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Vasodilator actions of abnormal‐cannabidiol in rat isolated small mesenteric artery

Vasodilator actions of abnormal‐cannabidiol in rat isolated small mesenteric artery 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 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. 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/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 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). 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. British Journal of Pharmacology (2003) 138, 1320–1332. doi:10.1038/sj.bjp.0705160 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Vasodilator actions of abnormal‐cannabidiol in rat isolated small mesenteric artery

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References (59)

Publisher
Wiley
Copyright
2003 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0705160
pmid
12711633
Publisher site
See Article on Publisher Site

Abstract

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 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. 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/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 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). 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. British Journal of Pharmacology (2003) 138, 1320–1332. doi:10.1038/sj.bjp.0705160

Journal

British Journal of Pharmacology – Wiley

Published: Apr 1, 2003

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