The nitric oxide synthase inhibitor NG-nitro-L-arginine decreases defibrillation-induced free radical generation

Objectives: To demonstrate that nitric oxide (NO) contributes to free radical generation after epicardial shocks and to determine the effect of a nitric oxide synthase (NOS) inhibitor, N-G-nitro-L-arginine (L-NNA), on free radical generation. Background: Free radicals are generated by direct current shocks for defibrillation. NO reacts with the superoxide (O-2(.-)) radical to form peroxynitrite (0=NOO-), which is toxic and initiates additional free radical generation. The contribution of NO to free radical generation after defibrillation is not fully defined. Methods and results: Fourteen open chest dogs were studied. In the initial eight dogs, 40 J damped sinusoidal monophasic epicardial shocks was administered. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc(.-)), a measure of free radical generation (total oxidative flux). Epicardial shocks were repeated after L-NNA, 5 mg/kg IV. In six additional dogs, immunohistochemical staining was done to identify nitrotyrosine, a marker of reactive nitrogen species-mediated injury, in post-shock myocardial tissue. Three of these dogs received L-NNA pre-shock. After the initial 40 J shock, Asc(.-) rose 39+/-2.5% from baseline. After L-NNA infusion, a similar 40 J shock caused Asc(.-) to increase only 2+/-3% from baseline (P < 0.05, post-L-NNA shock versus initial shock). Nitrotyrosine staining was more prominent in control animals than dogs receiving L-NNA, suggesting prevention of O=NOO- formation. Conclusions: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of 0=NOO-. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.