ABSTRACT:
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The nonpsychoactive cannabinoid abnormal-cannabidiol (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) (abn-cbd) produced concentration-dependent relaxation of methoxamine-precontracted rat small mesenteric artery. Endothelial removal reduced abn-cbd potency six-fold without affecting the maximum relaxation.
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In endothelium-intact vessels, abn-cbd was less potent under 60 mm KCl-induced tone and inhibited by combination of l–NG-nitroarginine methyl ester (l-NAME) (nitric oxide synthase inhibitor; 300 μm), apamin (small conductance Ca2+-activated K+ channels inhibitor; 50 nm) and charybdotoxin (inhibitor of intermediate conductance Ca2+-activated K+ channels and large conductance Ca2+-activated K+ channels BKCa; 50 nm). l-NAME alone or in combination with either toxin alone had little effect.
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In intact vessels, relaxations to abn-cbd were inhibited by SR 141716A (cannabinoid receptor antagonist; 1 or 3 μm). Concomitant addition of l-NAME, apamin and charybdotoxin had no further effect. Other cannabinoid receptor antagonists either had little (SR 144528; 1 μm and AM 251; 1 μm) or no effect (AM 630; 10 μm and AM 281; 1 μm). Inhibition of gap junctions, Gi/oprotein coupling and protein kinase A also had no effect.
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Endothelium-independent relaxation to abn-cbd was unaffected by l-NAME, apamin plus charybdotoxin or capsaicin (10 μm). Abn-cbd inhibited CaCl2-induced contractions in vessels with depleted intracellular Ca2+ stores and stimulated with methoxamine or KCl. This was insensitive to SR 141716A (3 μm) but greatly reduced in vessels stimulated with ionomycin (Ca2+ ionophore; 1 μm).
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We conclude that abn-cbd relaxes the rat small mesenteric artery by endothelium-dependent activation of K+ channels via SR 141716A-sensitive pathways, which do not involve CB1 and CB2 receptors. It also causes endothelium-independent, SR 141716A-insensitive, relaxation by inhibiting Ca2+ entry through voltage-gated Ca2+ channels.
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