Nakamura M, Thourani V H, Ronson R S, Velez D A, Ma X L, Katzmark S, Robinson J, Schmarkey L S, Zhao Z Q, Wang N P, Guyton R A, Vinten-Johansen J
Emory University School of Medicine, Atlanta, GA, USA.
Circulation. 2000 Nov 7;102(19 Suppl 3):III332-8. doi: 10.1161/01.cir.102.suppl_3.iii-332.
NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO(-)). ONOO(-) in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO(-) may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO(-) and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia.
In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 micromol/L authentic ONOO(-); catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO(-). In 1 group (CP+GSH, n=5), the cardioplegia contained 500 micromol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, n=6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0+/-2.4 versus CP+GSH 10.6+/-1.3 mm Hg/mL) or diastolic chamber stiffness (ss-coefficient: CCP 0.35+/-0.2 versus CP+GSH 0.31+/-0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CP+GSH versus CCP (2.2+/-0.7 versus 5.4+/-1.2, P:<0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CP+GSH than in CCP (118+/-6% versus 92+/-5%, P:<0.05), with a smaller EC(50) value (-7. 10+/-0.05 versus -6.98+/-0.03, respectively, P:<0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CP+GSH than in CCP (98+/-18 versus 234+/-36 neutrophils/mm(2), P:<0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO(-) and GSH, was greater in CP+GSH than in CCP (4.1+/-2.3 versus 0.4+/-0.2 microg/mL, P:<0.05).
GSH in crystalloid cardioplegia detoxifies ONOO(-) and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage.
一氧化氮（NO）已被提倡作为心脏停搏液的添加剂。然而，NO与超氧阴离子发生快速双自由基反应生成过氧亚硝酸盐（ONOO⁻）。晶体心脏停搏液中的ONOO⁻在心脏停搏和再灌注后会导致冠状动脉内皮损伤和收缩功能受损。然而，在与其众所周知的抗氧化作用无关的反应中，ONOO⁻可能会被谷胱甘肽（GSH）降解为致死性较低或具有心脏保护作用的中间产物。我们假设，当GSH存在于晶体心脏停搏液中时，它能使ONOO⁻解毒，并逆转内皮功能和收缩功能的缺陷。
在体外循环下的麻醉犬中，进行45分钟的全身常温缺血，随后进行60分钟的间歇性冷晶体心脏停搏（Plasmalyte）和2小时的再灌注。心脏停搏液含有5 μmol/L的纯ONOO⁻；加入过氧化氢酶以减弱GSH的潜在抗氧化作用，并揭示其对ONOO⁻的影响。在一组（CP+GSH，n=5）中，心脏停搏液含有500 μmol/L的GSH，而另一组接受不含GSH的晶体心脏停搏液（CCP，n=6）。心脏停搏后左心室收缩功能（收缩末期压力-容积关系，阻抗导管：CCP为10.0±2.4，而CP+GSH为10.6±1.3 mmHg/mL）或舒张期心室僵硬度（ss系数：CCP为0.35±0.2，而CP+GSH为0.31±0.18）两组间无差异。与CCP相比，CP+GSH组心肌中性粒细胞聚集（髓过氧化物酶活性）减弱（2.2±0.7对5.4±1.2，P<0.05）。在实验后的冠状动脉中，CP+GSH组的最大内皮依赖性舒张大于CCP组（118±6%对92±5%，P<0.05），EC50值较小（分别为-7.10±0.05对-6.98±0.03，P<0.05）。两组平滑肌舒张均完全。作为内皮功能指标，CP+GSH组实验后冠状动脉中中性粒细胞的黏附少于CCP组（98±18对234±36个中性粒细胞/mm²，P<0.05）。ONOO⁻与GSH反应的副产物亚硝基谷胱甘肽在CP+GSH组中比CCP组中更高（4.1±2.3对0.4±0.2 μg/mL，P<0.05）。
晶体心脏停搏液中的GSH使ONOO⁻解毒并形成具有心脏保护作用的亚硝基谷胱甘肽，通过抑制中性粒细胞介导的损伤，导致中性粒细胞黏附减弱和选择性内皮保护。
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