7-Nitroindazole inhibits brain nitric oxide synthase and cerebral vasodilatation in response to N-methyl-D-aspartate

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.

We measured diameters of cerebral arterioles (baseline diameter, 89 +/- 7 microns) 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.

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 mumol/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 mumol/L) was similar in vehicle- and 7-NI-treated animals (17 +/- 5% versus 21 +/- 4%; P > .05).

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.