K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca(2+) release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes

Basic Res Cardiol. 2011 Nov;106(6):1009-22. doi: 10.1007/s00395-011-0218-4. Epub 2011 Sep 8.


K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca(2+)](o)). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca(2+) release and contractile events in isolated rat cardiomyocytes during β-adrenergic stimulation and elevated [Ca(2+)](o). Parallel experiments using confocal microscopy examined spontaneous diastolic Ca(2+) release events at an enhanced spatiotemporal resolution. 1.0 μmol/L K201 in the presence of 150 nmol/L isoproterenol (ISO) and 4.75 mmol/L [Ca(2+)](o) significantly decreased the amplitude of diastolic contractions to ~16% of control levels. The stimulated free Ca(2+) transient amplitude was significantly reduced, but stimulated cell shortening was not significantly altered. When intracellular buffering was taken into account, K201 led to an increase in action potential-induced SR Ca(2+) release. Myofilament sensitivity to Ca(2+) was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca(2+) waves (2-3) originating at various points along the cardiomyocyte length during each diastolic period. 1.0 μmol/L K201 significantly reduced the (a) frequency of diastolic events and (b) initiation points/diastolic interval in the remaining diastolic events to 61% and 71% of control levels respectively. 1.0 μmol/L K201 can reduce the probability of spontaneous diastolic Ca(2+) release and their associated contractions which may limit the propensity for the contractile dysfunction observed in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism*
  • Diastole / drug effects
  • Diastole / physiology
  • Heart Ventricles / drug effects*
  • Heart Ventricles / metabolism
  • Male
  • Microscopy, Confocal
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Thiazepines / pharmacology*


  • Thiazepines
  • K201 compound
  • Calcium