In Vivo Effects of the IKr Agonist NS3623 on Cardiac Electrophysiology of the Guinea Pig

Abstract

The long QT syndrome is characterized by a prolongation of the QT interval measured on the surface electrocardiogram. Prolonging the QT interval increases the risk of dangerous ventricular fibrillations, eventually leading to sudden cardiac death. Pharmacologically induced QT interval prolongations are most often caused by antagonizing effects on the repolarizing cardiac current called IKr. In humans IKr is mediated by the human ether-a-go-go related gene (hERG) potassium channel. We recently presented NS3623, a compound that selectively activates this channel. The present study was dedicated to examining the in vivo effects of NS3623. Injection of 30 mg/kg NS3623 shortened the corrected QT interval by 25 +/- 4% in anaesthetized guinea pigs. Accordingly, 50 mg/kg of NS3623 shortened the QT interval by 30 +/- 6% in conscious guinea pigs. Finally, pharmacologically induced QT prolongation by a hERG channel antagonist (0.15 mg/kg E-4031) could be reverted by injection of NS3623 (50 mg/kg) in conscious guinea pigs. In conclusion, the present in vivo study demonstrates that injection of the hERG channel agonist NS3623 results in shortening of the QTc interval as well as reversal of a pharmacologically induced QT prolongation in both anaesthetized and conscious guinea pigs.

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

“…In this context, dofetilide treatment continued to block the channel but at a somewhat higher IC 50 value (58 nM) compared with dofetilide treatment alone (11 nM). Hansen et al (2008) also reported that in vivo treatment of guinea pigs with NS3623 produced a reversal of E4031-induced prolongation of the QT interval. In the absence of pharmacologic blockade of hERG1, Patel and Antzelevitch (2008) reported that the hERG1 activator PD118057 abbreviated the QT interval but increased transmural dispersion of repolarization.…”

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…In line with theoretical considerations, the measured and corrected QT interval was reduced in both conditions. Furthermore, NS3623 reverses drug-induced QT prolongation (171). In rabbits, NS1643 has demonstrated antiarrhythmic properties in a pharmacological and nonpharmacological model for ventricular fibrillation.…”

Molecular Determinants of Humanether-à-go-go-Related Gene 1 (hERG1) K+Channel Activation by NS1643

“…It was therefore expected that hERG1 channel agonists could decrease the proclivity for these biomarkers, and this assumption has been confirmed in a number of different experimental settings. hERG1 channel agonists decrease dispersion and triangulation, prevent bradypacing and pharmacological-induced arrhythmias, shorten QT intervals in vivo, and directly protect against arrhythmias (Kang et al, 2005;Hansen et al, 2007Hansen et al, , 2008Diness et al, 2008Diness et al, , 2009). However, hERG1 agonists can also be proarrhythmic under certain settings (Larsen et al, 2008;Lu et al, 2008), placing obvious restrictions on their potential therapeutic use.…”