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.


METHODS
Randomized within cohort; nonblinded study.


METHODS
University basic science laboratory.


METHODS
Halothane-anesthetized male Wistar rats (n = 53).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Harukuni
I
I
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Traystman
R J
RJ
Kirsch
J R
JR
D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D002545:Brain Ischemia / Q000150:complications*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
C102136:ARL 17477; D000578:Amidines; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat