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(Circulation. 1999;100:II-384.)
© 1999 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

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

Russell S. Ronson, MD; Vinod H. Thourani, MD; Xin-Liang Ma, MD, PhD; Sara L. Katzmark, BS; David Han, MD; Zhi-Qing Zhao, PhD; Masanori Nakamura, MD; Robert A. Guyton, MD; Jakob Vinten-Johansen, PhD

From the Cardiothoracic Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Carlyle Fraser Heart Center of Crawford Long Hospital and Emory University, Atlanta, Ga.

Correspondence to Jakob Vinten-Johansen, PhD, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, 550 Peachtree St NE, Atlanta, GA 30365-2225. E-mail jvinten{at}emory.edu

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.)

Key Words: peroxynitrite • cardioplegia • cardiopulmonary bypass • nitric oxide • superoxide