Copyright © 2007, European Society of Cardiology
K201 modulates excitation–contraction coupling and spontaneous Ca2+ release in normal adult rabbit ventricular cardiomyocytes
aInstitute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, UK
bFaculty of Biomedical & Life Sciences, University of Glasgow, UK
cDepartment of Cardiology and Pneumology, Georg-August-University Goettingen, D-37075, Goettingen, Germany
dDepartment of Cardiology and Pneumology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, Japan
*Corresponding author. Faculty of Biomedical & Life Sciences, West Medical Building, Level 4, Glasgow, G12 8QQ, UK. Tel.: +44 141 330 6309; fax: +44 141 330 4612. g.smith{at}bio.gla.ac.uk
Objectives The drug K201 (JTV-519) increases inotropy and suppresses arrhythmias in failing hearts, but the effects of K201 on normal hearts is unknown.
Methods The effect of K201 on excitation–contraction (E–C) coupling in normal myocardium was studied by using voltage-clamp and intracellular Ca2+ measurements in intact cells. Sarcoplasmic reticulum (SR) function was assessed using permeabilised cardiomyocytes.
Results Acute application of <1 µmol/L K201 had no significant effect on E–C coupling. K201 at 1 µmol/L decreased Ca2+ transient amplitude (to 83±7%) without affecting ICa,L or the SR Ca2+ content. At 3 µmol/L K201 caused a larger reduction of Ca2+ transient amplitude (to 60±7%) with accompanying reductions in ICa,L amplitude (to 66±8%) and SR Ca2+ content (74±9%). Spontaneous SR Ca2+ release during diastole was induced by increasing intracellular [Ca2+]. At 1 µmol/L K201 reduced the frequency of spontaneous Ca2+ release. The effect of K201 on SR-mediated Ca2+ waves and Ca2+ sparks was examined in β-escin-permeabilised cardiomyocytes by confocal microscopy. K201 (1 µmol/L) reduced the frequency and velocity of SR Ca2+ waves despite no change in SR Ca2+ content. At 3 µmol/L K201 completely abolished Ca2+ waves and reduced the SR Ca2+ content (to 
73%). K201 at 1 µmol/L reduced Ca2+ spark amplitude and frequency. Assays specific to SR Ca2+-ATPase and RyR2 activity indicated that K201 inhibited both SR Ca2+ uptake and release.
Conclusions K201 modifies E–C coupling in normal cardiomyocytes. A dual inhibitory action on SERCA and RyR2 explains the ability of K201 to suppress spontaneous diastolic Ca2+ release during Ca2+ overload without significantly affecting Ca2+ transient amplitude.
KEYWORDS Calcium cycling/excitation–contraction coupling; Electrophysiology; Arrhythmias
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