Blockade by NIP-142, an antiarrhythmic agent, of carbachol-induced atrial action potential shortening and GIRK1/4 channel.
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.
Matsuda
Tomoyuki
T
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Ito
Mie
M
Ishimaru
Sayoko
S
Tsuruoka
Noriko
N
Saito
Tomoaki
T
Iida-Tanaka
Naoko
N
Hashimoto
Norio
N
Yamashita
Toru
T
Tsuruzoe
Nobutomo
N
Tanaka
Hikaru
H
Shigenobu
Koki
K
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
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