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

M. Nakamura, V. H. Thourani, R. S. Ronson, D. A. Velez, X.-L. Ma, S. Katzmark, J. Robinson, L. S. Schmarkey, Z.-Q. Zhao, N.-P. Wang, R. A. Guyton, J. Vinten-Johansen
2000 Circulation  
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 Ϫ ). ONOO Ϫ in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO Ϫ may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We
more » ... ant effects. We hypothesized that GSH detoxifies ONOO Ϫ 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 mol/L authentic ONOO Ϫ ; catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO Ϫ . In 1 group (CPϩGSH, nϭ5), the cardioplegia contained 500 mol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, nϭ6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0Ϯ2.4 versus CPϩGSH 10.6Ϯ1.3 mm Hg/mL) or diastolic chamber stiffness (␤coefficient: CCP 0.35Ϯ0.2 versus CPϩGSH 0.31Ϯ0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CPϩGSH versus CCP (2.2Ϯ0.7 versus 5.4Ϯ1.2, PϽ0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CPϩGSH than in CCP (118Ϯ6% versus 92Ϯ5%, PϽ0.05), with a smaller EC 50 value (Ϫ7.10Ϯ0.05 versus Ϫ6.98Ϯ0.03, respectively, PϽ0.05). 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 CPϩGSH than in CCP (98Ϯ18 versus 234Ϯ36 neutrophils/mm 2 , PϽ0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO Ϫ and GSH, was greater in CPϩGSH than in CCP (4.1Ϯ2.3 versus 0.4Ϯ0.2 g/mL, PϽ0.05). Conclusions-GSH in crystalloid cardioplegia detoxifies ONOO Ϫ and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage. (Circulation. 2000;102[suppl III]:III-332-III-338.)
doi:10.1161/01.cir.102.suppl_3.iii-332 fatcat:ufnwzhle5fhs3dkhounbulxpeq