A role for NO in the control of cardiac metabolism is receiving support from an increasing number of studies. We recently found that the acute blockade of NO synthase (NOS) in normal dogs and the fall in NO production during pacing induced heart failure are both associated with a switch from free fatty acids (FFA) to carbohydrate utilization by the heart. The mechanisms underlying these phenomena are unknown. This research proposal will determine the role of NO in the control of cardiac substrate utilization and whether this role is lost during heart failure. The first specific aim is to determine whether NO controls cardiac FFA and carbohydrate metabolism. The rate of FFA and carbohydrate oxidation in the heart, before and after NOS blockade, will be measured in conscious dogs by infusing isotope-labeled FFA, glucose and lactate. Labeled substrate accumulation and the activity of key enzymes for carbohydrate and FFA oxidation will be measured in cardiac biopsies freeze-clamped at the end of the in vivo experiment. The rapid freezing of the tissue will preserve the activation state of enzymes from in vivo to in vitro. The second specific aim is to determine whether the myocardial metabolic and biochemical alterations occurring during heart failure are similar to those found after NOS blockade in normal hearts and if they can be reversed by a NO-releasing agent. The same methods in vivo and in vitro will be employed. Heart failure will be induced in dogs by chronic pacing. The third specific aim is to determine whether acute alterations of arterial substrate concentration can affect cardiac oxygen consumption during heart failure and if this effect can be reversed by NO-releasing agents. Our preliminary data indicate that FFA consumption can cause increased in cardiac O2 consumption unrelated to hemodynamic changes, but only when NO is absent. These studies will elucidate the role of NO in the pathophysiology of heart failure. This will also provide a new pharmacological mechanism of NO-donors in the treatment of heart failure. based on direct control by these agents on cardiac metabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL062573-01A1
Application #
6044515
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
2000-02-04
Project End
2004-01-31
Budget Start
2000-02-04
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$327,367
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
d'Agostino, Chiara; Labinskyy, Volodymyr; Lionetti, Vincenzo et al. (2006) Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs. Am J Physiol Heart Circ Physiol 290:H1721-6
Lei, Biao; Matsuo, Ken; Labinskyy, Volodymyr et al. (2005) Exogenous nitric oxide reduces glucose transporters translocation and lactate production in ischemic myocardium in vivo. Proc Natl Acad Sci U S A 102:6966-71
Lionetti, Vincenzo; Linke, Axel; Chandler, Margaret P et al. (2005) Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure. Cardiovasc Res 66:454-61
Post, Heiner; Kajstura, Jan; Lei, Biao et al. (2003) Adeno-associated virus mediated gene delivery into coronary microvessels of chronically instrumented dogs. J Appl Physiol 95:1688-94
Post, Heiner; d'Agostino, Chiara; Lionetti, Vincenzo et al. (2003) Reduced left ventricular compliance and mechanical efficiency after prolonged inhibition of NO synthesis in conscious dogs. J Physiol 552:233-9
Linke, Axel; Zhao, Gong; Recchia, Fabio A et al. (2003) Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes. Am J Physiol Heart Circ Physiol 285:H1007-14
Kinugawa, Shintaro; Post, Heiner; Kaminski, Pawel M et al. (2003) Coronary microvascular endothelial stunning after acute pressure overload in the conscious dog is caused by oxidant processes: the role of angiotensin II type 1 receptor and NAD(P)H oxidase. Circulation 108:2934-40
Osorio, Juan Carlos; Stanley, William C; Linke, Axel et al. (2002) Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 106:606-12
Recchia, Fabio A; Osorio, Juan Carlos; Chandler, Margaret P et al. (2002) Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 282:E197-206