A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials
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A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials. / Calloe, Kirstine; Di Diego, José M; Hansen, Rie Schultz; Nagle, Shea A; Treat, Jacqueline A; Cordeiro, Jonathan M.
In: Biochemical Pharmacology, Vol. 108, 19.03.2016, p. 36-46.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - 2016/3/19
Y1 - 2016/3/19
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
VL - 108
SP - 36
EP - 46
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
ER -
ID: 159675352