Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor

Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel... 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 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). 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). 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. British Journal of Pharmacology (2006) 147, 560–568. doi:10.1038/sj.bjp.0706643 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor

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Publisher
Wiley
Copyright
2006 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0706643
pmid
16415907
Publisher site
See Article on Publisher Site

Abstract

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 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). 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). 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. British Journal of Pharmacology (2006) 147, 560–568. doi:10.1038/sj.bjp.0706643

Journal

British Journal of PharmacologyWiley

Published: Mar 1, 2006

References

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