EFFECT OF MILD HYPOTHERMIA ON NITRIC-OXIDE SYNTHESIS DURING FOCAL CEREBRAL-ISCHEMIA

THE CEREBROPROTECTIVE EFFECTS of mild hypothermia have been extensivel y studied in various animal models of ischemia, but the mechanism by w hich mild hypothermia diminishes ischemic injury is not well understoo d. Nitric oxide (NO) has been implicated as a mediator of glutamate ex citotoxicity in primary neuronal cultures, and its synthesis is acutel y increased during focal ischemia in vivo. To evaluate possible mechan isms of hypothermic neuroprotection, we measured markers of NO synthes is-nitrite and cyclic guanosine monophosphate (cGMP) levels and NO syn thase activity-during right middle cerebral artery occlusion (MCAO) in the rat under normothermic (36.5 degrees C) and mild hypothermic (33 degrees C) conditions. There was a significant increase in nitrite con centration in the right hemisphere versus the left under normothermic conditions at 10 and 20 minutes after MCAO (P < 0.01), with a return t o baseline levels by 60 minutes. The increase in cortical nitrite leve ls in the right hemisphere versus the left was not observed with mild hypothermia. There was a threefold increase in cGMP synthesis in the n ormothermic right cortex 10 minutes after MCAO (P < 0.05). This rise i n cGMP did not occur in hypothermic animals, and the right to left cor tical disparity in cGMP production was abolished. Finally, the signifi cant increase in NO synthase activity seen in the normothermic ischemi c cortex was absent in hypothermic rats (P < 0.05). These results sugg est that mild hypothermia (33 degrees C) modulates the burst of nitric oxide synthesis during cerebral ischemia and may account, at least pa rtially, for its cerebroprotective effects.