Vasorelaxation to N-oleoylethanolamine in rat isolated arteries: mechanisms of action and modulation via cyclooxygenase activity.
OBJECTIVE
The endocannabinoid-like molecule N-oleoylethanolamine (OEA) is found in the small intestine and regulates food intake and promotes weight loss. The principal aim of the present study was to evaluate the vascular effects of OEA.


METHODS
Perfused isolated mesenteric arterial beds were pre-contracted with methoxamine or high potassium buffers and concentration-response curves to OEA were constructed. Combinations of inhibitors to block nitric oxide production, sensory nerve activity, cyclooxygenase activity, potassium channels, chloride channels and gap junctions, and a cannabinoid CB(1) receptor antagonist, were used during these experiments. The effects of OEA on caffeine-induced contractions in calcium-free buffer were also assessed. Isolated thoracic aortic rings were used as a comparison.


RESULTS
OEA caused concentration-dependent vasorelaxation in rat isolated mesenteric arterial beds and thoracic aortic rings, with a greater maximal response in mesenteric vessels. This relaxation was sensitive to inhibition of sensory nerve activity and endothelial removal in both preparations. The cyclooxygenase inhibitor indomethacin reversed the effects of capsaicin pre-treatment in perfused mesenteric arterial beds and indomethacin alone enhanced vasorelaxation to OEA. The OEA-induced vasorelaxation was inhibited by a CB(1) receptor antagonist only in aortic rings. In mesenteric arteries, OEA suppressed caffeine-induced contractions in calcium-free buffer.


CONCLUSIONS
The vasorelaxant effects of OEA are partly dependent on sensory nerve activity and a functional endothelium in the vasculature. In addition, vasorelaxation to OEA is enhanced following cyclooxygenase inhibition. OEA may also interfere with the release of intracellular calcium in arterial preparations.
Wheal
A J
AJ
Smooth Muscle Pharmacology Group, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK. amanda.wheal@nottingham.ac.uk
Alexander
S P H
SP
Randall
M D
MD
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001095:Arachidonic Acids / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004983:Ethanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009829:Oleic Acids; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D011984:Sensory Receptor Cells / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
D001095:Arachidonic Acids; D018118:Chloride Channels; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C033595:N-oleoylethanolamine; D009569:Nitric Oxide; D002110:Caffeine; C103505:AM 251; D011451:Prostaglandin-Endoperoxide Synthases; D002211:Capsaicin; C078814:anandamide; D007213:Indomethacin