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(Circulation. 2002;105:3032.)
© 2002 American Heart Association, Inc.

Basic Science Reports

S-Nitroso Human Serum Albumin Treatment Reduces Ischemia/Reperfusion Injury in Skeletal Muscle via Nitric Oxide Release

Seth Hallström, PhD; Harald Gasser, MD; Christoph Neumayer, MD; Alexander Fügl, MD; Joseph Nanobashvili, MD; Andrzej Jakubowski, MD, PhD; Ihor Huk, MD; Günther Schlag, MD; Tadeusz Malinski, PhD

From the Department of Chemistry and Biochemistry, Ohio University, Athens (S.H., A.J., T.M.); and the Ludwig Boltzmann-Institute for Experimental and Clinical Traumatology, Vienna (H.G., G.S.), and the Department of Vascular Surgery, University of Vienna (C.N., A.F., J.N., I.H.), Vienna, Austria.

Correspondence to Tadeusz Malinski, PhD, Department of Chemistry and Biochemistry, 350 W State St, Ohio University, Athens, OH 45701-2970. E-mail malinski{at}ohio.edu

Background— Peroxynitrite generated from nitric oxide (NO) and superoxide (O₂^-) contributes to ischemia/reperfusion (I/R) injury. Feedback inhibition of endothelial NO synthase by NO may inhibit O₂^- production generated also by endothelial NO synthase at diminished local L-arginine concentrations accompanying I/R.

Methods and Results— During hindlimb I/R (2.5 hours/2 hours), in vivo NO was monitored continuously (porphyrinic sensor), and high-energy phosphates, reduced and oxidized glutathione (chromatography), and I/R injury were measured intermittently. Rabbits receiving human serum albumin (HSA) (controls) were compared with those receiving S-nitroso human serum albumin (S-NO-HSA) beginning 30 minutes before reperfusion for 1 hour or 30 minutes before ischemia for 3.5 hours (0.1 µmol · kg^-1 · h^{- 1}). The onset of ischemia led to a rapid increase of NO from its basal level (50±12 nmol/L) to 120±20 and 220±15 nmol/L in the control and S-NO-HSA–treated groups, respectively. In control animals, NO dropped below basal levels at the end of ischemia and to undetectable levels (<1 nmol/L) during reperfusion. In S-NO-HSA–treated animals, maximal NO levels never decreased below basal concentration and on reperfusion were 100±15 nmol/L (S-NO-HSA preischemia group, 175±15 nmol/L). NO supplementation by S-NO-HSA led to partial and in the preischemia group to total preservation of high-energy phosphates and glutathione status in reperfused muscle (eg, preischemia groups: ATP, 30.23±5.02 µmol/g versus control, 15.75±4.33 µmol/g, P<0.0005; % oxidized glutathione, 4.49± 1.87% versus control, 22.84±6.39%, P<0.0001). S-NO-HSA treatment in all groups led to protection from vasoconstriction and reduced edema formation after reperfusion (eg, preischemia groups: interfiber area, 12.94±1.36% versus control, 27.83±1.95%, P< 0.00001).

Conclusions— Long-lasting release of NO by S-NO-HSA provides significant protection of skeletal muscle from I/R injury.

Key Words: ischemia • reperfusion • nitric oxide • free radicals

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