Missan Sergey, Zhabyeyev Pavel, Dyachok Oksana, Jones Stephen E, McDonald Terence F
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Br J Pharmacol. 2003 Nov;140(5):863-70. doi: 10.1038/sj.bjp.0705518. Epub 2003 Oct 6.
The objective of this study was to determine the concentration-dependent effects of nisoldipine, a dihydropyridine Ca2+ channel blocker, on K+ currents in guinea-pig ventricular myocytes. Myocytes in the conventional whole-cell configuration were bathed in normal Tyrode's solution or K+-free Tyrode's solution for the measurement of the effects of 0.01-100 microM nisoldipine on rapidly activating delayed-rectifier K+ current (I(Kr)), slowly activating delayed-rectifier K+ current (I(Ks)), inwardly rectifying K+ current (I(K1)), and reference L-type Ca2+ current (I(Ca,L)). Nisoldipine inhibited I(Kr) with an IC(50) of 23 microM, and I(Ks) with an IC(50) of 40 microM. The drug also had weak inhibitory effects on inward- and outward-directed I(K1); the IC(50) determined for outward-directed current was 80 microM. Investigation of nisoldipine action on I(Ks) showed that inhibition occurred in the absence of previous pulsing, and with little change in the time courses of activation and deactivation. However, the drug-induced inhibition was significantly weaker at >or =+30 mV than at +10 mV.5 We estimate that nisoldipine is about 30 times less selective for delayed-rectifier K+ channels than for L-type Ca2+ channels in fully polarised guinea-pig ventricular myocytes, and several orders less selective in partially depolarised myocytes.
本研究的目的是确定二氢吡啶类钙通道阻滞剂尼索地平对豚鼠心室肌细胞钾电流的浓度依赖性作用。采用传统全细胞模式，将肌细胞置于正常台氏液或无钾台氏液中，以测量0.01 - 100微摩尔尼索地平对快速激活延迟整流钾电流（I(Kr)）、缓慢激活延迟整流钾电流（I(Ks)）、内向整流钾电流（I(K1)）以及作为对照的L型钙电流（I(Ca,L)）的影响。尼索地平抑制I(Kr)的半数抑制浓度（IC(50)）为23微摩尔，抑制I(Ks)的IC(50)为40微摩尔。该药物对内向和外向I(K1)也有微弱的抑制作用；外向电流的IC(50)为80微摩尔。对尼索地平作用于I(Ks)的研究表明，在无预脉冲的情况下即发生抑制作用，且激活和失活的时间进程变化不大。然而，在膜电位≥ +30 mV时，药物诱导的抑制作用明显弱于 +10 mV时。我们估计，在完全极化的豚鼠心室肌细胞中，尼索地平对延迟整流钾通道的选择性比对L型钙通道低约30倍，而在部分去极化的肌细胞中，选择性要低几个数量级。
