Effect of tirilazad on brain nitric oxide synthase activity during cerebral ischemia in rats.
The effect of the 21-aminosteroid tirilazad mesylate (10 mg/kg, i.p.) on nitric oxide synthase (NOS) activity in the brain cortex was studied in male Wistar rats subjected to cerebral global transient ischemia induced by bilateral clamping of the carotids for 10 min and reduction of arterial pressure (to 50 mm Hg) by intravenous infusion of 1.5 ml of a solution of trimethaphan (5 mg/ml). NOS activity was determined by measuring the rate of conversion of [3H]arginine to [3H]citrulline in brain cortex. Our results show for the first time that tirilazad suppresses the increase of NOS activity in brain cortex induced by cerebral ischemia (136 +/- 16 vs. 60 +/- 9 pmol [3H]citrulline/min per mg protein) and also suppresses the increase in K(m) of NOS (5.7 +/- 0.1 vs. 1.2 +/- 0.2 mumol/l). These effects are attributed to the fact that tirilazad acts as a scavenger of oxygen free radicals formed during cerebral ischemia. These results document the neuroprotective efficacy of tirilazad mesylate in cerebral ischemia.
del Pilar Fernandez Rodriguez
M
M
Department of Pharmacology, School of Medicine, University of Santiago de Compostela, Spain. ffpifer@usc.es
Belmonte
A
A
Meizoso
M J
MJ
Garcia-Novio
M
M
Garcia-Iglesias
E
E
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002956:Citrulline / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011281:Pregnatrienes; D002956:Citrulline; D001120:Arginine; D019001:Nitric Oxide Synthase; C053355:tirilazad