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Pharmacol Res. 2014 Mar;81:74-82. doi: 10.1016/j.phrs.2014.02.001. Epub 2014 Feb 16.

Cyclooxygenase metabolism mediates vasorelaxation to 2-arachidonoylglycerol (2-AG) in human mesenteric arteries.

Author information

  • 1School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, United Kingdom. Electronic address: mbzso@nottingham.ac.uk.
  • 2School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, United Kingdom.

Abstract

OBJECTIVE:

The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans.

APPROACH:

Mesenteric arteries were obtained from patients receiving colorectal surgery and mounted on a myograph. Arteries were contracted and 2-AG concentration-response curves were carried out. Mechanisms of action were characterised pharmacologically. Post hoc analysis was carried out to assess the effects of cardiovascular disease/risk factors on 2-AG responses.

RESULTS:

2-AG caused vasorelaxation of human mesenteric arteries, independent of cannabinoid receptor or transient receptor potential vanilloid-1 activation, the endothelium, nitric oxide or metabolism via monoacyglycerol lipase or fatty acid amide hydrolase. 2-AG-induced vasorelaxation was reduced in the presence of indomethacin and flurbiprofen, suggesting a role for cyclooxygenase metabolism 2-AG. Responses to 2-AG were also reduced in the presence of Cay10441, L-161982 and potentiated in the presence of AH6809, suggesting that metabolism of 2-AG produces both vasorelaxant and vasoconstrictor prostanoids. Finally, 2-AG-induced vasorelaxation was dependent on potassium efflux and the presence of extracellular calcium.

CONCLUSIONS:

We have shown for the first time that 2-AG causes vasorelaxation of human mesenteric arteries. Vasorelaxation is dependent on COX metabolism, activation of prostanoid receptors (EP4 & IP) and ion channel modulation. 2-AG responses are blunted in patients with cardiovascular risk factors.

Copyright © 2014. Published by Elsevier Ltd.

KEYWORDS:

2-Arachidonoylglycerol; Cyclooxygenase; Endocannabinoid; Human; Prostanoid; Vasorelaxation

PMID:
24548820
[PubMed - indexed for MEDLINE]
PMCID:
PMC3992009
Free PMC Article
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