Abstract P34: Nitrite Therapy upon Resuscitation from Cardiac Arrest Reversibly Inhibits Mitochondrial Complex I Reducing ROS Burst and Improving Cardiac Function and Survival
Nitrite reversibly S-nitrosates mitochondrial electron transport chain complex I (cxI) resulting in transient inhibition and reduction of pathological ROS burst after ischemia. We hypothesized that nitrite therapy at CPR initiation could thus improve cardiac contractility and mortality. Anesthetized C57BL/6 mice underwent hyperkalemic cardiac arrest maintained for 12min at 36.5C prior to randomly receiving blinded IV nitrite or saline placebo, epinephrine, chest compressions and ventilation for up to 150 sec. ROSC was obtained in excess of 90% in both groups. Hearts were excised just prior to asystole, 5 or 60 minutes after the initiation of CPR and mitochondria isolated. Respiration was assessed by oxygen consumption after providing the cxI substrate pyruvate or the complex II (cxII) substrate succinate. CxI activity was directly assayed by NADH oxidation, peroxide generation measured by Amplex Red peroxidation and ATP production quantified by luciferin luminescence. Nitrite therapy was associated with improved hemodynamics and significantly improved LVEF and RVEF (Table 1⇓) and better 22h survival (HR 2.72 [95% CI:1.1– 6.7]). Nitrite significantly reduced cxI mediated respiration 5 min post-CPR with loss of inhibition by 60min based on respiration and ATP production (Table II⇓). Respiration efficiency (respiratory control ratio) did not change, nor was there significant cxII inhibition. Early cxI inhibition was associated with significantly less ROS. Nitrite therapy transiently and reversibly inhibits cxI reducing reperfusion ROS-mediated injury and resulting in less myocardial dysfunction and death after cardiac arrest.