A comparative study of the effects of two nitric oxide synthase inhibitors and two nitric oxide donors on temporary focal cerebral ischemia in the Wistar rat.

Abstract

A critical review of the literature indicates that the effects of nitric oxide synthase (NOS) inhibitors on focal cerebral ischemia are contradictory. In this experiment the authors methodically examined the dose-dependent effects of two NOS inhibitors and two NO donors on cortical infarction volume in an animal model of temporary focal cerebral ischemia simulating potential ischemia during neurovascular interventions. Ninety-two Wistar rats underwent 3 hours of combined left middle cerebral artery and bilateral common carotid artery occlusion after having been anesthetized with 1% halothane. A nonselective NOS inhibitor, N(G)-nitro-L-arginine-methyl-ester (L-NAME), and two NO donors, 3-morpholinosydnonimine hydrochloride and NOC-18, DETA/NO, (Z)-1-[2(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate, were administered intravenously 30 minutes before ischemia was induced. A selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), was administered intraperitoneally in dimethyl sulfoxide (DMSO) 60 minutes before ischemia was induced. Two ischemic control groups, to which either saline or DMSO was administered, were also included in this study. Seventy-two hours after flow restoration, the animals were perfused with tetrazolium chloride for histological evaluation. Cortical infarction volume was significantly reduced by 71% in the group treated with 1 mg/kg L-NAME when compared with the saline-treated ischemic control group (27.1+/-37 mm3 compared with 92.5+/-26 mm3, p < 0.05). The NOS inhibitor 7-NI significantly reduced cortical infarction volume by 70% and by 92% at doses of 10 and 100 mg/kg: 35.2+/-32 mm3 (p < 0.05) and 9+/-13 mm3 (p < 0.005), respectively, when compared with the DMSO-treated ischemic control group (119+/-43 mm3). There was no significant difference between the saline-treated and DMSO-treated ischemic control groups. Treatment with NO donors did not significantly alter cortical infarction volume. These results support an important role for NO in ischemic neurotoxicity and indicate that neuronal NOS inhibition may be valuable in reducing cortical injury in patients suffering temporary focal cerebral ischemia during neurovascular procedures.