Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619

C. J. Hillard, W. S V Ho, J. Thompson, K. M. Gauthier, C. E. Wheelock, H. Huang, B. D. Hammock

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background and purpose: Cerebrovascular smooth muscle cells express the CB 1 cannabinoid receptor and CB 1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A 2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2-AG produces a CB 1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E max for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC 50 for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.

Original languageEnglish (US)
Pages (from-to)691-698
Number of pages8
JournalBritish Journal of Pharmacology
Volume152
Issue number5
DOIs
StatePublished - Nov 2007

Fingerprint

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Thromboxanes
Middle Cerebral Artery
Vasoconstriction
Endocannabinoids
2-arachidonylglycerol
Cannabinoid Receptors
Video Microscopy
Cerebral Arteries
varespladib methyl
Vasodilation
Smooth Muscle Myocytes
Dilatation
Serotonin
Stroke

Keywords

  • 2-arachidonoylglycerol
  • Cannabinoid receptor
  • CB receptor
  • DETFP
  • Endocannabinoid
  • Fatty acid amide hydrolase
  • Middle cerebral artery
  • Monoacylglycerol lipase
  • U-46619
  • URB754

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619. / Hillard, C. J.; Ho, W. S V; Thompson, J.; Gauthier, K. M.; Wheelock, C. E.; Huang, H.; Hammock, B. D.

In: British Journal of Pharmacology, Vol. 152, No. 5, 11.2007, p. 691-698.

Research output: Contribution to journalArticle

Hillard, C. J. ; Ho, W. S V ; Thompson, J. ; Gauthier, K. M. ; Wheelock, C. E. ; Huang, H. ; Hammock, B. D. / Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619. In: British Journal of Pharmacology. 2007 ; Vol. 152, No. 5. pp. 691-698.
@article{49f83b0770174ff6b8f397a049e767c8,
title = "Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619",
abstract = "Background and purpose: Cerebrovascular smooth muscle cells express the CB 1 cannabinoid receptor and CB 1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A 2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2-AG produces a CB 1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E max for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC 50 for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.",
keywords = "2-arachidonoylglycerol, Cannabinoid receptor, CB receptor, DETFP, Endocannabinoid, Fatty acid amide hydrolase, Middle cerebral artery, Monoacylglycerol lipase, U-46619, URB754",
author = "Hillard, {C. J.} and Ho, {W. S V} and J. Thompson and Gauthier, {K. M.} and Wheelock, {C. E.} and H. Huang and Hammock, {B. D.}",
year = "2007",
month = "11",
doi = "10.1038/sj.bjp.0707468",
language = "English (US)",
volume = "152",
pages = "691--698",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619

AU - Hillard, C. J.

AU - Ho, W. S V

AU - Thompson, J.

AU - Gauthier, K. M.

AU - Wheelock, C. E.

AU - Huang, H.

AU - Hammock, B. D.

PY - 2007/11

Y1 - 2007/11

N2 - Background and purpose: Cerebrovascular smooth muscle cells express the CB 1 cannabinoid receptor and CB 1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A 2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2-AG produces a CB 1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E max for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC 50 for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.

AB - Background and purpose: Cerebrovascular smooth muscle cells express the CB 1 cannabinoid receptor and CB 1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A 2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2-AG produces a CB 1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E max for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC 50 for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.

KW - 2-arachidonoylglycerol

KW - Cannabinoid receptor

KW - CB receptor

KW - DETFP

KW - Endocannabinoid

KW - Fatty acid amide hydrolase

KW - Middle cerebral artery

KW - Monoacylglycerol lipase

KW - U-46619

KW - URB754

UR - http://www.scopus.com/inward/record.url?scp=35649005473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35649005473&partnerID=8YFLogxK

U2 - 10.1038/sj.bjp.0707468

DO - 10.1038/sj.bjp.0707468

M3 - Article

VL - 152

SP - 691

EP - 698

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -