TNF-alpha and IL-1beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes

Cell Calcium. 2010 Apr;47(4):378-86. doi: 10.1016/j.ceca.2010.02.002. Epub 2010 Mar 12.


Sepsis is associated with ventricular dysfunction and increased incidence of atrial and ventricular arrhythmia however the underlying pro-arrhythmic mechanisms are unknown. Serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are elevated during sepsis and affect Ca2+ regulation. We investigated whether pro-inflammatory cytokines disrupt cellular Ca2+ cycling leading to reduced contractility, but also increase the probability of pro-arrhythmic spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). Isolated rat ventricular myocytes were exposed to TNF-alpha (0.05 ng ml(-1)) and IL-1beta (2 ng ml(-1)) for 3 hr and then loaded with fura-2 or fluo-3 to record the intracellular Ca2+ concentration ([Ca2+](i)). Cytokine treatment decreased the amplitude of the spatially averaged Ca2+ transient and the associated contraction, induced asynchronous Ca2+ release during electrical stimulation, increased the frequency of localized Ca2+ release events, decreased the SR Ca2+ content and increased the frequency of spontaneous Ca2+ waves at any given cytoplasmic Ca2+. These data suggest that TNF-alpha and IL-1beta increase the SR Ca2+ leak from the SR, which contributes to the depressed Ca2+ transient and contractility. Increased susceptibility to spontaneous SR Ca2+ release may contribute to arrhythmias in sepsis as the resulting Ca2+ extrusion via NCX is electrogenic, leading to cell depolarisation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / complications
  • Arrhythmias, Cardiac / immunology*
  • Calcium Signaling / drug effects
  • Calcium Signaling / immunology
  • Cells, Cultured
  • Disease Susceptibility
  • Heart Ventricles / pathology
  • Interleukin-1beta / pharmacology*
  • Male
  • Muscle Cells / drug effects*
  • Muscle Cells / immunology
  • Muscle Cells / metabolism
  • Muscle Cells / pathology
  • Myocardial Contraction / immunology
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum / metabolism
  • Sepsis / complications
  • Sepsis / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha