Regulation of the cerebral circulation by cytochrome P450 epoxygenase activity

Abstract

Cytochrome P450 epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which can dilate cerebral vessels. In glial cell cultures, glutamate stimulates the release of EETs. Thus, an astrocyte-based epoxygenase pathway could form a link in the coupling of blood flow to neuronal activity. To test this hypothesis, neuronal activation was produced by mechanical displacement of the whiskers of anesthetized rats while monitoring red cell flux by laser-Doppler flowmetry over whisker barrel sensory cortex. N-methylsulfonyl-6-(2-propargyloxyphenol) hexanamide (MS-PPOH) or miconazole, two different types of P450 epoxygenase inhibitors, were superfused over the cortical surface in different groups of rats. Both inhibitors markedly reduced the increase in cortical perfusion during whisker stimulation. To test the effect of these inhibitors on the increase in blood flow evoked by N-methyl- d-aspartate (NMDA), drugs were delivered via microdialysis probes in the striatum, while local blood flow was measured by the hydrogen clearance technique. Both MS-PPOH and miconazole blocked the increase in striatal blood flow during microdialysis perfusion of NMDA. These results support a role for P450 epoxygenase activity in the coupling of cortical blood flow to whisker stimulation and to pharmacological activation of NMDA receptors in striatum.