NEUROPROTECTIVE EFFICACY OF N-OMEGA-NITRO-L-ARGININE AFTER FOCAL CEREBRAL-ISCHEMIA IN THE MOUSE AND INHIBITION OF CORTICAL NITRIC-OXIDE SYNTHASE

The neuroprotective effects of various doses of N-omega-nitro-L-arginine have been correlated with the degree of N-omega-nitro-L-arginine-induced inhibition of cortical nitric oxide synthase activity measured ex vivo. Following focal cerebral ischemia induced by permanent occlusion of middle cerebral artery in the mouse, repeated administration of 1 mg/kg i.p. of N-omega-nitro-L-arginine (beginning 5 min after surgery) reproducibly decreased by 66-76% the infarct volume measured at 6 days post-occlusion. This dose of N-omega-nitro-L-arginine decreased cortical nitric oxide (NO) synthase activity by 70-73%. The neuroprotective efficacy of N-omega-nitro-L-arginine increased dose-dependently over the range of doses of 0.1-1 mg/kg. Within this dose range of N-omega-nitro-L-arginine, there was a good parallelism between the extent of inhibition of cortical NO synthase activity measured ex vivo and the degree of neuroprotection. However, higher doses of N-omega-nitro-L-arginine (3 and 10 mg/kg i.p.), which inhibited NO synthase activity more effectively (up to 94%) failed to significantly reduce the infarct size. Repeated administrations of increasing doses of L-arginine (up to 30 mg/kg i.p.) with a low dose of N-omega-nitro-L-arginine (1 mg/kg i.p.) caused a dose-dependent reduction in the neuroprotective efficacy of N-omega-nitro-L-arginine while the extent of NO synthase inhibition measured ex vivo did not decrease significantly. These results demonstrate that, after a focal cerebral ischemia in the mouse, low doses of N-omega-nitro-L-arginine are neuroprotective while high doses are ineffective and suggest that a partial inhibition of NO synthase is sufficient to obtain an optimal neuroprotective effect.