Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor.
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 microM, 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 microM, 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 microM, Rmax=58.4+/-1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 microM for 30 min) shifted the oleamide concentration-response curve approximately 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 microM, Rmax=66.8+/-4.5%, n=6; P<0.01). Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 microM) significantly inhibited relaxation induced by oleamide (EC50=3.5+/-0.3 microM, Rmax=75.1+/-1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 microM), nor the CB2 antagonist, SR144528 (1 microM), had significant effects. O-1918 (10 microM), 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 (KC)) and involve capsaicin-sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O-1918, and coupled to KC) 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.
Hoi
Pui Man
PM
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Hiley
C Robin
CR
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009829:Oleic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D009829:Oleic Acids; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014665:Vasodilator Agents; C081565:arachidonyltrifluoromethane; C029407:oleylamide; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin