Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product.
OBJECTIVE
The endocannabinoid virodhamine is a partial agonist at the cannabinoid CB(1) receptor and a full agonist at the CB(2) receptor, and relaxes rat mesenteric arteries through endothelial cannabinoid receptors. Its concentration in the periphery exceeds that of the endocannabinoid anandamide. Here, we examined the influence of virodhamine on the human pulmonary artery.


METHODS
Isolated human pulmonary arteries were obtained during resections for lung carcinoma. Vasorelaxant effects of virodhamine were examined on endothelium-intact vessels precontracted with 5-HT or KCl.


RESULTS
Virodhamine, unlike WIN 55,212-2, relaxed 5-HT-precontracted vessels concentration dependently. The effect of virodhamine was reduced by endothelium denudation, two antagonists of the endothelial cannabinoid receptor, cannabidiol and O-1918, and a high concentration of the CB(1) receptor antagonist rimonabant (5 muM), but only slightly attenuated by the NOS inhibitor L-NAME and not affected by a lower concentration of rimonabant (100 nM) or by the CB(2) and vanilloid receptor antagonists SR 144528 and capsazepine, respectively. The COX inhibitor indomethacin and the fatty acid amide hydrolase inhibitor URB597 and combined administration of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance Ca(2+)-activated K(+) channels attenuated virodhamine-induced relaxation. The vasorelaxant potency of virodhamine was lower in KCl- than in 5-HT-precontracted preparations.


CONCLUSIONS
Virodhamine relaxes the human pulmonary artery through the putative endothelial cannabinoid receptor and indirectly through a COX-derived vasorelaxant prostanoid formed from the virodhamine metabolite, arachidonic acid. One or both of these mechanisms may stimulate vasorelaxant Ca(2+)-activated K(+) channels.
Kozłowska
H
H
Department of Experimental Physiology, Medical University of Białystok, Białystok, Poland. hkozl@umwb.edu.pl
Baranowska
M
M
Schlicker
E
E
Kozłowski
M
M
Laudañski
J
J
Malinowska
B
B
D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002186:Cannabinoids; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D001095:Arachidonic Acids; D002186:Cannabinoids; D024681:Potassium Channels, Calcium-Activated; D043882:Receptors, Cannabinoid; C456739:virodhamine; D016718:Arachidonic Acid; D012701:Serotonin; D011189:Potassium Chloride; D011451:Prostaglandin-Endoperoxide Synthases