(Stroke. 2000;31:1974.)
© 2000 American Heart Association, Inc.
Original Contributions |
Role of Endothelial Nitric Oxide Generation and Peroxynitrite Formation in Reperfusion Injury After Focal Cerebral Ischemia
, MDFrom the Department of Neurology, Faculty of Medicine, and Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Correspondence to Turgay Dalkara, Department of Neurology, Hacettepe University Hospitals, Ankara, 06100, Turkey. E-mail dalkara{at}tr-net.net.tr
Background and Purpose—Reperfusion injury is one of the factors that unfavorably affects stroke outcome and shortens the window of opportunity for thrombolysis. Surges of nitric oxide (NO) and superoxide generation on reperfusion have been demonstrated. Concomitant generation of these radicals can lead to formation of the strong oxidant peroxynitrite during reperfusion.
Methods—We have examined the role of NO generation and peroxynitrite formation on reperfusion injury in a mouse model of middle cerebral artery occlusion (2 hours) and reperfusion (22 hours). The infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride staining; blood-brain barrier permeability was evaluated by Evans blue extravasation. Nitrotyrosine formation and matrix metalloproteinase-9 expression were detected by immunohistochemistry.
Results—Infarct volume was significantly decreased (47%) in
animals treated with the nonselective nitric oxide synthase (NOS)
inhibitor N
-nitro-L-arginine
(L-NA) at reperfusion. The specific inhibitor of neuronal
NOS, 7-nitroindazole (7-NI), given at reperfusion, showed no
protection, although preischemic treatment with 7-NI
decreased infarct volume by 40%. Interestingly, prereperfusion
administration of both NOS inhibitors decreased tyrosine
nitration (a marker of peroxynitrite toxicity) in the ischemic
area. L-NA treatment also significantly reduced vascular damage, as
indicated by decreased Evans blue extravasation and matrix
metalloproteinase-9 expression.
Conclusions—These data support the hypothesis that in addition to the detrimental action of NO formed by neuronal NOS during ischemia, NO generation at reperfusion plays a significant role in reperfusion injury, possibly through peroxynitrite formation. Contrary to L-NA, failure of 7-NI to protect against reperfusion injury suggests that the source of NO is the cerebrovascular compartment.
Editorial Comment
Department of Anesthesiology University of Alabama at Birmingham
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