A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

Biochem Pharmacol. 2016 May 15;108:36-46. doi: 10.1016/j.bcp.2016.03.015. Epub 2016 Mar 19.

Abstract

Background: A loss of repolarization reserve due to downregulation of K(+) currents has been observed in cultured ventricular myocytes. A similar reduction of K(+) currents is well documented under numerous pathophysiological conditions. We examined the extent of K(+) current downregulation in cultured canine cardiac myocytes and determined whether a dual K(+) current activator can normalize K(+) currents and restore action potential (AP) configuration.

Methods and results: Ventricular myocytes were isolated and cultured for up to 48 h. Current and voltage clamp recordings were made using patch electrodes. Application of NS3623 to coronary-perfused left ventricular wedges resulted in increased phase 1 magnitude, epicardial AP notch and J wave amplitude. Patch clamp measurements of IKr and Ito revealed an increase in the magnitude of both currents. Culturing of Mid ventricular cells resulted in a significant decrease in Ito and IKr density. NS3623 increased Ito from 16.4 ± 2.23 to 31.8 ± 4.5 pA/pF, and IKr from 0.28 ± 0.06 to 0.47 ± 0.09 pA/pF after 2 days in culture. AP recordings from 2 day cultured cells exhibited a reduced phase 1 repolarization, AP prolongation, and early afterdepolarizations (EADs). NS3623 restored the AP notch and was able to suppress EADs.

Conclusions: NS3623 is a dual Ito and IKr activator. Application of this compound to cells with a reduced repolarization reserve resulted in an increase in these currents and a shortening of AP duration, increase in phase 1 repolarization and suppression of EADs. Our results suggest a potential benefit of K(+) current activators under conditions of reduced repolarization reserve including heart failure.

Keywords: Action potential repolarization; Cultured cells; Electrophysiology; NS3623; Repolarization reserve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Animals
  • Cells, Cultured
  • Dogs
  • Female
  • Heart Ventricles / cytology
  • Male
  • Muscle Cells / drug effects*
  • Muscle Cells / physiology
  • Myocardium / cytology*
  • Phenylurea Compounds / pharmacology*
  • Potassium Channels / physiology*
  • Tetrazoles / pharmacology*

Substances

  • NS 3623
  • Phenylurea Compounds
  • Potassium Channels
  • Tetrazoles