Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes.
Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes.
复制标题
新型 Na /Ca2 交换抑制剂 YM-244769 对豚鼠心室肌细胞 Na /Ca2 交换电流的抑制作用。
DOI：
10.1007/s00210-016-1282-y
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kimura J.
中科院分区：
文献类型：
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作者：
Yamashita K;Watanabe Y;Kita S;Iwamoto T;Kimura J.
最近，YM-244769烟酰胺((N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy})被报道为一种新的有效和选择性的钠/钙交换(Ncx)抑制剂，通过使用45Ca2+荧光技术将NCX基因导入多种细胞。然而，YM-244769在NCX上的电生理研究尚未在哺乳动物心脏上进行。采用全细胞电压钳技术，观察YM-244769对豚鼠单个心肌细胞Ncx电流的影响。YM-244769以浓度依赖的方式抑制双向INCX。YM-244769对双向外向和内向INCX的IC50值均约为0.1M。YM-244769对单向外向INCX(钙进入模式)的IC50值为0.05M，对单向内向INCX(钙退出模式)的IC50值较小，YM-244769的10μM对单向外向INCX的抑制作用仅为50%左右。当细胞内Na+浓度为5 mM时，YM-244769对INCX的抑制作用强于0 mM[Na+]i，经吸管液胞内应用胰酶不改变YM-244769的阻断作用。综上所述，YM-244769对NCX细胞钙离子内流模式的抑制作用强于钙离子外流模式，且YM-244769的抑制作用依赖于[Na+]i，对胰酶不敏感。这些特性类似于其他苄氧基苯类NCX抑制剂，如KB-R7943、SEA0400和SN-6。YM-244769作为NCX1抑制剂的效力高于KB-R7943和SN-6，与SEA0400相近。
Recently, YM-244769 (N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide) has been reported as a new potent and selective Na+/Ca2+exchange (NCX) inhibitor by using various cells transfected with NCX using the45Ca2+fluorescent technique. However, the electrophysiological study of YM-244769 on NCX had not been performed in the mammalian heart. We examined the effects of YM-244769 on NCX current (INCX) in single cardiac ventricular myocytes of guinea pigs by using the whole-cell voltage clamp technique. YM-244769 suppressed the bidirectional INCXin a concentration-dependent manner. The IC50values of YM-244769 for the bidirectional outward and inward INCXwere both about 0.1 μM. YM-244769 suppressed the unidirectional outward INCX(Ca2+entry mode) with an IC50value of 0.05 μM. The effect on the unidirectional inward INCX(Ca2+exit mode) was less potent, with 10 μM of YM-244769 resulting in the inhibition of only about 50 %. At 5 mM intracellular Na+concentration, YM-244769 suppressed INCXmore potently than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM-244769. In conclusion, YM-244769 inhibits the Ca2+entry mode of NCX more potently than the Ca2+exit mode, and inhibition by YM-244769 is [Na+]i-dependent and trypsin-insensitive. These characteristics are similar to those of other benzyloxyphenyl derivative NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The potency of YM-244769 as an NCX1 inhibitor is higher than those of KB-R7943 and SN-6 and is similar to that of SEA0400.