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 mediato r in the deleterious effects of nitric oxide (NO) in crystalloid solutions, possibly due to a lack of detoxification mechanisms, leading to the format ion of . OH. In contrast, ONOO- may exert cardioprotective effects in blood environments secondary to detoxification and the subsequent formation of N O-donating nitrosothiols. This dichotomy in physiological effects of ONOO- may exist between crystalloid and blood cardioplegia (BCP) environments. in the pl present study, we tested the hypothesis that ONOO- is cardiotoxic i n crystalloid cardioplegia hut cardioprotective in BCP in ischemically inju red hearts. Methods and Results - In anesthetized dogs on cardiopulmonary bypass, globa l 37 degrees C ischemia was imposed for 30 minutes, followed by 60 minutes of intermittent 4 degrees C hyperkalemic crystalloid (Plegisol) or BCP with (+) or without (-) 5 mu mol/L authentic ONOO-. After 2 hours of reperfusio n, left ventricular (LV) function tend-systolic pressure-volume relations, in percent of baseline) was 56 +/- 3% in Plegisol-, which was further reduc ed 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 significantl y 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 ki nase activity was significantly increased in Plegisol+ (48 +/- 6) compared with that in Plegisol- (31 +/- 6) but was unchanged in BCP- (14 +/- 2) rela tive to BCP+ (18 +/- 1). Nitrotyrosine (ng/mg protein) accumulation in LV m yocardial biopsy samples confirmed myocardial exposure to ONOO- or its meta bolites (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 effec ts of ONOO- depend on its environment and (2) ONOO- in crystalloid solution impairs postcardioplegia systolic and diastolic functional recovery, where as (3) ONOO- in BCP increases functional recovery. This environment-depende nt dichotomy in the effect of ONOO- may affect the benefits of NO-related a djuncts to crystalloid or BCP solutions (*P < 0.05 versus group without ONO O-).