The effects of tumor necrosis factor-alpha on systolic and diastolic function in rat ventricular myocytes

Greensmith, DJ; Nirmalan, M

Abstract

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is associated with myocardial dysfunction observed in sepsis and septic shock. There are two fundamental components to this dysfunction. (1) systolic dysfunction; and (2) diastolic dysfunction. The aim of these experiments was to determine if any aspect of whole-heart dysfunction could be explained by alterations to global intracellular calcium ([Ca(2+)]i), contractility, and [Ca(2+)]i handling, by TNF-α, at the level of the individual rat myocyte. We took an integrative approach to simultaneously measure [Ca(2+)]i, contractility and sarcolemmal Ca fluxes using the Ca indicator fluo-3, video edge detection, and the perforated patch technique, respectively. All experiments were performed at 37°C. The effects of 50 ng/mL TNF-α were immediate and sustained. The amplitude of systolic [Ca(2+)]i was reduced by 31% and systolic shortening by 19%. Diastolic [Ca(2+)]i, myocyte length and relaxation rate were not affected, nor were the activity of the [Ca(2+)]i removal mechanisms. The reduction in systolic [Ca(2+)]i was associated with a 14% reduction in sarcoplasmic reticulum (SR) content and a 11% decrease in peak L-type Ca current (IC a-L). Ca influx was decreased by 7% associated with a more rapid IC a-L inactivation. These data show that at the level of the myocyte, TNF-α reduces SR Ca which underlies a reduction in systolic [Ca(2+)]i and thence shortening. Although these findings correlate well with aspects of systolic myocardial dysfunction seen in sepsis, in this model, acutely, TNF-α does not appear to provide a cellular mechanism for sepsis-related diastolic myocardial dysfunction.

Citation

Greensmith, D., & Nirmalan, M. (2013). The effects of tumor necrosis factor-alpha on systolic and diastolic function in rat ventricular myocytes. Physiological Reports, 1(4), e00093. https://doi.org/10.1002/phy2.93

• Journal Article Type: Article
• Publication Date: Sep 1, 2013
• Deposit Date: Feb 10, 2015
• Publicly Available Date: Apr 5, 2016
• Journal: Physiological reports
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Issue: 4
• Pages: e00093
• DOI: https://doi.org/10.1002/phy2.93
• Publisher URL: http://dx.doi.org/10.1002/phy2.93
• Related Public URLs: http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%292051-817X