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(Circulation. 1995;92:1911-1918.)
© 1995 American Heart Association, Inc.
Articles |
Protection Against Ischemic Injury by Nonvasoactive Concentrations of Nitric Oxide Synthase Inhibitors in the Perfused Rabbit Heart
From the Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, University of Louvain Medical School, Brussels, Belgium (C.D., J.-L.V., L.H.), and the Laboratory of Experimental NMR, Department of Medical Imaging, University of Louvain Medical School, Louvain-la-Neuve, Belgium (J.-F.G., I.M.).
Correspondence to Prof L. Hue, HORM Unit, ICP-UCL 7529, Avenue Hippocrate, 75, B-1200 Brussels, Belgium. E-mail hue@horm.ucl.ac.be.
Background The functional and metabolic effects of inhibitors of nitric oxide (NO) synthase on ischemic hearts have not been investigated. This work was designed to perform such a study in isolated perfused rabbit hearts submitted to low-flow ischemia.
Methods and Results After a 30-minute equilibration period, the hearts were submitted to low-flow ischemia for 60 minutes followed by reperfusion for 30 minutes. Functional and metabolic parameters were followed in hearts perfused with or without inhibitors of NO synthase or NO precursors, which were added 15 minutes before ischemia but were absent during reperfusion. Ischemic contracture was delayed and reduced in hearts perfused with 1 µmol/L L-N-monomethylarginine (L-NMMA) or 1 µmol/L L-N-arginine methylester, two inhibitors of NO synthase, but not with D-N-monomethylarginine, the inactive enantiomer of L-NMMA. The protection was suppressed by addition to the perfusate containing L-NMMA of 1 mmol/L L-arginine or 0.1 mmol/L sodium nitroprusside but not by addition of 10 µmol/L 8-bromo cGMP, a cGMP analogue. The functional protection by 1 µmol/L L-NMMA was related to a stimulation of glycolysis from exogenous glucose and a preservation of the glycogen stores. This resulted in a better maintenance of high-energy phosphates and a lower acidosis as measured by 31P nuclear magnetic resonance spectroscopy. During reperfusion, functional recovery was more than doubled, and enzyme release was halved in L-NMMA–treated hearts compared with controls. The functional and metabolic protection was maximal at 1 nmol/L to 1 µmol/L L-NMMA, ie, below the vasoactive concentrations of the inhibitor.
Conclusions Nonvasoactive concentrations of NO synthase inhibitors protect the heart against ischemic damage; this relates to a stimulation of glycolysis from exogenous glucose.
Key Words: glucose • ischemia
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