac metabolism. Our approach will combine physiologic studies quantifying NO production and changes in cardiac metabolism over an extended period of time (5 weeks) after alloxan induced diabetes in chronically instrumented conscious dogs with in vitro studies of tissues from those dogs to determine microvessel NO production, ecNOS gene expression and the control of cardiac metabolism by NO. We will examine the potential consequences of alterations in NOS gene expression in the reduced NO production which we have already documented. A major focus of our studies both in vivo and in vitro will be the potential role of NO in the control of cardiac oxygen consumption and myocardial substrate utilization. We hypothesize that the loss of NO production during the development of diabetes contributes to the metabolic consequences of this disease. Since we have previously shown that exercise can upregulate NO production and mild regular exercise is beneficial in patients with diabetes we will test the hypothesis that regular exercise training will at least partially restore NO dependent control of tissue metabolism by increasing ecNOS. Furthermore, we will test the hypothesis that administration of Simvastatin (since """"""""statins"""""""" increase the message half life for ecNOS and since our preliminary data suggest that NO production in vivo and in vitro is increased by statins) to correct the decrease in ecNOS enzyme, restores the cardiac metabolic dysfunction associated with diabetes. Thus, our aims will provide for an integrated approach to study: 1) the mechanism of the reduction in NO production we have found in diabetes, 2) the potential that this results in a cardiac metabolic defect, and, 3) the treatment of the cardiovascular complications of diabetes with exercise or Simvastatin corrects the cardiac metabolic defect.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061290-03
Application #
6498973
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Liang, Isabella Y
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$300,660
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Zhao, Gong; Zhang, Suhua; Shryock, John C et al. (2012) Selective action of metoprolol to attenuate regadenoson-induced tachycardia in conscious dogs. J Nucl Cardiol 19:109-17
Zhao, Gong; Walsh, Erin; Shryock, John C et al. (2011) Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs. J Cardiovasc Pharmacol 57:639-47
Ojaimi, Caroline; Kinugawa, Shintaro; Recchia, Fabio A et al. (2010) Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism. Cardiovasc Diabetol 9:43
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Williams, Jeffrey G; Ojaimi, Caroline; Qanud, Khaled et al. (2008) Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog. Am J Physiol Heart Circ Physiol 294:H2516-23
Zhao, Gong; Serpllion, Sabrina; Shryock, John et al. (2008) Regadenoson, a novel pharmacologic stress agent for use in myocardial perfusion imaging, does not have a direct effect on the QT interval in conscious dogs. J Cardiovasc Pharmacol 52:467-73
Zhao, Gong; Messina, Eric; Xu, Xiaobin et al. (2007) Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist. J Cardiovasc Pharmacol 49:369-75
Williams, Jeffrey G; Rincon-Skinner, Tibisay; Sun, Dong et al. (2007) Role of nitric oxide in the coupling of myocardial oxygen consumption and coronary vascular dynamics during pregnancy in the dog. Am J Physiol Heart Circ Physiol 293:H2479-86
Ojaimi, Caroline; Qanud, Khaled; Hintze, Thomas H et al. (2007) Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs. Physiol Genomics 29:76-83
Zhao, Gong; Messina, Eric; Xu, Xiaobin et al. (2006) Ranolazine, a novel anti-anginal agent, does not alter isosorbide dinitrate- or sildenafil-induced changes in blood pressure in conscious dogs. Eur J Pharmacol 541:171-6

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