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N ‐arachidonoyl glycine, an endogenous lipid that acts as a vasorelaxant via nitric oxide and large conductance calcium‐activated potassium channels
Author(s) -
Parmar Neelam,
Ho WS Vanessa
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00622.x
Subject(s) - iberiotoxin , chemistry , anandamide , mesenteric arteries , nitric oxide , endocannabinoid system , cannabinoid receptor , apamin , trpv1 , biochemistry , pharmacology , endocrinology , medicine , receptor , calcium , transient receptor potential channel , antagonist , biology , organic chemistry , artery
Background and purpose: N ‐arachidonoyl glycine (NAGly) is an endogenous lipid that is structurally similar to the endocannabinoid, N ‐arachidonoyl ethanolamide (anandamide). While NAGly does not activate cannabinoid receptors, it exerts cannabimimetic effects in pain regulation. Here, we have determined if NAGly, like anandamide, modulates vascular tone. Experimental approach: In rat isolated small mesenteric arteries, the relaxant responses to NAGly were characterized. Effects of N ‐arachidonoyl serine and N ‐arachidonoyl γ‐aminobutyric acid were also examined. Key results: In endothelium‐intact arteries, NAGly‐induced relaxation (pEC 50% = 5.7 ± 0.2; relaxation at 30 µM = 98 ± 1%) was attenuated by l ‐NAME (a nitric oxide synthase inhibitor) or iberiotoxin [selective blocker of large conductance Ca 2+ ‐activated K + channels (BK Ca )], and abolished by high extracellular K + concentration. Endothelial removal reduced the potency of NAGly, and the resultant relaxation was inhibited by iberiotoxin, but not l ‐NAME. NAGly responses were sensitive to the novel cannabinoid receptor antagonist O‐1918 independently of endothelial integrity, whereas pertussis toxin, which uncouples G i/o proteins, attenuated NAGly relaxation only in endothelium‐intact arteries. Treatments with antagonists for CB 1 , CB 2 and TRPV1 receptors, or inhibitors of fatty acid amide hydrolase and COX had no effect. The two other arachidonoyl amino acids also induced iberiotoxin‐ and L‐NAME‐sensitive relaxations. Conclusion and implications: NAGly acts as a vasorelaxant predominantly via activation of BK Ca in rat small mesenteric arteries. We suggest that NAGly activates an unknown G i/o ‐coupled receptor, stimulating endothelial release of nitric oxide which in turn activates BK Ca in the smooth muscle. In addition, NAGly might also activate BK Ca through G i/o ‐ and nitric oxide‐independent mechanisms.