Effect of desmethyl tirilazad, dizocilpine maleate and nimodipine on brain nitric oxide synthase activity and cyclic guanosine monophosphate during cerebral ischemia in rats.
The present study was designed to evaluate the effects of pretreatment with a combination of desmethyl tirilazad (21-aminosteroid) plus dizocilpine maleate (N-methyl-D-aspartate receptor antagonist) and nimodipine (calcium channel antagonist) on constitutive nitric oxide synthase (cNOS) activity and cyclic guanosine monophosphate (cGMP) levels in brain homogenates of rats subjected to global cerebral transient ischemia induced by bilateral clamping of the carotids for 30 min and reduction of arterial pressure (to 50-60 mm Hg) by intravenous infusion of trimethaphan (30 mg/kg). Our results show that cerebral ischemia produced an increase in cNOS activity and cGMP levels in brain homogenates. Pretreatment with desmethyl tirilazad or dizocilpine maleate or nimodipine individually significantly suppressed (p < 0.01) the increase in cNOS activity and cGMP levels induced by cerebral ischemia, which may be related to their neuroprotective effect. Similar results were obtained with pretreatment by a combination of desmethyl tirilazad plus dizocilpine maleate plus nimodipine.
del Pilar Fernandez
M
M
Department of Pharmacology, School of Medicine, University of Santiago de Compostela, Spain. ffpifer@usc.es
Meizoso
M J
MJ
Lodeiro
M J
MJ
Belmonte
A
A
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D006152:Cyclic GMP / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011281:Pregnatrienes; C074965:U 74389F; D009553:Nimodipine; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP