title: Pharmacological characterization of Ca2+ entry channels in endothelin-1-induced contraction of rat aorta using LOE 908 and SK&F 96365.
abstract: We have recently shown that endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and store-operated Ca2+ channel (SOCC). These channels can be pharmacologically discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908. Here we characterized Ca2+ entry channels involved in ET-1-induced contractions of rat thoracic aortic rings and increases in the intracellular free Ca2+ concentration ([Ca2+]i) of single smooth muscle cells using these blockers. LOE 908 or a blocker of voltage-operated Ca2+ channel nifedipine had no effect on the contractions and increases in [Ca2+]i induced by thapsigargin or ionomycin, whereas SK&F 96365 abolished them. The contractions and increases in [Ca2+]i induced by ET-1 depended on extracellular Ca2+ but were resistant to nifedipine. The responses to lower concentrations (< or =0.1 nM) of ET-1 were abolished by either SK&F 96365 or LOE 908. The responses to higher concentrations (> or = 1 nM) were abolished by SK&F 96365, but were partially resistant to LOE 908. SK&F 96365 inhibited the LOE 908-resistant contractions induced by higher concentrations of ET-1 with IC50 values similar to those for contractions induced by thapsigargin or ionomycin. These results show that the contractions and increases in [Ca2+]i of rat aortic smooth muscles at lower concentrations of ET-1 involve only one Ca2+ entry channel which is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whereas those at higher concentrations of ET-1 involve another Ca2+ entry channel which is sensitive to SK&F 96365 but resistant to LOE 908 (SOCC) in addition to the former channel.
authors.affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Japan.
authors.forename: X F
authors.initials: XF
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamuro
authors.forename: T
authors.initials: T
authors.lastname: Enoki
authors.forename: M
authors.initials: M
authors.lastname: Okazawa
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Komuro
authors.forename: T
authors.initials: T
authors.lastname: Minowa
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: H
authors.initials: H
authors.lastname: Furutani
authors.forename: S
authors.initials: S
authors.lastname: Miwa
authors.forename: T
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000081:Acetamides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019332:Endothelin-1; D007093:Imidazoles; D007546:Isoquinolines; C081356:LOE 908; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; D002118:Calcium