ABSTRACT:
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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.
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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).
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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).
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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.
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