ABSTRACT
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.
Subject(s)
Brain/enzymology , Enzyme Inhibitors/pharmacology , Ischemic Attack, Transient/enzymology , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Pregnatrienes/pharmacology , Animals , Arginine/metabolism , Brain/drug effects , Citrulline/metabolism , Kinetics , Male , Rats , Rats, WistarABSTRACT
Experiments were conducted to evaluate the effects of desmethyl tirilazad (10 mg/kg, i.p.), a 21-aminosteroid, on constitutive nitric oxide synthase (cNOS) activity and cyclic guanosine monophosphate (cGMP) levels in brain homogenates of rats subjected to cerebral global transient ischemia induced by bilateral clamping of the carotids for 30 minutes and reduction of arterial pressure (to 50-60 mmHg) by intravenous infusion of 1.5 ml of a solution of trimethaphan (5 mg/ml). Our results show that ischemia induces a rise in cNOS activity (from 62.0 +/- 6.1 to 133.3 +/- 13.3 pmol/min/mg protein) and cGMP levels (from 459.3 +/- 49.6 to 1074.1 +/- 132.1 fmol/mg protein). Pretreatment with desmethyl tirilazad abolishes these increases. These results are in agreement with the neuroprotective efficacy of desmethyl tirilazad in cerebral ischemia.
