Diness Jonas Goldin, Abildgaard Lea, Bomholtz Sofia Hammami, Skarsfeldt Mark Alexander, Edvardsson Nils, Sørensen Ulrik S, Grunnet Morten, Bentzen Bo Hjorth
Acesion Pharma, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Front Pharmacol. 2020 May 20;11:749. doi: 10.3389/fphar.2020.00749. eCollection 2020.
Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents.Small conductance Ca-activated K-channels (K2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions K2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca.
To study the effects of pharmacological K2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC).
The current at +10 mV was compared in HEK293 cells stably expressing K2.3 perfused first with normo- and then hypokalemic solutions (4 mM K and 2.5 mM K, respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp-Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded.
Hypokalemia slightly increased K2.3 current compared to normokalemia. Application of K2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the K2 channel inhibitors increased Tp-Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the K2 channel inhibitors AP30663, ICA, or AP14145, respectively.
Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different K2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that K2 inhibition may be associated with a better safety and tolerability profile than dofetilide.
低钾血症会降低心脏复极储备。这会延长QT间期并增加室性心律失常的风险；而使用经典的3类抗心律失常药物会加剧这种风险。小电导钙激活钾通道（K2）是治疗心房颤动有前景的新的心房选择性靶点。在生理条件下，K2在心室复极中作用较小。然而，在低钾血症情况下，由于心室肌细胞内钙的同时增加，这种情况可能会改变。
研究与多非利特及单独低钾血症的时间匹配对照（TMC）相比，化合物AP14145、ICA或AP30663在低钾血症条件下对K2通道进行药理学抑制的效果。
在稳定表达K2.3的HEK293细胞中，先灌注正常钾溶液，然后灌注低钾溶液（分别为4 mM钾和2.5 mM钾），比较 +10 mV时的电流。分离豚鼠心脏，先用正常钾（4 mM钾）的Krebs-Henseleit溶液灌注，然后用药物或载体对照灌注。然后在药物存在的情况下将灌注液换成低钾溶液（2.5 mM钾）。30只动物随机分为5组：ICA组、AP14145组、AP30663组、多非利特组或TMC组。记录QT间期、T波顶峰至终点的间期（Tp-Te）、心室有效不应期（VERP）、心律失常评分和心室颤动（VF）发生率。
与正常钾血症相比，低钾血症使K2.3电流略有增加。应用K2通道抑制剂和多非利特可延长经心率校正的QT间期。多非利特在低钾血症期间会增加Tp-Te，但K2通道抑制剂均无此作用。在低钾血症期间，TMC组6只心脏中有4只发生VF（2只自发，2只通过S1S2刺激），而多非利特组6只心脏中有5只发生VF（2只自发, 3只通过S1S2刺激）。相比之下，用K2通道抑制剂AP30663、ICA或AP14145治疗时，6只心脏中分别有0只、1只和1只发生VF。
低钾血症与VF发生率增加有关，多非利特存在时也可见此效应。相比之下，结构和功能不同的K2通道抑制剂ICA、AP14145和AP30663可保护心脏免受低钾血症诱导的VF。这些结果支持，与多非利特相比，抑制K2可能具有更好的安全性和耐受性。
