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

TY - JOUR

T1 - A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

AU - Calloe, Kirstine

AU - Di Diego, José M

AU - Hansen, Rie Schultz

AU - Nagle, Shea A

AU - Treat, Jacqueline A

AU - Cordeiro, Jonathan M

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/5/15

Y1 - 2016/5/15

N2 - 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 48h. 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±4.5pA/pF, and IKr from 0.28±0.06 to 0.47±0.09pA/pF after 2days in culture. AP recordings from 2day 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.

AB - 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 48h. 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±4.5pA/pF, and IKr from 0.28±0.06 to 0.47±0.09pA/pF after 2days in culture. AP recordings from 2day 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.

U2 - 10.1016/j.bcp.2016.03.015

DO - 10.1016/j.bcp.2016.03.015

M3 - Journal article

C2 - 27002181

SN - 0006-2952

VL - 108

SP - 36

EP - 46

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

ER -