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Epoxyeicosatrienoic acid‐dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation
Author(s) -
liu xiaoguang,
Hwang Sung Hee,
Jones Paul D,
Hammock Bruce D,
Roman Richard J,
Harder David R,
Koehler Raymond C
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1151.4
Subject(s) - metabotropic glutamate receptor , chemistry , epoxide hydrolase 2 , agonist , cerebral blood flow , vasodilation , glutamate receptor , pharmacology , cerebral circulation , antagonist , anesthesia , medicine , biochemistry , receptor , enzyme
Activation of metabotropic glutamate receptors (mGluRs) on astrocytes participates in neurovascular coupling. Epoxyeicosatrienoic acids (EETs) may be involved in downstream signaling. 3,5‐Dihydroxyphenylglycine (DHPG) was used as a type I mGluR agonist for pharmacological activation. Cerebral blood flow (CBF), measured by laser‐Doppler flowmetry in isoflurane anesthetized rats, increased by 30±7% (±SD) at 20 min of subarachnoid superfusion of DHPG (1 mM) over the cortical surface. The increase was blocked by the mGluR antagonists MPEP and LY367385 but was unaffected by inhibitors of NO synthase, heme oxygenase, or 20‐HETE synthesis. However, the CBF response to DHPG was markedly reduced by prior superfusion of the EET antagonist 14,15‐EEZE (5±11%) or the EET synthesis inhibitor MS‐PPOH (8±7%). EETs are metabolized by soluble epoxide hydrolase (sEH). The maximal CBF increase induced by DHPG was augmented from 30±7% to 43±6% by superfusion of the sEH inhibitor t‐AUCB. Furthermore, the CBF response to DHPG alone subsided to 12±12% at 60 min of superfusion, but was sustained by co‐superfusion of the sEH inhibitors t‐AUCB (34±14%) and MPTPU (21 ± 5%). These results demonstrate that EETs are a major contributor to the cerebral vasodilation evoked by type I mGluR activation and that inhibiting EETs metabolism augments the CBF response during prolonged activation. (Supported by NIH grant HL59996)