TNF-alpha and IL-1beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes.
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.
Multidisciplinary Cardiovascular Research Centre, Institute of Membrane and Systems Biology, University of Leeds, Leeds LS29JT, UK.
David J
DJ
Duncan
Zhaokang
Z
Yang
Philip M
PM
Hopkins
Derek S
DS
Steele
Simon M
SM
Harrison
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004198:Disease Susceptibility; D006352:Heart Ventricles / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D032342:Muscle Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009200:Myocardial Contraction / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha