Inhibition of brain P-450 arachidonic acid epoxygenase decreases baseline cerebral blood flow

Nabil J. Alkayed, Eric K. Birks, Antal G. Hudetz, Richard J. Roman, Lisa Henderson, David R. Harder

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Arachidonic acid (AA) is metabolized by the cytochrome P-450 (P-450) epoxygenase pathway to epoxyeicosatrienoic acids (EETs) in the brain parenchymal tissue and perivascular astrocytes. EETs dilate cerebral microvessels and enhance K+ current in cerebrovascular smooth muscle cells. In the current study, the effect of a subdural administration of miconazole, an inhibitor of P-450 epoxygenase, on microvascular perfusion of rat cerebral cortex was evaluated using laser-Doppler flowmetry (LDF). Baseline cerebral blood flow (CBF) decreased by 29.7 ± 7.3% (n = 5) after administration of 20 μM miconazole into the subdural space for 30 min. Responses of CBF to sodium nitroprusside and 5-hydroxytryptamine were unaltered by miconazole treatment. Administration of vehicle alone in time-control experiments had no effect on CBF. In other experiments, the effects of miconazole on the metabolism of [14C]AA by cultured rat astrocytes and on nitric oxide synthase activity in homogenates of rat brain were examined. Miconazole inhibited conversion of AA to EETs by cultured astrocytes but had no effect on the conversion of L- arginine to L-citrulline by homogenates of rat brain. These results implicate endogenous P-450 epoxides of AA in the regulation of basal blood flow in cerebral microcirculation.

Original languageEnglish (US)
Pages (from-to)H1541-H1546
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume271
Issue number4 40-4
DOIs
StatePublished - Oct 1996

Keywords

  • cerebral microcirculation
  • cytochrome P- 450
  • epoxyeicosatrienoic acids
  • laser-Doppler flowmetry
  • miconazole

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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