ARL-17477, A POTENT AND SELECTIVE NEURONAL NOS INHIBITOR DECREASES INFARCT VOLUME AFTER TRANSIENT MIDDLE CEREBRAL-ARTERY OCCLUSION IN RATS

We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage a nd 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. An imals were administered ARL 17477 (i.v.): 10 mg/kg; 3 mg/kg; 1 mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administ ration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic inf arct 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 acti vity by 86 +/- 14.9 and 91 +/- 8.9% at 10 min or 3 h, respectively, an d did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) s ignificantly reduced rCBF by 23 +/- 9.8% and NOS activity by 81 +/- 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg a nd 1 mg/kg ARL 17477 reduced rCBF by only 2.4 +/- 4.5 and 0%, respecti vely, 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 174 77 inhibits nNOS in the rat brain and causes a dose-dependent reductio n in infarct volume after transient MCA occlusion.