hERG-activating compound ICA-105574 induces P-wave disappearance and cardiac arrest in isoflurane-anesthetized guinea pigs

Abstract

The human ether-à-go-go-related gene 1 (hERG1) encodes the pore subunit of a voltage-dependent K⁺ channel that mediates the rapid delayed-rectifier K⁺ current (I_Kr). Since patients with short QT syndrome (SQTS) carrying gain-of-function mutation in hERG1 have an elevated risk of lethal arrhythmias, small compounds that activate hERG/I_Kr channels may also pose a similar arrhythmic risk. To investigate the proarrhythmic risks associated with an hERG activator, we examined electrocardiogram (ECG) changes in an isoflurane-anesthetized guinea pig model upon the administration of ICA-105574, which has been reported to increase I_Kr in guinea pig myocytes. In the 10 mg/kg ICA-105574 group, ECG changes including pronounced QT shortening were observed. Meanwhile, all the animals treated with 30 mg/kg ICA-105574 exhibited cardiac arrest. The estimated unbound plasma concentration at the maximal point of action at 10 mg/kg of ICA-105574 was 0.54 µM, which was comparable to the half maximal effective concentration of hERG activation by ICA-105574 in the patch clamp study (0.49 µM). Furthermore, 0.15 mg/kg E-4031, a selective hERG inhibitor, prevented cardiac arrest induced by 30 mg/kg ICA-105574. These findings suggest that increased I_Kr induced by ICA-105574 causes cardiac arrest. Our data demonstrated that ICA-105574 has serious proarrhythmic risks, including cardiac arrest. For the development of ICA-105574 and other hERG-activating compounds as candidate therapeutic agents, it is imperative that proarrhythmic risks should be comprehensively evaluated before such agents are used in human patients.