The nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) increases free radical generation and degrades left ventricular function after myocardial ischemia-reperfusion

[摘要] Background: During reperfusion of ischemic myocardium nitric oxide (NO) reacts with superoxide radicals to form cardiotoxic peroxynitrite, which causes lipid peroxidation. Our hypothesis was that infusion of a NO donor S-nitroso-N-acetylpenicillamine (SNAP) during ischemia-reperfusion would exacerbate the oxidative damage to the myocardium by increased formation of nitrogen radicals. Methods and results: In 19 open-chest dogs, left anterior descending (LAD) coronary occlusion (15 min)reperfusion (15 min) sequences were created. Using electron paramagnetic resonance (EPR), we monitored the coronary sinus concentration of ascorbate free radical (Asc*(-)), a measure of free radical generation (total oxidative flux). Seven control dogs (Group 1) received intravenous saline infusion during occlusion-reperfusion, while 12 dogs received SNAP infusion (Group 2: 2.5 mug/min per kg SNAP, and Group 3: 5 mug/min per kg SNAP). Left ventricular fractional area shortening was determined by echocardiography. Dogs in Group 3 receiving a high dose of SNAP (5 mug/min per kg) demonstrated a higher Asc*(-)concentration increase than the control group. Percent fractional area shortening in Group I declined from 77 +/-4.0 (baseline) to 54+/-9.0% during ischemia (P < 0.05), and then fully recovered to 74 +/- 3.7% with reperfusion. In the SNAP-treated dogs, the percent fractional area shortening during reperfusion was significantly lower than baseline in Group 2 (55 +/- 3.9 vs. baseline 74 +/- 4.4%, P < 0.05) and in Group 3 (49 +/- 5.0 vs. baseline 71 +/- 4.5%, P < 0.01). In five additional dogs, nitrotyrosine imnumohistochemistry showed heavy staining of the ischemic-reperfused myocardium. Conclusions: The NO donor SNAP increased free radical concentration and exacerbated myocardial oxidative damage after ischemia-reperfusion. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

[发布日期] 2003-12-01

[关键词] nitric oxide;ischemia;reperfusion;free radicals;ascorbate;stunning;S-nitroso-N-acetylpenicillamine