title: Epoxyeicosatrienoic acid-dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation in vivo.
abstract: Group I metabotropic glutamate receptors (mGluR) on astrocytes have been shown to participate in cerebral vasodilation to neuronal activation in brain slices. Pharmacological stimulation of mGluR in brain slices can produce arteriolar constriction or dilation depending on the initial degree of vascular tone. Here, we examined whether pharmacological stimulation of mGluR in vivo increases cerebral blood flow. A 1-mM solution of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) superfused at 5 μl/min over the cortical surface of anesthetized rats produced a 30 ± 2% (±SE) increase in blood flow measured by laser-Doppler flowmetry after 15-20 min. The response was completely blocked by superfusion of group I mGluR antagonists and attenuated by superfusion of an epoxyeicosatrienoic acid (EET) antagonist (5 ± 4%), an EET synthesis inhibitor (11 ± 3%), and a cyclooxygenase-2 inhibitor (15 ± 3%). The peak blood flow response was not significantly affected by administration of inhibitors of cyclooxygenase-1, neuronal nitric oxide synthase, heme oxygenase, adenosine A(2B) receptors, or an inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE). The blood flow response gradually waned following 30-60 min of DHPG superfusion. This loss of the flow response was attenuated by a 20-HETE synthesis inhibitor and was prevented by superfusion of an inhibitor of epoxide hydrolase, which hydrolyzes EETs. These results indicate that pharmacological stimulation of mGluR in vivo increases cerebral blood flow and that the response depends on the release of EETs and a metabolite of cyclooxygenase-2. Epoxide hydrolase activity and 20-HETE synthesis limit the duration of the response to prolonged mGluR activation.
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Xiaoguang
authors: X
authors: Liu
authors: Chunyuan
authors: C
authors: Li
authors: Debebe
authors: D
authors: Gebremedhin
authors: Sung Hee
authors: SH
authors: Hwang
authors: Bruce D
authors: BD
authors: Hammock
authors: John R
authors: JR
authors: Falck
authors: Richard J
authors: RJ
authors: Roman
authors: David R
authors: DR
authors: Harder
authors: Raymond C
authors: RC
authors: Koehler
references: Stroke. 1996 May;27(5):971-9
references: 8623121
references: Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H2029-37
references: 12384482
references: J Pharmacol Exp Ther. 1998 Mar;284(3):966-73
references: 9495856
references: Nat Neurosci. 2006 Nov;9(11):1397-1403
references: 17013381
references: Am J Physiol. 1999 Aug;277(2):H799-811
references: 10444508
references: J Neurosci. 2000 Jan 15;20(2):763-70
references: 10632605
references: Brain Res. 1998 Jul 6;798(1-2):294-303
references: 9666151
references: Cereb Cortex. 2005 Aug;15(8):1250-60
references: 15616132
references: Neuroscience. 2006 Dec;143(3):703-16
references: 17027168
references: Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2455-65
references: 18952718
references: J Cardiovasc Pharmacol. 2010 Jan;55(1):67-73
references: 19834332
references: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2301-7
references: 16782846
references: Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2371-6
references: 12003848
references: J Cereb Blood Flow Metab. 2004 May;24(5):509-17
references: 15129182
references: Nat Rev Neurosci. 2010 Apr;11(4):227-38
references: 20300101
references: J Neurochem. 1993 Jul;61(1):150-9
references: 8515261
references: J Cereb Blood Flow Metab. 1997 Feb;17(2):153-60
references: 9040494
references: Circ Res. 1998 Nov 30;83(11):1069-79
references: 9831701
references: Am J Physiol. 1999 Sep;277(3):R607-23
references: 10484476
references: J Neurochem. 1994 Aug;63(2):769-72
references: 8035201
references: Br J Pharmacol. 2001 Jun;133(3):325-9
references: 11375247
references: Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R728-35
references: 16601261
references: J Physiol. 2003 Dec 1;553(Pt 2):407-14
references: 14500777
references: Nat Neurosci. 2006 Jun;9(6):816-23
references: 16699507
references: Am J Physiol. 1992 Aug;263(2 Pt 2):H519-25
references: 1510149
references: Nat Neurosci. 2006 Feb;9(2):260-7
references: 16388306
references: Eur J Pharm Sci. 2010 Jun 14;40(3):222-38
references: 20359531
references: Nature. 2004 Sep 9;431(7005):195-9
references: 15356633
references: Brain Res. 1996 Feb 5;708(1-2):197-200
references: 8720879
references: J Neurosci. 2003 Mar 1;23(5):1678-87
references: 12629172
references: Neuroimage. 2006 Aug 1;32(1):23-32
references: 16626973
references: Nature. 2008 Dec 11;456(7223):745-9
references: 18971930
references: Circ Res. 2001 Mar 30;88(6):600-8
references: 11282894
references: Circ Res. 2002 May 17;90(9):1028-36
references: 12016270
references: Circ Res. 2008 Feb 1;102(2):234-41
references: 17991880
references: Trends Neurosci. 2009 Mar;32(3):160-9
references: 19162338
references: J Neurosci. 2005 Jun 8;25(23):5502-10
references: 15944378
references: J Cereb Blood Flow Metab. 2008 Jan;28(1):111-25
references: 17519974
references: Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2897-904
references: 16891404
references: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3811-6
references: 20133576
references: Stroke. 1997 May;28(5):1066-72
references: 9158651
references: Nat Neurosci. 2003 Jan;6(1):43-50
references: 12469126
references: Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H619-31
references: 18502903
references: Anal Biochem. 2001 Nov 15;298(2):327-36
references: 11700990
references: FASEB J. 2006 Jul;20(9):1352-60
references: 16816110
references: J Appl Physiol (1985). 2006 Jan;100(1):336-42
references: 16166237
references: J Med Chem. 2007 Aug 9;50(16):3825-40
references: 17616115
references: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2855-63
references: 18456724