K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum

Basic Res Cardiol. 2010 Mar;105(2):279-87. doi: 10.1007/s00395-009-0057-8. Epub 2009 Aug 30.


In heart failure, intracellular Ca2+ leak from cardiac ryanodine receptors (RyR2s) leads to a loss of Ca2+ from the sarcoplasmic reticulum (SR) potentially contributing to decreased function. Experimental data suggest that the 1,4-benzothiazepine K201 (JTV-519) may stabilise RyR2s and thereby reduce detrimental intracellular Ca2+ leak. Whether K201 exerts beneficial effects in human failing myocardium is unknown. Therefore, we have studied the effects of K201 on muscle preparations from failing human hearts. K201 (0.3 microM; extracellular [Ca2+]e 1.25 mM) showed no effects on contractile function and micromolar concentrations resulted in negative inotropic effects (K201 1 microM; developed tension -9.8 +/- 2.5% compared to control group; P < 0.05). Interestingly, K201 (0.3 microM) increased the post-rest potentiation (PRP) of failing myocardium after 120 s, indicating an increased SR Ca2+ load. At high [Ca2+]e concentrations (5 mmol/L), K201 increased PRP already at shorter rest intervals (30 s). Strikingly, treatment with K201 (0.3 microM) prevented diastolic dysfunction (diastolic tension at 5 mmol/L [Ca2+]e normalised to 1 mmol/L [Ca2+]e: control 1.26 +/- 0.06, K201 1.01 +/- 0.03, P < 0.01). In addition at high [Ca2+]e) K201 (0.3 microM) treatment significantly improved systolic function [developed tension +27 +/- 8% (K201 vs. control); P < 0.05]. The beneficial effects on diastolic and systolic functions occurred throughout the physiological frequency range of the human heart rate from 1 to 3 Hz. Upon elevated intracellular Ca2+ concentration, systolic and diastolic contractile functions of terminally failing human myocardium are improved by K201.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Calcium / metabolism*
  • Cells, Cultured
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects*
  • Sarcoplasmic Reticulum / drug effects*
  • Sarcoplasmic Reticulum / metabolism
  • Thiazepines / pharmacology*
  • Thiazepines / therapeutic use


  • Thiazepines
  • K201 compound
  • Calcium