Relative contribution of cyclooxygenases, epoxyeicosatrienoic acids, and pH to the cerebral blood flow response to vibrissal stimulation

Xiaoguang Liu, Chunyuan Li, John R. Falck, David R. Harder, Raymond C Koehler

Research output: Contribution to journalArticle

Abstract

The increase in cerebral blood flow (CBF) during neuronal activation can be only partially attenuated by individual inhibitors of epoxyeicosatrienoic acids (EETs), cyclooxgenase-2, group I metabotropic glutamate receptors (mGluR), neuronal nitric oxide synthase (nNOS), N-methyl- D-aspartate receptors, or adenosine receptors. Some studies that used a high concentration (500 μM) of the cyclooxygenase-1 inhibitor SC-560 have implicated cyclooxygenase-1 in gliovascular coupling in certain model systems in the mouse. Here, we found that increasing the concentration of SC-560 from 25 μM to 500 μM over whisker barrel cortex in anesthetized rats attenuated the CBF response to whisker stimulation. However, exogenous prostaglandin E 2 restored the response in the presence of 500 μM SC-560 but not in the presence of a cyclooxygenase-2 inhibitor, thereby suggesting a limited permissive role for cyclooxygenase-1. Furthermore, inhibition of the CBF response to whisker stimulation by an EET antagonist persisted in the presence of SC-560 or a cyclooxygenase-2 inhibitor, thereby indicating that the EET-dependent component of vasodilation did not require cyclooxygenase-1 or -2 activity. With combined inhibition of cyclooxygenase-1 and -2, mGluR, nNOS, EETs, N-methyl-D-aspartate receptors, and adenosine 2B receptors, the CBF response was reduced by 60%. We postulated that the inability to completely block the CBF response was due to tissue acidosis resulting from impaired clearance of metabolically produced CO 2. We tested this idea by increasing the concentration of superfused bicarbonate from 25 to 60 μM and found a markedly reduced CBF response to hypercapnia. However, increasing bicarbonate had no effect on the initial or steady-state CBF response to whisker stimulation with or without combined inhibition. We conclude that the residual response after inhibition of several known vasodilatory mechanisms is not due to acidosis arising from impaired CO 2 clearance when the CBF response is reduced. An unidentified mechanism apparently is responsible for the rapid, residual cortical vasodilation during vibrissal stimulation.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number5
DOIs
StatePublished - Mar 2012

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Cerebrovascular Circulation
Prostaglandin-Endoperoxide Synthases
Cyclooxygenase 1
Vibrissae
Acids
Nitric Oxide Synthase Type I
Metabotropic Glutamate Receptors
Purinergic P1 Receptors
Cyclooxygenase 2 Inhibitors
Carbon Monoxide
Bicarbonates
Acidosis
N-Methyl-D-Aspartate Receptors
Vasodilation
Cyclooxygenase Inhibitors
Hypercapnia
Cyclooxygenase 2
Prostaglandins E

Keywords

  • Acidosis
  • Metabotropic glutamate receptor
  • Neurovascular unit
  • Prostaglandin e
  • Whisker barrel cortex

ASJC Scopus subject areas

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

Cite this

Relative contribution of cyclooxygenases, epoxyeicosatrienoic acids, and pH to the cerebral blood flow response to vibrissal stimulation. / Liu, Xiaoguang; Li, Chunyuan; Falck, John R.; Harder, David R.; Koehler, Raymond C.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 5, 03.2012.

Research output: Contribution to journalArticle

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AU - Koehler, Raymond C

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AB - The increase in cerebral blood flow (CBF) during neuronal activation can be only partially attenuated by individual inhibitors of epoxyeicosatrienoic acids (EETs), cyclooxgenase-2, group I metabotropic glutamate receptors (mGluR), neuronal nitric oxide synthase (nNOS), N-methyl- D-aspartate receptors, or adenosine receptors. Some studies that used a high concentration (500 μM) of the cyclooxygenase-1 inhibitor SC-560 have implicated cyclooxygenase-1 in gliovascular coupling in certain model systems in the mouse. Here, we found that increasing the concentration of SC-560 from 25 μM to 500 μM over whisker barrel cortex in anesthetized rats attenuated the CBF response to whisker stimulation. However, exogenous prostaglandin E 2 restored the response in the presence of 500 μM SC-560 but not in the presence of a cyclooxygenase-2 inhibitor, thereby suggesting a limited permissive role for cyclooxygenase-1. Furthermore, inhibition of the CBF response to whisker stimulation by an EET antagonist persisted in the presence of SC-560 or a cyclooxygenase-2 inhibitor, thereby indicating that the EET-dependent component of vasodilation did not require cyclooxygenase-1 or -2 activity. With combined inhibition of cyclooxygenase-1 and -2, mGluR, nNOS, EETs, N-methyl-D-aspartate receptors, and adenosine 2B receptors, the CBF response was reduced by 60%. We postulated that the inability to completely block the CBF response was due to tissue acidosis resulting from impaired clearance of metabolically produced CO 2. We tested this idea by increasing the concentration of superfused bicarbonate from 25 to 60 μM and found a markedly reduced CBF response to hypercapnia. However, increasing bicarbonate had no effect on the initial or steady-state CBF response to whisker stimulation with or without combined inhibition. We conclude that the residual response after inhibition of several known vasodilatory mechanisms is not due to acidosis arising from impaired CO 2 clearance when the CBF response is reduced. An unidentified mechanism apparently is responsible for the rapid, residual cortical vasodilation during vibrissal stimulation.

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