Inhibition of brain p450 arachidonic acid epoxygenase decreases
baseline cerebral blood flow.
Alkayed, Nabil J., Eric K. Birks, Antal G. Hudetz, Richard J. Roman,
Lisa Henderson, David R. Harder.
Cardiovascular Research Center, Department of Physiology, Medical
College of Wisconsin, Milwaukee, Wisconsin and Clement J. Zablocki
Veterans Affairs Medical Center, Milwaukee, Wisconsin
APStracts 3:0144H, 1996.
Arachidonic acid (AA) is metabolized by the cytochrome P450 (P450)
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 P450 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 [mu]M miconazole into
the subdural space for 30 minutes. Responses of cerebral blood flow
to sodium nitroprusside and 5-HT were unaltered by miconazole
treatment. Administration of vehicle alone in time-control
experiments had no effect on cortical blood flow. In other
experiments, the effects of miconazole on the metabolism of [14C]AA
by cultured rat astrocytes and on nitric oxide synthase (NOS)
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 P450 epoxides of AA
in the regulation of basal blood flow in the cerebral
microcirculation.
Received 12 December 1995; accepted in final form 28 March 1996.
APS Manuscript Number H1155-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 16 April 96