Oleamide (cis‐9‐octadecenoamide) exhibits some cannabimimetic responses despite its low affinities at the currently known cannabinoid receptors. Here we have investigated whether or not it is a vasorelaxant in rat small mesenteric arteries. Oleamide elicited vasorelaxation (EC50=1.2±0.2 μM, Rmax=99.1±3.9%, n=8) which was reduced by endothelial removal. Nitric oxide synthase inhibition reduced the response (EC50=5.3±1.6 μM, Rmax=59.2±7.7%, n=7; P<0.01) as did blockade of Ca2+‐sensitive K+ channels (KCa) with apamin plus charybdotoxin (both 50 nM) (EC50=2.1±0.2 μM, Rmax=58.4±1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 μM for 30 min) shifted the oleamide concentration–response curve ∼30‐fold to the right (n=7; P<0.01). Pertussis toxin (400 ng ml−1 for 2 h) caused a two‐fold shift in the response curve (EC50=2.2±0.4 μM, Rmax=66.8±4.5%, n=6; P<0.01). Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 μM) significantly inhibited relaxation induced by oleamide (EC50=3.5±0.3 μM, Rmax=75.1±1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 μM), nor the CB2 antagonist, SR144528 (1 μM), had significant effects. O‐1918 (10 μM), a putative antagonist at a novel endothelial cannabinoid receptor (abnormal‐cannabidiol site), markedly reduced the relaxation to oleamide (n=7; P<0.01). It is concluded that oleamide responses in the rat isolated small mesenteric artery are partly dependent on the presence of the endothelium, activation of Ca2+‐sensitive K+ channels (KCa) and involve capsaicin‐sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O‐1918, and coupled to KCa and Gi/o) with anandamide in this vessel. This might be distinct from both of the known cannabinoid receptors and the novel abnormal‐cannabidiol site. British Journal of Pharmacology (2006) 147, 560–568. doi:10.1038/sj.bjp.0706643
British Journal of Pharmacology – Wiley
Published: Mar 1, 2006
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