The nitric oxide synthase inhibitor N G-nitro- l-arginine decreases defibrillation-induced free radical generation

Abstract

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 (O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 ONOO −.