Blockade by NIP-142, an antiarrhythmic agent, of carbachol-induced atrial action potential shortening and GIRK1/4 channel

Author:

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

Journal:

JOURNAL OF PHARMACOLOGICAL SCIENCES

Issue Date:

2006

Abstract(summary):

Mechanisms for the atria-specific action potential-prolonging action of NIP-142 ((3R*,4S*)-4-cyclopropyl.amino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphen ylacetylamino)-7nitro-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 mu M. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC50 value of 44 mu M. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under P-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.

Page:

303---310