Hoi Pui Man, Hiley C Robin
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Br J Pharmacol. 2006 Mar;147(5):560-8. doi: 10.1038/sj.bjp.0706643.
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.
油酰胺（顺式-9-十八碳烯酰胺）尽管对目前已知的大麻素受体亲和力较低，但仍表现出一些拟大麻反应。在此，我们研究了它在大鼠小肠系膜动脉中是否为血管舒张剂。油酰胺引起血管舒张（半数有效浓度[EC50]=1.2±0.2微摩尔，最大反应率[Rmax]=99.1±3.9%，n=8），去除内皮后该反应减弱。一氧化氮合酶抑制降低了反应（EC50=5.3±1.6微摩尔，Rmax=59.2±7.7%，n=7；P<0.01），用蜂毒明肽加蝎毒素（均为50纳摩尔）阻断钙敏感钾通道（KCa）也降低了反应（EC50=2.1±0.2微摩尔，Rmax=58.4±1.9%，n=5；P<0.05）。用辣椒素（10微摩尔，作用30分钟）使香草酸受体脱敏使油酰胺浓度-反应曲线右移约30倍（n=7；P<0.01）。百日咳毒素（400纳克/毫升，作用2小时）使反应曲线发生两倍的位移（EC50=2.2±0.4微摩尔，Rmax=66.8±4.5%，n=6；P<0.01）。利莫那班（CB1大麻素受体拮抗剂；SR141716A；3微摩尔）显著抑制油酰胺诱导的舒张（EC50=3.5±0.3微摩尔，Rmax=75.1±1.9%；n=8；P<0.05）。相比之下，更具选择性的CB1受体拮抗剂AM251（1微摩尔）和CB2拮抗剂SR144528（1微摩尔）均无显著作用。O-1918（10微摩尔），一种新型内皮大麻素受体（异常大麻二酚位点）的假定拮抗剂，显著降低了对油酰胺的舒张反应（n=7；P<0.01）。结论是，在大鼠离体小肠系膜动脉中，油酰胺反应部分依赖于内皮的存在、钙敏感钾通道（KC）的激活，且涉及辣椒素敏感的感觉神经。在该血管中，油酰胺可能与花生四烯乙醇胺共享一种受体（对利莫那班和O-1918敏感，并与KC和Gi/o偶联）。这可能与已知的两种大麻素受体以及新型异常大麻二酚位点均不同。
