Cardiac Efficiency Is Improved After Ischemia by Altering Both the Source and Fate of Protons

Cardiac efficiency is decreased in hearts after severe ischemia. We determined whether reducing the production of H sup + from glucose metabolism or inhibiting the clearance of H sup + via Na sup +-H sup + exchange could increase cardiac efficiency during reperfusion. This was achieved using dichlor...

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Bibliographic Details
Published in:Circulation research 1996-11, Vol.79 (5), p.940-948
Main Authors: Liu, Bin, Clanachan, Alexander S, Schulz, Richard, Lopaschuk, Gary D
Format: Article
Language:English
Subjects:
Acetyl Coenzyme A - metabolism
Adenosine Triphosphate - biosynthesis
Amiloride - analogs & derivatives
Amiloride - pharmacology
Animals
Biological and medical sciences
Cardiology. Vascular system
Coronary heart disease
Dichloroacetic Acid - pharmacology
Glucose - metabolism
Glycolysis - drug effects
Heart
Heart - drug effects
Heart - physiopathology
In Vitro Techniques
Male
Medical sciences
Myocardial Ischemia - physiopathology
Myocardial Reperfusion
Oxidation-Reduction - drug effects
Palmitic Acid - metabolism
Protons
Rats
Rats, Sprague-Dawley
Time Factors
Tricarboxylic Acids - metabolism
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Summary:Cardiac efficiency is decreased in hearts after severe ischemia. We determined whether reducing the production of H sup + from glucose metabolism or inhibiting the clearance of H sup + via Na sup +-H sup + exchange could increase cardiac efficiency during reperfusion. This was achieved using dichloroacetate (DCA) to stimulate glucose oxidation and 5-(N,N-dimethyl)-amiloride (DMA) to inhibit Na sup +-H sup + exchange, respectively. Isolated working rat hearts were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Glycolysis and oxidation rates of glucose, lactate, and palmitate were measured. Recovery of cardiac work, O2 consumption (MVO2), and rates of acetyl-coenzyme A and ATP production during reperfusion were determined. After ischemia, cardiac work recovered to 35 +/- 5% of preischemic values in control hearts (n=23), although MVO2, tricarboxylic acid (TCA) cycle activity, and ATP production from glycolysis and oxidative metabolism rapidly recovered to preischemic levels. This decrease in cardiac efficiency was accompanied by a substantial production of H sup + from glucose metabolism. DCA caused a 2.2-fold increase in glucose oxidation, a 46 +/- 17% decrease in H sup + production, a 1.6-fold increase in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion (n=17). Inhibition of Na sup +-H sup + exchange with DMA did not alter TCA cycle activity and ATP production rates but did result in a 1.8-fold increase in cardiac efficiency and a 1.7-fold increase in cardiac work (n=12). These data show that cardiac efficiency and the contractile function after ischemia can be improved by either reducing the rate of H sup + production from glucose metabolism during reperfusion or inhibiting the clearance of H sup + via Na sup +-H sup + exchange. Our data suggest that an increased requirement for ATP to restore ischemia-reperfusion-induced alterations in ion homeostasis contributes to the decrease in cardiac efficiency and contractile function after ischemia.(Circ Res. 1996;79:940-948.)
ISSN:0009-7330
1524-4571
DOI:10.1161/01.res.79.5.940