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Three cannabinoid receptor agonists, anandamide (CB1 receptor-selective) and the aminoalkyl-indoles, JWH 015(2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone; (CB2 receptor-selective), R-(+)-WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; slightly CB2 receptor-selective), as well as the enantiomer S-(−)-WIN 55,212-3(S-(−)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; inactive at cannabinoid receptors), induced endothelium-independent relaxation of methoxamine-precontracted isolated small mesenteric artery of rat. KCL (60 mM) precontraction did not affect relaxation to the aminoalkylindoles, but reduced that to anandamide. SR14176A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 3 μM; CB1 receptor antagonist) inhibited relaxation only to JWH 015 and anandamide. Neither AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; CB1 antagonist) nor SR 144528 (N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; CB2 antagonist; both at 3 μM) affected any of the relaxations. Vanilloid receptor desensitisation with capsaicin reduced anandamide relaxation; addition of SR 141716A (3 μM) then caused further inhibition. SR 141716A did not affect capsaicin-induced relaxation. The aminoalkylindoles inhibited CaCl2-induced contractions in methoxamine-stimulated vessels previously depleted of intracellular Ca2+. These inhibitory effects were greatly reduced or abolished in ionomycin-(a calcium ionophore) contracted vessels. Anandamide also caused vanilloid receptor-independent, SR 141716A- (3 μM) insensitive, inhibition of CaCl2 contractions. In conclusion, the aminoalkylindoles JWH 015, R-(+)-WIN 55,212-2 and S-(−)-WIN 55,212-3 relax rat small mesenteric artery mainly by inhibiting Ca2+ influx into vascular smooth muscle. Anandamide causes vasorelaxation by activating vanilloid receptors, but may also inhibit Ca2+ entry. Relaxation to JWH 015 and anandamide was sensitive to SR 141716A, but there is no other evidence for the involvement of CB1 or CB2 receptors in responses to these compounds. British Journal of Pharmacology (2003) 139, 585–597. doi:10.1038/sj.bjp.0705280 |
