Ronson R S, Thourani V H, Ma X L, Katzmark S L, Han D, Zhao Z Q, Nakamura M, Guyton R A, Vinten-Johansen J
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 30365-2225, USA.
Circulation. 1999 Nov 9;100(19 Suppl):II384-91. doi: 10.1161/01.cir.100.suppl_2.ii-384.
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.
In anesthetized dogs on cardiopulmonary bypass, global 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 micromol/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*).
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.)
过氧亚硝酸盐（ONOO⁻）被认为是一氧化氮（NO）在晶体溶液中产生有害作用的主要介质，这可能是由于缺乏解毒机制，导致·OH的形成。相比之下，ONOO⁻在血液环境中可能通过解毒以及随后形成释放NO的亚硝基硫醇而发挥心脏保护作用。ONOO⁻生理效应的这种二分法可能存在于晶体停搏液和血液停搏液（BCP）环境之间。在本研究中，我们检验了以下假设：在缺血性损伤的心脏中，ONOO⁻在晶体停搏液中具有心脏毒性，但在BCP中具有心脏保护作用。
在体外循环的麻醉犬中，进行30分钟的37℃全心缺血，随后进行60分钟的间歇性4℃高钾晶体液（Plegisol）或BCP灌注，其中添加（+）或不添加（-）5μmol/L的纯ONOO⁻。再灌注2小时后，Plegisol组的左心室（LV）功能（收缩末期压力-容积关系，以基线的百分比表示）为56±3%，而Plegisol+组进一步降至40±4%。相比之下，BCP+组的缺血后收缩功能优于BCP-组（分别为96±2%和82±2%）。功能恢复的差异不能归因于血流动力学的差异。在Plegisol组（298±26%对466±30%）和BCP组（201±22%对267±13%）中，添加ONOO⁻后LV舒张末期僵硬度均显著增加。与LV腔僵硬度增加一致，BCP+组的心肌水肿比BCP-组增加（78.9±0.3%对76.4±0.3%），Plegisol+组比Plegisol-组增加（81.1±0.3%对79.6±0.4%）。与Plegisol-组（31±6）相比，Plegisol+组的肌酸激酶活性显著增加（48±6），但相对于BCP+组（18±1），BCP-组（14±2）的肌酸激酶活性没有变化。LV心肌活检样本中的硝基酪氨酸（ng/mg蛋白）积累证实心肌暴露于ONOO⁻或其代谢产物（Plegisol-组1.2±0.1，Plegisol+组3.31±0.3*，BCP-组1.4±0.2，BCP+组2.9±0.2*）。
我们得出以下结论：（1）ONOO⁻的心脏停搏后心脏动力学效应取决于其所处环境；（2）晶体溶液中的ONOO⁻会损害心脏停搏后的收缩和舒张功能恢复；（3）BCP中的ONOO⁻可增加功能恢复。ONOO⁻效应的这种环境依赖性二分法可能会影响与晶体液或BCP溶液相关的NO辅助剂的益处（*与不添加ONOO⁻的组相比，P<0.05。:II-384-II-391。）
