title: Physiological role of Ca2+-permeable nonselective cation channel in endothelin-1-induced contraction of rabbit aorta.
abstract: We previously showed a role for a nonselective cation channel (NSCC) in the ETA-dependent action of endothelin-1 in mouse fibroblast and rabbit aortic smooth-muscle cell. To clarify the physiological significance of NSCCs in endothelin-1 (ET-1)-induced vasocontraction, we examined the effects of NSCC blockers such as mefenamic acid and SK&F 96365 on the contractions of deendothelialized rabbit aortic rings induced by a low (10[-10] M) or high (10[-8] M) concentration of ET-1. Mefenamic acid (< or =10[-3] M) had little effect on the contraction induced by 45 x 10(-3) M K+ or 1 x 10(-6) M Bay K-8644 in combination with 15 x 10(-3) M K+, indicating that it does not affect voltage-operated calcium channels (VOCs) and contractile mechanisms. The contraction by a low concentration of ET-1 was abolished after removal of extracellular Ca2+, but it was reduced only to 50% by a maximally effective concentration (10[-5] M) of nifedipine, an inhibitor of L-type VOCs (L-VOC). Mefenamic acid and SK&F 96365 inhibited the ET-1-induced contraction with 50% inhibitory concentration (IC50) values of 10(-4) M and 2 x 10(-5) M, respectively, and abolished it at 10(-3) M and 10(-4) M. By contrast, nifedipine, mefenamic acid, or SK&F 96365 had little effect on the contraction by a high concentration of ET-1. The contraction induced by a low or high concentration of ET-1 was abolished by an ETA antagonist, BQ-123, but not by an ETB antagonist, BQ-788. These results demonstrate that the contraction induced by ET-1 is totally mediated exclusively by ETA, but that Ca2+ entry through NSCCs in addition to L-VOCs plays an important role in contractions induced by low concentrations of ET-1, whereas it plays only a minor role in contractions induced by high concentrations of ET-1.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Komuro
authors.forename: S
authors.initials: S
authors.lastname: Miwa
authors.forename: X F
authors.initials: XF
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Minowa
authors.forename: T
authors.initials: T
authors.lastname: Enoki
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Ninomiya
authors.forename: T
authors.initials: T
authors.lastname: Sawamura
authors.forename: K
authors.initials: K
authors.lastname: Kikuta
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamuro
authors.forename: H
authors.initials: H
authors.lastname: Furutani
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Uemura
authors.forename: H
authors.initials: H
authors.lastname: Kikuchi
authors.forename: T
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019332:Endothelin-1; D007093:Imidazoles; D008528:Mefenamic Acid; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; D011188:Potassium