CEREBROPROTECTIVE EFFECT OF THE NITRIC-OXIDE SYNTHASE INHIBITORS, 1-(2-TRIFLUOROMETHYLPHENYL) IMIDAZOLE AND 7-NITRO INDAZOLE, AFTER TRANSIENT FOCAL CEREBRAL-ISCHEMIA IN THE RAT

The novel neuronal nitric oxide synthase inhibitors, 1-(2-trifluoromet hylphenyl)imidazole (TRIM) and 7-nitro indazole (7-NI), were used to i nvestigate the role of nitric oxide in a model of transient focal cere bral ischemia in vivo. In halothane-anesthetized rats, the middle cere bral artery (MCA) was occluded for 2 hours using an intravascular thre ad and then reperfused for 22 hours before histologic evaluation. TRIM (10, 20, or 50 mg/kg), 7-NI (60 mg/kg), TRIM (50 mg/kg) plus L-argini ne (300 mg/kg), or L-arginine (300 mg/kg) alone was administered intra peritoneally, either at 5 or 90 minutes after MCA occlusion. Immediate administration (5 minutes after MCA occlusion) of TRIM produced a dos e-related reduction in lesion size, which was reversed with L-arginine coadministration. Similarly, delayed administration of TRIM (90 minut es after MCA occlusion, 50 mg/kg) decreased total lesion volume by 48. 3% +/- 13.0% in comparison to a reduction of 39.3% +/- 10.9% when TRIM (50 mg/kg) was administered immediately (5 minutes) after occlusion. 7-NI (60 mg/kg) reduced the total lesion volume by 38.5% +/- 13.7% whe n administered immediately (5 minutes) after MCA occlusion, but had no effect when administration was delayed (90 minutes). Neither TRIM (50 mg/kg) nor 7-NI (60 mg/kg), administered 5 minutes after MCA occlusio n, had any significant effect on mean arterial blood pressure througho ut the ischemic period or for up to 10 minutes after reperfusion. Thes e results indicate that immediate or delayed administration of the sel ective neuronal NOS inhibitor TRIM reduces the lesion volume after tra nsient MCA occlusion. In contrast, only immediate administration of 7- NI reduces lesion volume.