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Departments of 1 Anesthesiology/Critical Care Medicine and 2 Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and 4 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Application of glutamate to glial cell cultures stimulates the formation and release of epoxyeicosatrienoic acids (EETs) from arachidonic acid by cytochome P-450 epoxygenases. Epoxygenase inhibitors reduce the cerebral vasodilator response to glutamate and N-methyl-D-aspartate. We tested the hypothesis that epoxygenase inhibitors reduce the somatosensory cortical blood flow response to whisker activation. In chloralose-anesthetized rats, percent changes in cortical perfusion over whisker barrel cortex were measured by laser-Doppler flowmetry during whisker stimulation. Two pharmacologically distinct inhibitors were superfused subdurally: 1) N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), an epoxygenase substrate inhibitor; and 2) miconazole, a reversible cytochrome P-450 inhibitor acting on the heme moiety. Superfusion with 5 µmol/l MS-PPOH decreased the hyperemic response to whisker stimulation by 28% (from 25 ± 9 to 18 ± 7%, means ± SD, n = 8). With 20 µmol/l MS-PPOH superfusion, the response was decreased by 69% (from 28 ± 9% to 9 ± 4%, n = 8). Superfusion with 20 µmol/l miconazole decreased the flow response by 67% (from 31 ± 6% to 10 ± 3%, n = 8). Subsequent superfusion with vehicle restored the response to 26 ± 11%. Indomethacin did not prevent MS-PPOH inhibition of the flow response, suggesting that EET-related vasodilation was not dependent solely on cyclooxygenase metabolism of 5,6-EET. Neither MS-PPOH nor miconazole changed baseline flow, reduced the blood flow response to an adenosine A2 agonist, or decreased somatosensory evoked potentials. The marked reduction of the cortical flow response to whisker stimulation with two different types of epoxygenase inhibitors indicates that EETs play an important role in the physiological coupling of blood flow to neural activation.
arachidonic acid; astrocyte; cerebral blood flow; cytochrome P-450; epoxyeicosatrienoic acids; whisker barrel cortex
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