Sato R, Koumi S, Hisatome I, Takai H, Aida Y, Oyaizu M, Karasaki S, Mashiba H, Katori R
First Department of Internal Medicine, Kinki University, Osaka, Japan.
J Pharmacol Exp Ther. 1995 Jul;274(1):469-74.
We have studied the effects of MS-551 on the inward rectifier potassium channel (IK1) in isolated guinea-pig ventricular myocytes by use of whole-cell and single-channel recording techniques. MS-551 (5 microM) blocked the IK1 current. The percent blockade of the peak and steady-state IK1 current by MS-551 was constant at each test potential. In contrast 50 microM MS-551 failed to block either the sodium or the calcium current. Under cell-attached patch conditions, MS-551 reduced the open probability of IK1 channel activity by prolonging the interburst interval without changing either the unitary amplitude or the equilibrium potential. The blockade of IK1 was concentration-dependent. MS-551 did not change either the mean open time or mean closed time within a burst. Extracellular acidification (pH 6.4) strongly attenuated the effect of MS-551 on the open probability of IK1 channel activity when compared with its effect at pH 7.4. In summary, our results demonstrated that MS-551 blocked the IK1 channel. The neutral form of this drug molecules may penetrate the cardiac cell membrane via a hydrophobic pathway to block the steady-state IK1 current by reduction of open probability.
我们运用全细胞和单通道记录技术，研究了MS - 551对分离的豚鼠心室肌细胞内向整流钾通道（IK1）的影响。MS - 551（5微摩尔）阻断了IK1电流。在每个测试电位下，MS - 551对IK1电流峰值和稳态电流的阻断百分比是恒定的。相比之下，50微摩尔的MS - 551未能阻断钠电流或钙电流。在细胞贴附式膜片钳条件下，MS - 551通过延长爆发间期降低了IK1通道活性的开放概率，而不改变单通道幅度或平衡电位。IK1的阻断呈浓度依赖性。MS - 551在爆发期间既不改变平均开放时间也不改变平均关闭时间。与pH 7.4时相比，细胞外酸化（pH 6.4）强烈减弱了MS - 551对IK1通道活性开放概率的影响。总之，我们的结果表明MS - 551阻断了IK1通道。该药物分子的中性形式可能通过疏水途径穿透心肌细胞膜，通过降低开放概率来阻断稳态IK1电流。
