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Am J Physiol Heart Circ Physiol 279: H1616-H1624, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 4, H1616-H1624, October 2000

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

Anish Bhardwaj1,2, Frances J. Northington3, Juan R. Carhuapoma1,2, John R. Falck4, David R. Harder5, Richard J. Traystman2, and Raymond C. Koehler2

1 Departments of Neurology, 2 Anesthesiology and Critical Care Medicine, and 3 Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and 5 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Epoxyeicosatrienoic acids are cerebral vasodilators produced in astrocytes by cytochrome P-450 epoxygenase activity. The P-450 inhibitor miconazole attenuates the increase in cerebral blood flow (CBF) elicited by glutamate. We evaluated whether epoxygenase activity is involved in the CBF response to activation of the N-methyl-D-aspartate (NMDA) receptor subtype by using two structurally distinct inhibitors, miconazole and N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH), a selective epoxygenase substrate inhibitor. Drugs were delivered locally through microdialysis probes in striata of anesthetized rats. Local CBF was measured by hydrogen clearance and compared with CBF in contralateral striatum receiving vehicle. Microdialysis perfusion of NMDA doubled CBF and increased nitric oxide (NO) production estimated by recovery of labeled citrulline in the dialysate during labeled arginine infusion. Perfusion of miconazole or MS-PPOH blocked the increase in CBF without decreasing citrulline recovery. Perfusion of Nomega -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 nitroprusside. We conclude that both the P-450 epoxygenase and NO synthase pathways are involved in the local CBF response to NMDA receptor activation, and that the signaling pathway may be more complex than simply NO diffusion from neurons to vascular smooth muscle.

arachidonic acid; epoxyeicosatrienoic acid; glia; miconazole; microdialysis; nitric oxide; rat


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