Faculty Collaboration Database

Dependency of cortical functional hyperemia to forepaw stimulation on epoxygenase and nitric oxide synthase activities in rats. J Cereb Blood Flow Metab 2004 May;24(5):509-17

Date

05/07/2004

Pubmed ID

15129182

DOI

10.1097/00004647-200405000-00004

Scopus ID

2-s2.0-2342656895 (requires institutional sign-in at Scopus site)   74 Citations

Abstract

Individual inhibition of nitric oxide (NO) synthase and cytochrome P450 (CYP) epoxygenase activity attenuates cortical functional hyperemia evoked by whisker stimulation. The objectives of the present study were to determine (1) if administration of epoxygenase inhibitors attenuates cortical functional hyperemia by using a different modality of sensory activation (i.e., electrical stimulation of the rat forepaw), (2) if epoxygenase inhibition has an additive effect with NO synthase inhibition on the flow response, and (3) the cellular localization of the epoxygenase CYP2C11 in cerebral cortex. In six groups of anesthetized rats, the cortical surface was superfused for 90 minutes with (1) vehicle; (2) 1-mmol/L Nomega-nitro-L-arginine (L-NNA), to inhibit NO synthase activity; (3) 20-micromol/L N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-micromol/L miconazole, a reversible inhibitor at the heme site of P450 epoxygenase; and (6) miconazole plus L-NNA. The percent increases in laser-Doppler perfusion over primary sensory cortex during 20-second forepaw stimulation were reduced by 44% to 64% in all drug-treated groups. The addition of L-NNA to MS-PPOH produced no additional reduction (64%) compared with MS-PPOH alone (64%) or L-NNA alone (60%). The addition of L-NNA to miconazole also produced no additional reduction in the flow response. In situ hybridization of CYP2C11 mRNA showed localization in astrocytes, including those adjacent to blood vessels. Thus, activity of both epoxygenase, presumably localized in astrocytes, and NO synthase is required for generating a complete cortical hyperemic response evoked by electrical forepaw stimulation. The lack of additional blood flow attenuation with the combination of the NO synthase and the distinct epoxygenase inhibitors suggests that the signaling pathways do not act in a simple parallel fashion and that other mediators may be involved in coupling cortical blood flow to neuronal activation.

Author List

Peng X, Zhang C, Alkayed NJ, Harder DR, Koehler RC

MESH terms used to index this publication - Major topics in bold

Animals
Aryl Hydrocarbon Hydroxylases
Cerebral Cortex
Cerebrovascular Circulation
Cytochrome P450 Family 2
Electric Stimulation
Enzyme Inhibitors
Foot
Hyperemia
In Situ Hybridization
Laser-Doppler Flowmetry
Male
Nitric Oxide Synthase
Rats
Rats, Wistar
Regional Blood Flow
Steroid 16-alpha-Hydroxylase
Vibrissae