Peroxynitrite, the Breakdown Product of Nitric Oxide, Is Beneficial in Blood Cardioplegia but Injurious in Crystalloid Cardioplegia

Abstract

Background —Peroxynitrite (ONOO − ) has been implicated as a primary mediator in the deleterious effects of nitric oxide (NO) in crystalloid solutions, possibly due to a lack of detoxification mechanisms, leading to the formation of ·OH. In contrast, ONOO − may exert cardioprotective effects in blood environments secondary to detoxification and the subsequent formation of NO-donating nitrosothiols. This dichotomy in physiological effects of ONOO − may exist between crystalloid and blood cardioplegia (BCP) environments. In the present study, we tested the hypothesis that ONOO − is cardiotoxic in crystalloid cardioplegia but cardioprotective in BCP in ischemically injured hearts. Methods and Results —In anesthetized dogs on cardiopulmonary bypass, global 37°C ischemia was imposed for 30 minutes, followed by 60 minutes of intermittent 4°C hyperkalemic crystalloid (Plegisol) or BCP with (+) or without (−) 5 μmol/L authentic ONOO − . After 2 hours of reperfusion, left ventricular (LV) function (end-systolic pressure-volume relations, in percent of baseline) was 56±3% in Plegisol−, which was further reduced in Plegisol+ to 40±4%.* In contrast, postischemic systolic function was better in BCP+ groups than in BCP− groups (96±2%* versus 82±2%, respectively). Differences in functional recovery could not be attributed to differences in hemodynamics. LV end-diastolic stiffness was significantly increased with the addition of ONOO − in both Plegisol (298±26% versus 466±30%*) and BCP (201±22% versus 267±13%*) groups. Consistent with increased LV chamber stiffness, myocardial edema was increased in BCP+ compared with BCP− (78.9±0.3% versus 76.4±0.3%*) and in Plegisol+ compared with Plegisol− (81.1±0.3% versus 79.6±0.4%*). Creatine kinase activity was significantly increased in Plegisol+ (48±6) compared with that in Plegisol− (31±6) but was unchanged in BCP− (14±2) relative to BCP+ (18±1). Nitrotyrosine (ng/mg protein) accumulation in LV myocardial biopsy samples confirmed myocardial exposure to ONOO − or its metabolites (Plegisol− 1.2±0.1, Plegisol+ 3.31±0.3*, BCP− 1.4±0.2, BCP+ 2.9±0.2*). Conclusions —We conclude that (1) the postcardioplegic cardiodynamic effects of ONOO − depend on its environment and (2) ONOO − in crystalloid solution impairs postcardioplegia systolic and diastolic functional recovery, whereas (3) ONOO − in BCP increases functional recovery. This environment-dependent dichotomy in the effect of ONOO − may affect the benefits of NO-related adjuncts to crystalloid or BCP solutions (* P <0.05 versus group without ONOO − ). :II-384–II-391.)