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Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product
Author(s) -
Kozłowska H,
Baranowska M,
Schlicker E,
Kozłowski M,
Laudañski J,
Malinowska B
Publication year - 2008
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/bjp.2008.371
Subject(s) - capsazepine , endocannabinoid system , anandamide , cannabinoid , chemistry , pharmacology , cannabinoid receptor , fatty acid amide hydrolase , agonist , cannabinoid receptor antagonist , rimonabant , endocrinology , medicine , mesenteric arteries , cannabinoid receptor type 2 , trpv1 , receptor , biochemistry , transient receptor potential channel , artery
Background and purpose: 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. Experimental approach: 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. Key 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 μ M ), but only slightly attenuated by the NOS inhibitor L ‐NAME and not affected by a lower concentration of rimonabant (100 n M ) 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 and implications: 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. British Journal of Pharmacology (2008) 155 , 1034–1042; doi: 10.1038/bjp.2008.371 ; published online 22 September 2008