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

OBJECTIVES Our objective was to determine the effect of a nitric oxide synt hase 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 peroxynitrit e, which generates additional free radicals. Our hypothesis was that by inh ibiting NO production, free radical formation will be diminished, which sho uld be cardioprotective. METHODS Wye studied 32 dogs. Coronary occlusion-reperfusion (20 min each) s equences were created by intracoronary balloon angioplasty inflation-deflat ion. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc), a measure of total oxidativ e flux. The L-NNA (4.8 mg/kg total) was infused intravenously during occlus ion-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 fr om 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). Wit h L-NNA, FAS declined from 36 +/- 13% (baseline) to 27 +/- 12% (ischemia) b ut then rose to 33 +/- 14 with reperfusion (p = NS vs. baseline). Nitrotyro sine was present in the myocardium subjected to ischemia-reperfusion, but a lmost 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-reperfusio n. (J Am Coll Cardiol 2001;38:546-54) 2001 by the American College of Cardi ology.