Search

Background and Purposes: Reduced inward rectifier potassium channel (Kir2.1) functioning is associated with heart failure and may cause Andersen‐Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen–Tawil Syndrome patients are treated with β‐adrenoceptor antagonists (β‐blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (IK1) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen–Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances IK1 current, but it also exerts many off‐target effects. Therefore, discovering and exploring new IK1‐channel openers is necessary. Experimental Approach: Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single‐cell patch‐clamp electrophysiology. Kir2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human‐induced pluripotent stem cells–derived cardiomyocytes (hiPSC‐CMCs). Molecular docking was performed to obtain detailed information on drug‐channel interactions. Key Results: Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of IK1 while not affecting the Kir2.1 channel expression levels. GPV0057 did not block IKr at concentrations below 0.5 μmol L−1 nor NaV1.5 current below 1 μmol L−1. Moreover, hiPSC‐CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L−1. Structure analysis indicates a mechanism by which GPV0057 might enhance Kir2.1 channel activation. Conclusion and Implications: GPV0057 has a strong efficiency towards increasing IK1, which makes it a good candidate to address IK1 deficiency‐associated diseases. [ABSTRACT FROM AUTHOR]

Cantú syndrome (CS) is caused by dominant gain‐of‐function mutation in ATP‐dependent potassium channels. Cellular ATP concentrations regulate potassium current thereby coupling energy status with membrane excitability. No specific pharmacotherapeutic options are available to treat CS but IKATP channels are pharmaceutical targets in type II diabetes or cardiac arrhythmia treatment. We have been suggested that IKATP inhibitors, glibenclamide and HMR1098, normalize CS channels. IKATP in response to Mg‐ATP, glibenclamide and HMR1098 were measured by inside‐out patch‐clamp electrophysiology. Results were interpreted in view of cryo‐EM IKATP channel structures. Mg‐ATP IC50 values of outward current were increased for D207E (0.71 ± 0.14 mmol/L), S1020P (1.83 ± 0.10), S1054Y (0.95 ± 0.06) and R1154Q (0.75 ± 0.13) channels compared to H60Y (0.14 ± 0.01) and wild‐type (0.15 ± 0.01). HMR1098 dose‐dependently inhibited S1020P and S1054Y channels in the presence of 0.15 mmol/L Mg‐ATP, reaching, at 30 μmol/L, current levels displayed by wild‐type and H60Y channels in the presence of 0.15 mmol/L Mg‐ATP. Glibenclamide (10 μmol/L) induced similar normalization. S1054Y sensitivity to glibenclamide increases strongly at 0.5 mmol/L Mg‐ATP compared to 0.15 mmol/L, in contrast to D207E and S1020P channels. Experimental findings agree with structural considerations. We conclude that CS channel activity can be normalized by existing drugs; however, complete normalization can be achieved at supraclinical concentrations only. [ABSTRACT FROM AUTHOR]

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. K IR 2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (I K 1 ), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics. Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system. Here we defined the potential interference in K IR 2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited I K 1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased K IR 2.1 expression (2.0 ± 0.2-fold with amiodarone: 10 μM, 24 hrs; 2.3 ± 0.3-fold with dronedarone: 5 μM, 24 hrs) and late-endosomal/lysosomal K IR 2.1 accumulation. Increased K IR 2.1 expression level was also observed in the presence of Na v 1.5 co-expression. Augmented K IR 2.1 protein levels and intracellular accumulation were also observed in COS-7, END-2, MES-1 and EPI-7 cells. Both drugs had no effect on K v 11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at -120 mV, 5 μM) enhanced I KIR 2.1 upon 24-hrs treatment, whereas dronedarone tended to increase I KIR 2.1 and it did not reach significance (43.8 ± 5.5%, P = 0.26 at -120 mV; 2 μM). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced I K 1 by inhibiting K IR 2.1 degradation., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)