We investigated the putative role of nitric oxide in the expression of neuronal injury following both transient severe forebrain ischemia (CA1 neuronal injury) and transient or permanent middle cerebral artery occlusion (neocortical pannecrosis). Using the four-vessel occlusion model and increasing doses of N-omega-nitro-L-arginine, 2-40 mg/kg, we were unable to demonstrate any reduction in the percentage of CA1 cells injured following 10 min of transient severe forebrain ischemia followed by seven days of reperfusion. Higher doses proved toxic insofar as they increased the mortality following the ischemic insult. Saline-treated animals (n = 8) had 77 +/- 10% CA1 injury while those treated with 2 mg/kg of nitro-arginine i.v. had 80 +/- 7% (n = 7), and those with 10 mg/kg i.v. had 78 +/- 11% (n = 8). Two of five rats given 20 mg/kg i.v., three of eight given 40 mg/kg i.v., and two of six given 10 mg/kg i.v. followed by 3 x 10 mg/kg i.p., died. Of those treated with high-dose nitro-arginine and which survived ischemia and seven days' reperfusion, no significant reduction in CA1 injury was detected. Wistar rats and spontaneously hypertensive rats treated with either saline or nitro-arginine i.v. were exposed to 2 h of transient middle cerebral artery occlusion followed by 22 h of reperfusion. There were seven animals in each group. Wistars treated with saline had 198 +/- 67 mm3 (mean +/- S.D.) of neocortical infarction, and those treated with 10 m/kg of nitro-arginine i.v. had 199 +/- 93 mm3. Spontaneously hypertensive rats, transiently ischemic, treated with saline had 164 +/- 25 mm3 of infarct volume, while those treated with 2 mg/kg i.v. had 151 +/- 53 mm3, and those treated with 10 mg/kg i.v. had 145 +/- 29 mm3. Animals treated with 40 mg/kg i.v. had a nonsignificantly larger mean infarct volume (191 +/- 81 mm3). High dose nitro-arginine caused an increase in hypertension in the spontaneously hypertensive rats and increased the severity of focal ischemia as measured by intra-ischemic regional cerebral blood flows. A final group of seven spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion and repeated dosing with N-omega-nitro-L-arginine i.p. In these animals an infarct volume of 234 +/- 60 mm3 was observed, which was again not statistically different from saline-treated controls (208 +/- 43 mm3, n = 7).(ABSTRACT TRUNCATED AT 400 WORDS)