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.(ABSTRACT TRUNCATED AT 250 WORDS)
Carreau
A
A
Preclinical Research Department, Bagneux, France.
Duval
D
D
Poignet
H
H
Scatton
B
B
Vigé
X
X
Nowicki
J P
JP
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000150:complications / Q000201:enzymology*; D002540:Cerebral Cortex / Q000201:enzymology; D002544:Cerebral Infarction / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase; D019335:Nitroarginine
D019335:Nitroarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases