Dependency of Cortical Functional Hyperemia to Forepaw Stimulation on Epoxygenase and Nitric Oxide Synthase Activities in Rats

Xinqi Peng, Chenyang Zhang, Nabil Alkayed, David R. Harder, Raymond C. Koehler

Research output: Contribution to journalArticle

61 Citations (Scopus)

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 Nω-nitro-L-arginine (L-NNA), to inhibit NO synthase activity; (3) 20-μmol/L N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-μmol/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.

Original languageEnglish (US)
Pages (from-to)509-517
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume24
Issue number5
StatePublished - May 2004

Fingerprint

Hyperemia
Nitric Oxide Synthase
Arginine
Miconazole
Astrocytes
Electric Stimulation
Vibrissae
Heme
Cerebral Cortex
Cytochrome P-450 Enzyme System
In Situ Hybridization
Blood Vessels
Lasers
Perfusion
Messenger RNA
N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
Pharmaceutical Preparations

Keywords

  • Astrocyte
  • Cerebral blood flow
  • Cytochrome P450
  • Epoxygenase
  • Functional activation
  • Nitric oxide

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Dependency of Cortical Functional Hyperemia to Forepaw Stimulation on Epoxygenase and Nitric Oxide Synthase Activities in Rats. / Peng, Xinqi; Zhang, Chenyang; Alkayed, Nabil; Harder, David R.; Koehler, Raymond C.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 24, No. 5, 05.2004, p. 509-517.

Research output: Contribution to journalArticle

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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 Nω-nitro-L-arginine (L-NNA), to inhibit NO synthase activity; (3) 20-μmol/L N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-μmol/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.",
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N2 - 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 Nω-nitro-L-arginine (L-NNA), to inhibit NO synthase activity; (3) 20-μmol/L N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-μmol/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.

AB - 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 Nω-nitro-L-arginine (L-NNA), to inhibit NO synthase activity; (3) 20-μmol/L N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-μmol/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.

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