Peroxynitrite, the breakdown product of nitric oxide, is beneficial in blood cardioplegia but injurious in crystalloid cardioplegia

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^-).