The Effect of Nitric Oxide Synthase Inhibition on Infarct Volume After Reversible Focal Cerebral Ischemia in Conscious Rats

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Abstract

Background and Purpose

Previous in vitro and in vivo studies of the effects of nitric oxide synthase inhibition in the central nervous system have yielded conflicting results concerning the role of nitric oxide in the events that lead to ischemic injury. In this study, we tested the hypothesis that preischemic inhibition of nitric oxide synthase increases infarct volume after reversible focal cerebral ischemia in rats.

Methods

NG-nitro-L-arginine methyl ester hydrochloride 15 mg/kg IV or an equivalent volume of saline was administered to adult Wistar rats 15 minutes before middle cerebral artery occlusion by the intraluminal suture method. After 2 hours of ischemia, the suture was withdrawn, and rats were allowed to survive for 3 days. Areas of infarction in 10 hematoxylin-eosin-stained sections were measured and used to determine infarct volume.

Results

Administration of NG-nitro-L-arginine methyl ester hydrochloride increased hemispheric infarct volume by 137% over control (60.9±30.5 to 144.3±19.6 mm3, P<.05; mean±SEM). Cortical and subcortical infarct volumes were increased by 176% (33.8±21.9 to 93.3±15.2 mm3, P<.05) and 103% (25.1±9.4 to 51.0±5.5 mm3, P<.03), respectively.

Conclusions

Nitric oxide synthase inhibition increases infarct volume and decreases the variability of the response to middle cerebral artery occlusion in Wistar rats, a strain that is normally resistant to focal cerebral ischemic injury owing to extensive collateralization. The mechanism of the deleterious effect of nitric oxide synthase inhibition likely involves a more severe degree of blood flow reduction during and after middle cerebral artery occlusion, primarily by preventing the vasodilatory response of collateral vessels to proximal middle cerebral artery occlusion. Maintenance of nitric oxide synthase activity during and after focal cerebral ischemia appears to minimize ischemic injury.

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