Mechanisms of vasorelaxation induced by oleoylethanolamide in the rat small mesenteric artery

• Published in: European journal of pharmacology 2013-02, Vol.702 (1-3), p.1-11
• Main Authors: AlSuleimani, Yousuf M, Hiley, C Robin
• Format: Article
• Language: English
• Subjects: Animals; antagonists; blood flow; Ca2+-activated K+ channels; calcium; Cannabinoid receptors; cannabinoids; capsaicin; Endocannabinoids; endothelium; Endothelium, Vascular - physiology; food intake; In Vitro Techniques; Male; mesenteric arteries; Mesenteric Arteries - physiology; monounsaturated fatty acids; myo-inositol; nerve tissue; Nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - physiology; Oleic Acids - pharmacology; Oleoylethanolamide; pertussis toxin; pharmacology; Phospholipase C; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - physiology; Potassium Channels, Calcium-Activated - antagonists & inhibitors; Potassium Channels, Calcium-Activated - physiology; potassium chloride; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - physiology; receptors; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - physiology; satiety; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - physiology; Type C Phospholipases - antagonists & inhibitors; Type C Phospholipases - physiology; vasodilation; Vasodilation - drug effects; Vasodilation - physiology; Vasorelaxation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.01.006

The actions of the anandamide-like mono-unsaturated fatty acid oleoylethanolamide (OEA) were first linked to satiety and control of food intake and recently reported to relax resistance vessels. This study characterizes its vasorelaxant mechanisms. Vasorelaxation to OEA were assessed in third order branches of rat superior mesenteric artery using a wire myograph. The roles of the endothelium, KCa channels, perivascular sensory nerves, NO, cannabinoid receptors, and the phospholipase C (PLC)/inositol trisphosphate (InsP3) and RhoA/ROCK signalling pathways, were assessed. OEA caused concentration- and endothelium-dependent vasorelaxation (pEC50=6.7±0.1, Rmax=93.1±2.5%). L-NAME greatly reduced the response (residual relaxation of only 24.6±12.8%). Capsaicin and pertussis toxin significantly reduced the vasorelaxation. Precontraction with KCl abolished the response. TRAM-34 had no effect, but both iberiotoxin and apamin+charybdotoxin markedly shifted the OEA concentration–response curve to the right (∼5-fold). O-1918 but not rimonabant attenuated the vasorelaxation. Both the CB1 receptor antagonist, AM251 and the CB2 receptor antagonist, AM630, given alone or in combination, reduced the response to OEA. Inhibition of PLC by U73122, ROCK by Y-27632 and antagonism of inositol trisphosphate (InsP3) receptors by 2-APB abolished OEA vasorelaxation. OEA vasorelaxation involves an endothelial site of action but not the known cannabinoid receptors. It involves Ca2+ released from InsP3-sensitive endothelial stores by mechanisms involving RhoA kinase and phospholipase C. It is likely that the released Ca2+ causes NO generation and opening of mainly large-conductance KCa channels. This study demonstrates a possible novel endothelial target that might be important in the control of regional blood flow induced by this lipid molecule.