Matsuda Tomoyuki, Ito Mie, Ishimaru Sayoko, Tsuruoka Noriko, Saito Tomoaki, Iida-Tanaka Naoko, Hashimoto Norio, Yamashita Toru, Tsuruzoe Nobutomo, Tanaka Hikaru, Shigenobu Koki
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
J Pharmacol Sci. 2006 Aug;101(4):303-10. doi: 10.1254/jphs.fp0060324. Epub 2006 Aug 5.
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.
对NIP-142（(3R*,4S*)-4-环丙基氨基-3,4-二氢-2,2-二甲基-6-(4-甲氧基苯乙酰氨基)-7-硝基-2H-1-苯并吡喃-3-醇）这种终止实验性房性心律失常的苯并吡喃化合物的心房特异性动作电位延长作用机制进行了研究。在分离的豚鼠心房组织中，NIP-142逆转了由卡巴胆碱或腺苷诱导的动作电位时程缩短。这些作用可被替地品模拟，但不能被E-4031模拟。NIP-142浓度依赖性地阻断在HEK-293细胞中表达的人G蛋白偶联内向整流钾通道电流（GIRK1/4通道电流），其半数有效浓度（EC50）值为0.64微摩尔。在较高浓度下，NIP-142以44微摩尔的EC50值阻断人去甲肾上腺素能相关基因（HERG）通道电流。在分离的豚鼠乳头肌中，NIP-142在β-肾上腺素能刺激下对卡巴胆碱的负性肌力作用无影响，表明对毒蕈碱受体和Gi蛋白无作用。这些结果提示NIP-142直接抑制乙酰胆碱激活的钾电流。
