arl-17477 and Cerebral-Infarction

We tested whether AR-R 17477, a selective inhibitor of neuronal nitric oxide synthase, reduces brain injury in rats subjected to permanent focal ischemia.. Randomized within cohort; nonblinded study.. University basic science laboratory.. Halothane-anesthetized male Wistar rats (n = 53).. Rats were treated with either intravenous saline (diluent) or AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of ischemia.. Pretreatment with 1 mg/kg AR-R 17477 was associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride staining) in the striatum (saline, 81+/-7 mm3; AR-R 17477, 55+/-3 mm3) but not in the cortex at 18 hrs of occlusion (saline, 302+/-29 mm3; AR-R 17477, 237+/-36 mm3). 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 animals, 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 delayed 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 mm3; striatum, 67+/-8 mm3) or 3 mg/kg AR-R 17477 (cortex, 284+/-34 mm3; striatum, 75+/-5 mm3). In addition, only one of eight rats treated with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion, compared with three of eight rats treated with saline.. Neuronally generated nitric oxide is a mediator of brain injury during permanent focal ischemia in rats. However, severity of the ischemic insult appears to limit the therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR-R 17477.

Topics: Amidines; Animals; Blood Pressure; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Enzyme Inhibitors; Injections, Intravenous; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Oxygen Consumption; Rats; Rats, Wistar

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

Topics: Amidines; Animals; Arterial Occlusive Diseases; Blood Pressure; Cerebral Arteries; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Enzyme Inhibitors; Male; Neurons; Nitric Oxide Synthase; Rats; Rats, Wistar; Reperfusion