Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo

Abstract

Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCNQ1 (K v LQT1-Y315S) have a Long QT-Syndrome 1 (LQT1) phenotype. We evaluated for the first time the effect of nicorandil, an opener of ATP-sensitive potassium channels, and of isoproterenol on cardiac action potential duration and heart rate dependent dispersion of repolarisation in transgenic LQT1 rabbits.In vivo LQT1 and littermate control were subjected to transvenous electrophysiological studies; in vitro monophasic action potentials were recorded from explanted Langendorff-perfused hearts.In vivo ventricular effective refractory periods (VERP) at the right ventricular base were significantly prolonged in LQT1 as compared to littermate control, resulting in a more pronounced VERP dispersion in LQT1. This difference in VERP dispersion between LQT1 and littermate control disappeared after infusion of nicorandil. In vitro, mean action potential durations (APD 75 and APD90) of LQT1 were significantly prolonged compared to littermate control at baseline. Nicorandil decreased APD 75 and APD 90 in LQT1 and littermate control at all stimulated heart rates. After adding nicorandil, the APD 90 at all hearts rates and the APD75 at high heart rates were no longer different. Dispersion of repolarisation (ΔAPD 75 and ΔAPD 90 ) was heart rate dependently decreased after nicorandil at all tested stimulation cycle lengths only in LQT1.We demonstrated phenotypic differences of LQT1 and littermate control in vivo and in vitro. Nicorandil 20 μmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits.

Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation

“…The effect of two experimental potassium channel enhancers on cardiomyocyte FPD/APD was evaluated ( Figure 6 D and E ); nicorandil, an Ik ATP channel opener, 30 and PD-118057, a type 2 I kr channel enhancer that attenuates channel closing. 28 In LQT2–hiPSC myocytes, the APD was shortened by 18.6% with nicorandil and was sufficient to abolish spontaneously occurring EADs ( Figure 6 G ).…”

Modulation of the QT interval duration in hypertension with antihypertensive treatment

“…Nicorandil, in particular, shortens ventricular repolarization if prolonged experimentally 137 and modulates QT interval changes in humans. 35,138 However, nicorandil acts directly on ATP-sensitive K + channels; this action is predictable and is likely not associated with BP changes.…”

Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel

“…Reduction of I Ks current has been modeled both pharmacologically using a KCNQ1 inhibitor (23) and genetically with transgenic rabbits overexpressing loss-of-function pore mutants of KCNQ1 (4). Using these animal or pharmacological models, the attempts to rescue prolongation of APDs have been carried out using either an I Kr activator (24) or an opener of ATP-sensitive potassium channels (25). Pharmacological interventions aiming at influencing the APD have been in use for many years, such as class III antiarrhythmics for APD prolongation.…”