title: Blockade by NIP-142, an antiarrhythmic agent, of carbachol-induced atrial action potential shortening and GIRK1/4 channel.
abstract: Mechanisms for the atria-specific action potential-prolonging action of NIP-142 ((3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol), a benzopyran compound that terminates experimental atrial arrhythmia, was examined. In isolated guinea-pig atrial tissue, NIP-142 reversed the shortening of action potential duration induced by either carbachol or adenosine. These effects were mimicked by tertiapin, but not by E-4031. NIP-142 concentration-dependently blocked the human G protein-coupled inwardly rectifying potassium channel current (GIRK1/4 channel current) expressed in HEK-293 cells with an EC50 value of 0.64 microM. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC50 value of 44 microM. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under beta-adrenergic stimulation, indicating lack of effect on the muscarinic receptor and Gi protein. These results suggest that NIP-142 directly inhibits the acetylcholine-activated potassium current.
authors.affiliation: Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsuda
authors.forename: Mie
authors.initials: M
authors.lastname: Ito
authors.forename: Sayoko
authors.initials: S
authors.lastname: Ishimaru
authors.forename: Noriko
authors.initials: N
authors.lastname: Tsuruoka
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Saito
authors.forename: Naoko
authors.initials: N
authors.lastname: Iida-Tanaka
authors.forename: Norio
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Tsuruzoe
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
authors.forename: Koki
authors.initials: K
authors.lastname: Shigenobu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D001514:Bee Venoms; D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C427584:NIP142; D026902:Potassium Channel Blockers; D005576:Colforsin; C029738:tertiapin; D001285:Atropine; D002217:Carbachol; D000241:Adenosine