7-Nitroindazole Inhibits Brain Nitric Oxide Synthase and Cerebral Vasodilatation in Response to N -Methyl- d -aspartate

Abstract

Background and Purpose N -Methyl- d -aspartate (NMDA) produces dilatation of cerebral arterioles that is dependent on production of nitric oxide (NO). In these experiments we examined the hypothesis that cerebral vasodilatation in response to NMDA is mediated by the neuronal isoform of NO synthase. Methods We measured diameters of cerebral arterioles (baseline diameter, 89±7 μm) using a closed cranial window in anesthetized rabbits that received either vehicle (10 mL/kg IP peanut oil) or 7-nitroindazole (7-NI; 50 mg/kg IP). 7-NI is reported to be a selective inhibitor of neuronal NO synthase. Results Two hours after administration of 7-NI, activity of brain NO synthase (measured by conversion of l -arginine to l -citrulline) was reduced by 33% compared with vehicle (24±1 versus 16±3 pmol/min per milligram protein; n=7; P <.05). Dilatation of cerebral arterioles in response to NMDA (100 and 300 μmol/L) was inhibited by 30% to 40% by 7-NI compared with responses in the presence of vehicle (23±6% versus 14±5% and 30±4% versus 21±5%, respectively; P <.05 for both concentrations; n=10). In contrast, vasodilatation in response to acetylcholine (1 μmol/L) was similar in vehicle- and 7-NI–treated animals (17±5% versus 21±4%; P >.05). Conclusions These findings suggest that vasodilatation in response to NMDA is mediated by neuronally derived NO. 7-NI appears to produce selective inhibition of brain NO synthase but not endothelial NO synthase.