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EXPERIMENTAL STUDY

Nitric oxide synthase inhibitors decrease coronary sinus-free radical concentration and ameliorate myocardial stunning in an ischemia-reperfusion model

^a the Cardiovascular Center, University of Iowa, Iowa City, Iowa, USA

Manuscript received April 10, 1999; revised manuscript received April 19, 2001, accepted April 27, 2001.

Reprint requests and correspondence: Dr. Richard E. Kerber, Department of Internal Medicine, University of Iowa Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242.
richard-kerber{at}uiowa.edu

OBJECTIVES

Our objective was to determine the effect of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NNA) on free radical generation and myocardial contractility after ischemia-reperfusion.

BACKGROUND

Cardiotoxic free radicals are generated by ischemia-reperfusion sequences. Nitric oxide reacts with superoxide radical to form peroxynitrite, which generates additional free radicals. Our hypothesis was that by inhibiting NO production, free radical formation will be diminished, which should be cardioprotective.

METHODS

We studied 32 dogs. Coronary occlusion-reperfusion (20 min each) sequences were created by intracoronary balloon angioplasty inflation-deflation. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc^·–), a measure of total oxidative flux. The L-NNA (4.8 mg/kg total) was infused intravenously during occlusion-reperfusion; control dogs received saline. Immunohistochemical staining demonstrated the peroxynitration product nitrotyrosine.

RESULTS

In the control dogs Asc^·– rose from 3.2 ± SD 0.5 nmol/l to 4.8 ± 1.1 nmol/l with reperfusion, a 50% rise. With L-NNA the Asc^·– rose from 3.2 ± 0.9 nmol/l to 4.0 ± 1.2 nmol/l, a 25% rise (p < 0.01, L-NNA vs. control). Echocardiographic left ventricular fractional area shortening (FAS) in the control dogs declined from 38 ± 19% (baseline) to 26 ± 14% (ischemia), and to 22 ± 11% with reperfusion (p < 0.01 vs. baseline). With L-NNA, FAS declined from 36 ± 13% (baseline) to 27 ± 12% (ischemia) but then rose to 33 ± 14 with reperfusion (p = NS vs. baseline). Nitrotyrosine was present in the myocardium subjected to ischemia-reperfusion, but almost absent in dogs receiving L-NNA. Myocardial perfusion was not altered by L-NNA.

CONCLUSIONS

The NO synthase inhibitors decrease coronary sinus free radical concentration and ameliorate myocardial stunning after ischemia-reperfusion.

Abbreviations and Acronyms   Asc·– = ascorbate free radical   cGmp = cyclic guanosine monophosphate   EPR = electron paramagnetic resonance   HO· = hydroxyl radical   IV = intravenously   LAD = left anterior descending   L-NAME = NG-nitro-L-arginine methyl ester   L-NNA = NG-nitro-L-arginine   NAD = nicotinamide adenine dinucleotide   LOO·– = lipid peroxyl radicals   NO = nitric oxide [nitrogen monoxite]   NOS = nitric oxide synthase   O2·– = superoxide

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