P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-D-aspartate

Epoxyeicosatrienoic acids are cerebral vasodilators produced in astrocytes by cytochrome P-450 epoxygenase activity. The P-450 inhibitor miconazole at tenuates the increase in cerebral blood flow (CBF) elicited by glutamate. W e evaluated whether epoxygenase activity is involved in the CBF response to activation of the N-methyl-D-aspartate (NMDA) receptor subtype by using tw o structurally distinct inhibitors, miconazole and N-methylsulfonyl- 6-(2-p ropargyloxyphenyl) hexanamide (MS-PPOH), a selective epoxygenase substrate inhibitor. Drugs were delivered locally through microdialysis probes in str iata of anesthetized rats. Local CBF was measured by hydrogen clearance and compared with CBF in contralateral striatum receiving vehicle. Microdialys is perfusion of NMDA doubled CBF and increased nitric oxide (NO) production estimated by recovery of labeled citrulline in the dialysate during labele d arginine infusion. Perfusion of miconazole or MS-PPOH blocked the increas e in CBF without decreasing citrulline recovery. Perfusion of N-omega-nitro -L-arginine decreased baseline CBF and inhibited the CBF response to NMDA. Perfusion of MS-PPOH did not inhibit the CBF response to sodium nitroprussi de. We conclude that both the P-450 epoxygenase and NO synthase pathways ar e involved in the local CBF response to NMDA receptor activation, and that the signaling pathway may be more complex than simply NO diffusion from neu rons to vascular smooth muscle.