Characterization of vasorelaxant effects of oleoylethanolamide in rat small mesenteric artery

Yousuf M Al Suleimani, C. Robin Hiley. Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.

Oleoylethanolamide (OEA) is a monounsaturated fatty acid with a structure similar to the endocannabinoid, anandamide (arachidonoyl ethanolamide). Its actions were first linked to satiety and mechanisms controlling food intake but, recently, OEA has been shown to cause vasorelaxation in resistance vessels (Ho et al., 2008). Since the underlying mechanisms have not been explored in detail, the aim of this study was to characterize its mechanisms of vasorelaxation.

Male Wistar rats were killed with an overdose of sodium pentobarbital and third order branches of the superior mesenteric artery were isolated and mounted in a wire myograph. Vessels were precontracted with methoxamine (10μM) and a cumulative concentration-response curve to OEA was constructed. An antagonist or a channel blocker was given 30min before and was present during, construction of the concentration-response curve. Data were fitted to a logistic equation as detailed in White & Hiley (1997).

OEA caused concentration-dependent relaxation in endothelium-intact vessels (pEC50 = 6.7±0.1, Rmax = 93.1±2.5%, n = 7) and the effect was abolished by endothelial denudation. Pretreatment with L-NAME (300μM) greatly reduced the response, leaving a residual relaxation of only 24.6±12.8 % (n = 5). Atropine (0.1μM) had no significant effect on the response (pEC50 = 6.9±0.1, Rmax = 94.5±7.1%, n = 6), while mepyramine (1μM) slightly shifted the OEA curve to the right (n = 5). Pretreatment with capsaicin (10μM) significantly reduced the vasorelaxation to OEA with about 4-fold shift to the right of the curve (n = 6; P<0.01). Precontraction with 60mM KCl instead of methoxamine completely abolished OEA-induced relaxation. The combination of apamin (50nM) plus charybdotoxin (50nM) significantly inhibited relaxation (n = 4; P<0.01). O-1918 (10μM) markedly shifted (∼96-fold) the concentration-response curve to the right (n = 4; P<0.01). In contrast, rimonabant (3μM) slightly potentiated the response (pEC50 = 7.3±0.1, Rmax = 90.1±3.3%, n = 5). GW6471 (10μM), an antagonist of PPARα, also slightly enhanced OEA-induced vasorelaxation (10μM; pEC50 = 7.1±0.1, Rmax = 99.0±1.4%, n = 4). The CB1 receptor antagonist, AM251 (10μM) had no significant effect on the response, but the CB2 receptor antagonist, AM630 (10μM), greatly reduced the response with an upwards shift of the curve and a maximum relaxation of 57.1±9.5% (n = 5; P<0.01).

OEA produces concentration-dependent relaxation of the rat small mesenteric artery which is entirely endothelium-dependent and involves the release of NO and activation of Ca2+-activated K+ channels (Kca). The response is also dependent on cannabinoid CB2 but not CB1 receptors and a receptor at which O-1918, but not rimonabant, is an antagonist. In addition, activation of TPRV1 receptors, but not PPARα, contributes to this relaxant effect.

Ho, WSV et al. (2008) Br J Pharmacol 155, 837-846.
White, R., Hiley, C.R. (1997) Br J Pharmacol 122, 1573-1584.