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. 2014 Mar;81(100):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

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Free PMC article

Cyclooxygenase Metabolism Mediates Vasorelaxation to 2-arachidonoylglycerol (2-AG) in Human Mesenteric Arteries

Christopher P Stanley et al. Pharmacol Res. .
Free PMC article

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.

Keywords: 2-Arachidonoylglycerol; Cyclooxygenase; Endocannabinoid; Human; Prostanoid; Vasorelaxation.

Figures

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Fig. 1
Fig. 1
Trace data showing 2-AG-induced vasorelaxation (A). Vasorelaxant effects of 2-AG compared to vehicle-treated segments of mesenteric artery from the same patient (B). 2-AG effects on baseline tone compared to vehicle treated segments of mesenteric artery from same patient (C). Data given as means with error bars representing S.E.M. (Students paired t-test of area under curve *P < 0.05, ***P < 0.001).
Fig. 2
Fig. 2
2-AG-induced vasorelaxation of human mesenteric arteries after 10 min incubation with the CB1 antagonist AM251 (100 nmol/L) (A), CB2 antagonist AM630 (100 nmol/L) (B) and after 1 h desensitisation of the TRPV1 receptor using the TRPV1 agonist capsaicin (10 μmol/L) (C). Data given as means with error bars representing S.E.M. Comparisons made between control and intervention segments of the same artery using Students paired t-test of area under curve.
Fig. 3
Fig. 3
2-AG-induced vasorelaxation of human mesenteric arteries after removal of the endothelium (A), in the presence of l-NAME (300 μmol/L) (B), in the presence of the MAGL inhibitor JZL184 (1 μmol/L) (C) and the FAAH inhibitor URB597 (1 μmol/L). (D) Data given as means with error bars representing S.E.M. Comparisons made between control and intervention segments of the same artery using Students paired t-test of area under curve.
Fig. 4
Fig. 4
2-AG-induced vasorelaxation of human mesenteric arteries after addition of the non-selective COX inhibitor indomethacin (10 μmol/L) (A), the COX-1 inhibitor flurbiprofen (10 μmol/L) (B), the COX-2 inhibitor nimesulide (10 μmol/L) (C), the prostanoid IP receptor antagonist CAY10441 (100 nmol/L) (D) the prostanoid EP4 antagonist L-161,982 (1 mmol/L) (E) and the prostanoid EP1, EP2, EP3, DP and TP receptor antagonist (AH 6809, 1 μmol/L). Data given as means with error bars representing S.E.M. Comparisons made between control and intervention segments of the same artery using Students paired t-test of area under curve. **P < 0.01, ***P < 0.001.
Fig. 5
Fig. 5
2-AG-induced vasorelaxation of human mesenteric arteries in arteries contracted with KPSS (124 mmol/L) (A) and U46619 in Ca2+−free PSS buffer (B). The effects of 10 min incubation with 2-AG (10 and 100 μmol/L) and vehicle control (0.1% EtOH) on CaCl2 contraction in Ca2+ free KPSS (124 mmol/L). Data given as means with error bars representing S.E.M. Comparisons made between control and intervention segments of the same artery using Students paired t-test of area under curve (A and B) and one way ANOVA of area under the curve with Dunnets post hoc test (C). *P < 0.05, **P < 0.01, ***P < 0.001.

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