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Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery.
Br J Pharmacol 2003; 138(7):1320-32BJ

Abstract

1. 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. 2. In endothelium-intact vessels, abn-cbd was less potent under 60 mM KCl-induced tone and inhibited by combination of L-N(G)-nitroarginine methyl ester (L-NAME) (nitric oxide synthase inhibitor; 300 micro M), apamin (small conductance Ca(2+)-activated K(+) channels inhibitor; 50 nM) and charybdotoxin (inhibitor of intermediate conductance Ca(2+)-activated K(+) channels and large conductance Ca(2+)-activated K(+) channels BK(Ca); 50 nM). L-NAME alone or in combination with either toxin alone had little effect. 3. In intact vessels, relaxations to abn-cbd were inhibited by SR 141716A (cannabinoid receptor antagonist; 1 or 3 micro M). Concomitant addition of L-NAME, apamin and charybdotoxin had no further effect. Other cannabinoid receptor antagonists either had little (SR 144528; 1 micro M and AM 251; 1 micro M) or no effect (AM 630; 10 micro M and AM 281; 1 micro M). Inhibition of gap junctions, G(i/o) protein coupling and protein kinase A also had no effect. 4. Endothelium-independent relaxation to abn-cbd was unaffected by L-NAME, apamin plus charybdotoxin or capsaicin (10 micro 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 micro M) but greatly reduced in vessels stimulated with ionomycin (Ca(2+) ionophore; 1 micro M). 5. 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.

Authors+Show Affiliations

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12711633

Citation

Ho, W-S Vanessa, and C Robin Hiley. "Vasodilator Actions of Abnormal-cannabidiol in Rat Isolated Small Mesenteric Artery." British Journal of Pharmacology, vol. 138, no. 7, 2003, pp. 1320-32.
Ho WS, Hiley CR. Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br J Pharmacol. 2003;138(7):1320-32.
Ho, W. S., & Hiley, C. R. (2003). Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. British Journal of Pharmacology, 138(7), pp. 1320-32.
Ho WS, Hiley CR. Vasodilator Actions of Abnormal-cannabidiol in Rat Isolated Small Mesenteric Artery. Br J Pharmacol. 2003;138(7):1320-32. PubMed PMID: 12711633.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. AU - Ho,W-S Vanessa, AU - Hiley,C Robin, PY - 2003/4/25/pubmed PY - 2003/12/16/medline PY - 2003/4/25/entrez SP - 1320 EP - 32 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 138 IS - 7 N2 - 1. 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. 2. In endothelium-intact vessels, abn-cbd was less potent under 60 mM KCl-induced tone and inhibited by combination of L-N(G)-nitroarginine methyl ester (L-NAME) (nitric oxide synthase inhibitor; 300 micro M), apamin (small conductance Ca(2+)-activated K(+) channels inhibitor; 50 nM) and charybdotoxin (inhibitor of intermediate conductance Ca(2+)-activated K(+) channels and large conductance Ca(2+)-activated K(+) channels BK(Ca); 50 nM). L-NAME alone or in combination with either toxin alone had little effect. 3. In intact vessels, relaxations to abn-cbd were inhibited by SR 141716A (cannabinoid receptor antagonist; 1 or 3 micro M). Concomitant addition of L-NAME, apamin and charybdotoxin had no further effect. Other cannabinoid receptor antagonists either had little (SR 144528; 1 micro M and AM 251; 1 micro M) or no effect (AM 630; 10 micro M and AM 281; 1 micro M). Inhibition of gap junctions, G(i/o) protein coupling and protein kinase A also had no effect. 4. Endothelium-independent relaxation to abn-cbd was unaffected by L-NAME, apamin plus charybdotoxin or capsaicin (10 micro 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 micro M) but greatly reduced in vessels stimulated with ionomycin (Ca(2+) ionophore; 1 micro M). 5. 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12711633/Vasodilator_actions_of_abnormal_cannabidiol_in_rat_isolated_small_mesenteric_artery_ L2 - https://doi.org/10.1038/sj.bjp.0705160 DB - PRIME DP - Unbound Medicine ER -