Background and purpose: The endocannabinoid N-arachidonoylethanolamide (anandamide) is co-synthesized with other N-acylethanolamides, namely N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which have been shown to potentiate anandamide responses (so-called 'entourage effects') in non-vascular tissues. It remains unclear whether such interactions occur in the circulation. Experimental approach: In rat isolated small mesenteric arteries, the effects of PEA and OEA on relaxation to anandamide and tissue contents of the N-acylethanolamides were examined under myographic conditions. Key results: Anandamide-induced relaxation was potentiated by pretreatment with PEA (10 mM) or OEA (1 mM), or in combination. The potentiation by PEA and OEA was endothelium-independent and abolished by treatment with capsaicin (10 mM), which desensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor system, or by the TRPV1 receptor antagonist, N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) (2 mM). It was also observed at molar ratios of anandamide and PEA (or OEA) similar to those found in mesenteric arteries. PEA and inhibition of anandamide hydrolysis by 3 0 -carbamoylbiphenyl-3-yl-cyclohexylcarbamate (URB597) (1 mM) additively potentiated anandamide responses. On the other hand, PEA and OEA also induced vasorelaxation per se (rank order of potency: anandamide4OEA4PEA), but relaxation to the three N-acylethanolamides displayed different sensitivity to treatment with capsaicin, SB366791 and URB597. For example, relaxations to anandamide and OEA, but not PEA, were attenuated by both capsaicin and SB366791. Conclusion and implications: This study shows that PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxation per se, suggesting a function for the N-acylethanolamides in vascular control.

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An endothelium-derived hyperpolarizing factor (EDHF) is now widely recognized to mediate endothelium-dependent vascular relaxations that are independent of nitric oxide (NO) and prostanoid synthesis (Mombouli & Vanhoutte, 1997). Although the chemical identity of EDHF remains controversial, there is accumulating evidence that this mediator normally effects relaxation following diffusion from the endothelium to smooth muscle via myoendothelial gap junctions rather than the extracellular space Taylor et al. 1998;Dora et al. 1999;Hutcheson et al. 1999). Anatomically, this hypothesis is supported by the demonstration of myoendothelial gap junction plaques in rabbit conduit arteries (Spagnoli et al. 1982), and functional dye transfer experiments confirm direct chemical coupling between endothelium and subjacent smooth muscle (Little et al. 1995). Gap junctions are membrane structural proteins which consist of two hemichannels or connexons contributed by apposing cells, with each connexon being formed from six protein subunits or connexins arranged around an aqueous central pore that permits intercellular transfer of electrical current and molecules < 1 kDa in size (Yeager & Nicholson, 1996). Connexin 43 (Cx43) is present in both endothelial and vascular smooth muscle cells, and EDHFmediated relaxations and hyperpolarizations of rabbit