title: Pharmacological evidence showing significant roles for potassium channels and CYP epoxygenase metabolites in the relaxant effects of docosahexaenoic acid on the rat aorta contracted with U46619.
abstract: Docosahexaenoic acid (DHA) shows more pronounced relaxation when blood vessel is contracted with prostanoid receptor agonists than other stimulants. The present study was carried out to obtain information on the mechanisms underlying prostanoid receptor-selective relaxant action of DHA, particularly focusing on the possible roles for K(+) channels and its CYP epoxygenase (EOX) metabolites. In endothelium-denuded rat thoracic aorta, DHA (10(-5) M) almost completely relaxed U46619 (a thromboxane A2 (TP) receptor agonist)-contracted muscle without substantially affecting noradrenaline (NA)-induced contraction. DHA-induced relaxation was not affected by a large conductance, calcium- and voltage-activated K(+) (BK) channels inhibitor iberiotoxin (IbTX, 10(-7) M) but was almost abolished by high-KCl (8×10(-2) M) or 10(-2) M tetraethylammonium (TEA) which non-selectively inhibits K(+) channel activity. DHA also prominently relaxed U46619-contracted aorta even in the presence of CYP inhibitors (SKF525A or miconazole, each at 10(-5) M). However, in the presence of these CYP inhibitors, the relaxant action of DHA was not affected by 10(-2) M TEA. In supporting a significant role for CYP EOX metabolites in the blood vessel relaxation to DHA, 16,17-epoxy docosapentaenoic acid (16,17-EpDPE), but not 19,20-EpDPE, showed a potent relaxation in U46619-contracted aorta, and this action was significantly attenuated by 10(-2) M TEA. The present findings suggest that the relaxant action of DHA shown in the rat aorta contracted through the stimulation with TP receptor is generated by DHA itself and its CYP EOX metabolites. The relaxant effect of DHA metabolites seems to be partly triggered by the activation of K(+) channels though the role for BK channel is insignificant.
authors.affiliation: Department of Pharmacology, Toho University School of Pharmaceutical Sciences.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Sato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Chino
authors.forename: Nanako
authors.initials: N
authors.lastname: Nishioka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kanai
authors.forename: Mika
authors.initials: M
authors.lastname: Aoki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Obara
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001013:Aorta, Thoracic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D004281:Docosahexaenoic Acids; D013928:Thromboxane A2; D019789:Tetraethylammonium; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003577:Cytochrome P-450 Enzyme System