Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery.
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.
Ho
W-S Vanessa
WS
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD.
Hiley
C Robin
CR
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D002122:Calcium Chloride / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology*; D002185:Cannabidiol / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D017629:Gap Junctions / Q000502:physiology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009213:Myography; D010880:Piperidines / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D000077285:Rimonabant; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
D015220:Calcium Channels; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D045462:Endothelium-Dependent Relaxing Factors; D010880:Piperidines; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C110630:SR 144528; D002185:Cannabidiol; D020962:Heterotrimeric GTP-Binding Proteins; D002122:Calcium Chloride; D000077285:Rimonabant