K201 modulates excitation-contraction coupling and spontaneous Ca2+ release in normal adult rabbit ventricular cardiomyocytes

Loughrey, C. , Otani, N., Seidler, T., Craig, M., Matsuda, R., Kaneko, N. and Smith, G. (2007) K201 modulates excitation-contraction coupling and spontaneous Ca2+ release in normal adult rabbit ventricular cardiomyocytes. Cardiovascular Research, 76(2), pp. 236-246. (doi:10.1016/j.cardiores.2007.06.014)

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Abstract

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 mu mol/L K201 had no significant effect on E-C coupling. K201 at 1 mu mol/L decreased Ca2+ transient amplitude (to 83 +/- 7%) without affecting I-ca,I-L or the SR Ca2+ content. At 3 mu mol/L K201 caused a larger reduction of Ca2+ transient amplitude (to 60 +/- 7%) with accompanying reductions in I-ca,I-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 p mol/L K201 reduced the frequency of spontaneous Ca2+ release. The effect of K201 on SR-mediated Ca2+ waves and Ca2+ sparks was examined in beta-escin-permeabilised cardiomyocytes by confocal microscopy. K201 (1 mu mol/L) reduced the frequency and velocity of SR Ca2+ waves despite no change in SR Ca2+ content. At 3 mu mol/L K201 completely abolished Ca2+ waves and reduced the SR Ca2+ content (to similar to 73%). K201 at 1 mu mol/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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Loughrey, Professor Christopher
Authors: Loughrey, C., Otani, N., Seidler, T., Craig, M., Matsuda, R., Kaneko, N., and Smith, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences
Journal Name:Cardiovascular Research
Publisher:Elsevier
ISSN:0008-6363

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