Guérard N C, Traebert M, Suter W, Dumotier B M
Novartis Pharma Ag, Exploratory Development, Safety Pharmacology, Basel, Switzerland.
J Pharmacol Toxicol Methods. 2008 Jul-Aug;58(1):32-40. doi: 10.1016/j.vascn.2008.05.129. Epub 2008 Jun 8.
The role of IKr (rapidly-activating delayed rectifier K(+) current) block in triangulation of monophasic action potentials (MAP) and in development of torsade de pointes (TdP) arrhythmia is known. Combined IKr and IKs (slowly-activating delayed rectifier K(+) current) block has been demonstrated to promote TdP. The aim of this study was to describe a possible implication of IKs block in MAP triangulation.
Four contact electrodes were placed on the epicardium of the left ventricle of Langendorff-perfused rabbit hearts to record monophasic action potentials (MAP), with an IKr blocker d,l-sotalol (3 to 100 microM, n=6) or a non-selective IKr blocker, quinidine (1 to 30 microM, n=6). Their effects were assessed with or without a specific IKs blocker chromanol 293B (20 microM, n=6), on MAP duration at 30, 60 and 90% of repolarization (APD30, 60 and 90, respectively) and MAP triangulation (APD90-APD30) at 1 and 0.2 Hz.
D,L-sotalol increased significantly APD90 and triangulation with reverse use-dependency for concentrations > or =10 microM. Quinidine markedly prolonged APD90 and triangulation with reverse use-dependency at concentrations > or =3 microM. Chromanol 293B alone had no effects on APD, but when combined with D,L-sotalol or quinidine (i) increased APD prolonging effects, (ii) lowered values of pro-arrhythmic concentrations, (iii) increased incidence and length of D,L-sotalol- or quinidine-induced Early Afterdepolarizations (EADs) and TdP. All these events were primarily due to an important slowing of final repolarization, i.e. a marked increased triangulation.
IKs, even of low amplitude in rabbits, plays a key role in ventricular repolarization. IKs is involved in prolonged MAP duration mainly by triangulation and subsequent increased drug arrhythmogenicity. Therefore drug affinity for IKs must be evaluated with IKr studies as part of preclinical drug cardiac safety assessment.
已知IKr（快速激活延迟整流钾电流）阻滞在单相动作电位（MAP）的三角测量以及尖端扭转型室性心动过速（TdP）心律失常的发生中所起的作用。IKr和IKs（缓慢激活延迟整流钾电流）联合阻滞已被证明可促进TdP的发生。本研究的目的是描述IKs阻滞在MAP三角测量中可能产生的影响。
将四个接触电极置于Langendorff灌注兔心脏左心室的心外膜上，以记录单相动作电位（MAP），使用IKr阻滞剂d，l-索他洛尔（3至100微摩尔，n = 6）或非选择性IKr阻滞剂奎尼丁（1至30微摩尔，n = 6）。在有或没有特异性IKs阻滞剂色满醇293B（20微摩尔，n = 6）的情况下，评估它们对复极化30%、60%和90%时的MAP持续时间（分别为APD30、60和90）以及1赫兹和0.2赫兹时的MAP三角测量（APD90 - APD30）的影响。
对于浓度≥10微摩尔的d，l-索他洛尔，显著增加了APD90并伴有反向使用依赖性的三角测量。对于浓度≥3微摩尔的奎尼丁，显著延长了APD90并伴有反向使用依赖性的三角测量。单独使用色满醇293B对APD无影响，但与d，l-索他洛尔或奎尼丁联合使用时，（i）增强了APD延长效应，（ii）降低了促心律失常浓度的值，（iii）增加了d，l-索他洛尔或奎尼丁诱导的早期后除极（EAD）和TdP的发生率及持续时间。所有这些事件主要是由于最终复极化明显减慢，即三角测量显著增加。
IKs即使在兔中幅度较低，在心室复极化中也起关键作用。IKs主要通过三角测量以及随后增加的药物致心律失常性参与延长MAP持续时间。因此，在临床前药物心脏安全性评估中，必须将对IKs的药物亲和力评估与IKr研究一起进行。
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