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