NITRIC-OXIDE PRODUCTION DURING FOCAL CEREBRAL-ISCHEMIA IN RATS

Background and Purpose: Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures. Methods: A number of indicators of brain nitric oxide production (nitrite and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats. Results: Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P<.05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P<.05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P<.05). Pretreatment of rats with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP. Conclusions: These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase.