title: The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant.
abstract: N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodynamic effects and mechanisms of vasorelaxation. Hemodynamic effects of NAGLY in rats were assessed using a Biopac system and its vascular responses were assessed using a wire myograph. NAGLY (1mg/kg) decreased blood pressure by 69.4±5.5% and reduced renal blood flow by 88±12% and the effects were not sensitive to inhibition by O-1918 (3mg/kg). In resistant vessels, NAGLY (1-30µM) induced concentration- and endothelium-dependent vasorelaxation and the effect was inhibited by the nitric oxide synthase inhibitor, L-NAME (300µM), a cGMP synthase inhibitor, ODQ (10µM), the antagonists of "endothelial anandamide" receptor, rimonabant (3µM) and O-1918 (10µM) and the inhibitor of Na+/Ca2+exchanger (NCX), KB-R7943 (10µM). On the other hand, NAGLY-induced vasorelaxation was not affected by CID 16020046 (GPR55 antagonist), AM 251 (cannabinoid CB1receptor antagonist), AM 630 (cannabinoid CB2receptor antagonist), capsazepine (TRPV1 antagonist), indomethacin (cyclooxygenase inhibitor), TRAM34 (IKCa channel blocker), iberiotoxin (BKCa channel blocker) and GW9662 (PPARɤ antagonist). At low concentrations of carbachol, NAGLY potentiated carbachol-induced vasorelaxation. NAGLY is an endothelium-dependent vasodilator and hypotensive lipid. The vasorelaxation is predominantly via activation of nitric oxide-cGMP pathway and NCX and probably mediated by the "endothelial anandamide" receptor, while the hypotensive effect of NAGLY appears not to involve the anandamide receptor. NAGLY also potentiates carbachol-induced vasorelaxation, the mechanism of which might involve stimulation of NO release.
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, 35, Alkoudh 123, Sultanate of Oman. Electronic address: ymksqu@hotmail.com.
authors.forename: Yousuf M
authors.initials: YM
authors.lastname: Al Suleimani
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, 35, Alkoudh 123, Sultanate of Oman.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Al Mahruqi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D000077285:Rimonabant; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C552735:1,3-dimethoxy-5-methyl-2-(3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)benzene; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000840:Anisoles; D001095:Arachidonic Acids; D003510:Cyclohexanes; C465623:N-arachidonylglycine; D010069:Oxadiazoles; D010880:Piperidines; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D011810:Quinoxalines; D010656:Phenylephrine; D009569:Nitric Oxide; D002217:Carbachol; D013890:Thiourea; D006152:Cyclic GMP; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester
keywords: Hypotensive; N-arachidonoyl glycine; Na(+)/Ca(2+) exchanger; Nitric oxide; Vasorelaxation