title: ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats.
abstract: We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage and regional cerebral blood flow (rCBF), in rats subjected to transient (2 h) middle cerebral artery (MCA) occlusion and 166 h of reperfusion (n = 48) and in rats without MCA occlusion (n = 25), respectively. Animals were administered ARL 17477 (i.v.): 10 mg/kg; 1 mg/kg; 3mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic infarct volume by 53 (p < 0.05), 23, and 6.5%, respectively. L-NA 1 mg/kg and 10 mg/kg increased infarct volume by 2 and 15%, respectively (p > 0.05). Administration of ARL 17477 (10 mg/kg) significantly (p < 0.05) decreased rCBF by 27 +/- 5.3 and 24 +/- 14.08% and cortical NOS activity by 86 +/- 14.9 and 91 +/- 8.9% at 10 min or 3 h, respectively, and did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) significantly reduced rCBF by 23 +/- 9.8% and NOS activity by 81 +/- 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg and 1 mg/kg ARL 17477 reduced rCBF by only 2.4 +/- 4.5 and 0%, respectively, even when NOS activity was reduced by 63 +/- 13.4 and 45 +/- 15.7% at 3 h, respectively, (p < 0.05). The data demonstrate that ARL 17477 inhibits nNOS in the rat brain and causes a dose-dependent reduction in infarct volume after transient MCA occlusion.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Reif
authors.forename: J
authors.initials: J
authors.lastname: Macdonald
authors.forename: W X
authors.initials: WX
authors.lastname: Tang
authors.forename: D K
authors.initials: DK
authors.lastname: Kamp
authors.forename: R J
authors.initials: RJ
authors.lastname: Gentile
authors.forename: W C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: R J
authors.initials: RJ
authors.lastname: Murray
authors.forename: M
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology* / Q000503:physiopathology; D001794:Blood Pressure; D002536:Cerebral Arteries; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion
chemical_list: C102136:ARL 17477; D000578:Amidines; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase