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(Circulation. 2000;102:III-332.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Glutathione Reverses Endothelial Damage From Peroxynitrite, the Byproduct of Nitric Oxide Degradation, in Crystalloid Cardioplegia

Masanori Nakamura, MD, PhD; Vinod H. Thourani, MD; Russell S. Ronson, MD; Daniel A. Velez, MD; Xin-Liang Ma, MD, PhD; Sara Katzmark, BS; Jill Robinson, BS; L. Susan Schmarkey, BS; Zhi-Qing Zhao, MD, PhD; Ning-Ping Wang, MD; Robert A. Guyton, MD; Jakob Vinten-Johansen, PhD

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

Background—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.

Methods and Results—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 µmol/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 µmol/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 EC₅₀ 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/mm², 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 µg/mL, P<0.05).

Conclusions—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.

Key Words: cardioplegia • nitric oxide • endothelium

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