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Blockade by NIP-142, an Antiarrhythmic Agent, of Carbachol-Induced Atrial Action Potential Shortening and GIRK1/4 Channel

2006; Elsevier BV; Volume: 101; Issue: 4 Linguagem: Inglês

10.1254/jphs.fp0060324

1347-8648

Tomoyuki Matsuda, Mie Ito, Sayoko Ishimaru, Noriko Tsuruoka, Tomoaki Saito, Naoko Iida‐Tanaka, Norio Hashimoto, Toru Yamashita, Nobutomo Tsuruzoe, Hikaru Tanaka, Koki Shigenobu,

Receptor Mechanisms and Signaling

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 μM. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC50 value of 44 μM. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under β-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.