KCNH2 Channel Activators Increase Ikr in Hl-1 Cardiomyocytes and May Prevent the Occurrence of Torsades De Pointes in Long QT Syndrome

Abstract

Introduction: Several KCNH2 channel activators may provide a novel pharmacological approach for the treatment of long QT syndrome (LQTS). We therefore investigated the effects of the activators on IKr and action potential of cardiac myocytes.Methods: We characterized the actions of three KCNH2 channel activators, mallotoxin (MTX), PD-118057 (PD), and NS1643 (NS) on IKr of HL-1 cardiomyocytes, using the whole cell patch clamp technique. With a mathematical model of human ventricular myocytes, we further evaluated the impact of activator-induced changes in IKr kinetics on the action potential configuration in normal and LQTS.Results: The maximum tail currents of IKr were 23.4±3.5 nA/pF with 10 μM MTX (n=12), 22.1±2.7 nA/pF with 10 μM PD (n=13), and 23.3±2.7 nA/pF with 10 μM NS (n=16), which were significantly greater than 12.8±1.0 nA/pF in control (n=38). The half-maximal activation voltage was significantly shifted from −1.8±2.7 (n=38) to −13.0±2.3 (n=11), −8.3±2.1 (n=13), and −14.7±3.2 (n=14) mV by MTX, PD, and NS, respectively. Deactivation during the repolarization to −40 mV was significantly slowed by MTX, but not by PD or NS. The half-maximal inactivation voltage was significantly shifted from −6.6±2.2 (n=28) to −29.9±2.9 (n=15) mV by MTX, but not by PD, and NS. Simulation study showed that the activator-induced changes of IKr increased the amplitude of IKr during phase 2 of action potentials and consequently shortened the action potential duration by 19.7-23.6% in LQT1 and LQT3 models. A reduction of IKr in the LQT3 model evoked early afterdepolarization, which was abolished by the activator-induced enhancement of IKr.Conclusion: KCNH2 channel activators, mallotoxin, PD-118057, and NS1643 increases IKr through distinct kinetic mechanisms and can be utilized for potential therapy of LQTS and torsades de pointes.