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Vasodilator actions of abnormal‐cannabidiol in rat isolated small mesenteric artery
Author(s) -
Vanessa Ho WS,
Hiley C Robin
Publication year - 2003
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 - 10.1038/sj.bjp.0705160
Subject(s) - apamin , charybdotoxin , chemistry , cannabinoid receptor antagonist , cannabidiol , pharmacology , mesenteric arteries , iberiotoxin , methoxamine , potassium channel , biophysics , antagonist , medicine , biochemistry , receptor , cannabinoid receptor , biology , agonist , membrane potential , artery , cannabis , psychiatry
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. In endothelium‐intact vessels, abn‐cbd was less potent under 60 m M KCl‐induced tone and inhibited by combination of L ‐ N G ‐nitroarginine methyl ester ( L ‐NAME) (nitric oxide synthase inhibitor; 300 μ M ), apamin (small conductance Ca 2+ ‐activated K + channels inhibitor; 50 n M ) and charybdotoxin (inhibitor of intermediate conductance Ca 2+ ‐activated K + channels and large conductance Ca 2+ ‐activated K + channels BK Ca ; 50 n M ). L ‐NAME alone or in combination with either toxin alone had little effect. In intact vessels, relaxations to abn‐cbd were inhibited by SR 141716A (cannabinoid receptor antagonist; 1 or 3 μ M ). Concomitant addition of L ‐NAME, apamin and charybdotoxin had no further effect. Other cannabinoid receptor antagonists either had little (SR 144528; 1 μ M and AM 251; 1 μ M ) or no effect (AM 630; 10 μ M and AM 281; 1 μ M ). Inhibition of gap junctions, G i/o protein coupling and protein kinase A also had no effect. Endothelium‐independent relaxation to abn‐cbd was unaffected by L ‐NAME, apamin plus charybdotoxin or capsaicin (10 μ M ). Abn‐cbd inhibited CaCl 2 ‐induced contractions in vessels with depleted intracellular Ca 2+ stores and stimulated with methoxamine or KCl. This was insensitive to SR 141716A (3 μ M ) but greatly reduced in vessels stimulated with ionomycin (Ca 2+ ionophore; 1 μ M ). 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 CB 1 and CB 2 receptors. It also causes endothelium‐independent, SR 141716A‐insensitive, relaxation by inhibiting Ca 2+ entry through voltage‐gated Ca 2+ channels.British Journal of Pharmacology (2003) 138 , 1320–1332. doi: 10.1038/sj.bjp.0705160