Effect of AR-R 17477, a potent neuronal nitric oxide synthase inhibitor, on infarction volume resulting from permanent focal ischemia in rats

Objective: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia. Design: Randomized within cohort; nonblinded study. Setting: University basic science laboratory. Subjects: Halothane-anesihetized male Wistar rats (n = 53). Interventions: Rats were treated with either intravenous saline (diluent) o r AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of pe rmanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia. Measurements and Main Results: Pretreatment with 1 mg/kg AR-R 17477 was ass ociated with a decreased infarct volume (2,3,5-triphenyltetrazolium chlorid e staining) in the striatum (saline, 81 +/- 7 mm(3); AR-R 17477, 55 +/- 3 m m(3)) but not in the cortex at 18 hrs of occlusion (saline, 302 +/- 29 mm(3 ); AR-R 17477, 237 +/- 36 mm(3)). However, this therapeutic effect of AR-R 17477 was no longer evident if the rats were allowed to survive for 48 hrs before analysis of infarction volume. In fact, in this separate cohort of a nimals, three of eight AR-R 17477-treated and five of eight saline-treated rats died before completing 48 hrs of ischemia, Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when drug treatment was dela yed until 1 hr after the onset of ischemia, Infarction volume at 18 hrs of ischemia was similar between rats treated with saline, 1 mg/kg (cortex, 229 +/- 43 mm(3); striatum, 67 +/- 8 mm(3)) or 3 mg/kg AR-R 17477 (cortex, 284 +/- 34 mm(3); striatum, 75 +/- 5 mm(3)). In addition, only one of eight ra ts treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of o cclusion, compared with three of eight rats treated with saline. Conclusions: Neuronally generated nitric oxide is a mediator of brain injur y during permanent focal ischemia in rats. However, severity of the ischemi c insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.