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

Physiological Reports

David J. Greensmith¹ 

[1] Unit of Cardiac Physiology, Institute of Cardiovascular Science, Manchester Academic Health Science Centre, Core Technology Facility, Manchester, U.K.

关键词: Calcium;    L‐type calcium channel;    myocyte;    sarcoplasmic reticulum;    tumor necrosis factor‐alpha;   

DOI  :  10.1002/phy2.93

来源: Wiley

【 摘 要 】

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 ([Ca²⁺]_i), contractility, and [Ca²⁺]_i handling, by TNF-α, at the level of the individual rat myocyte. We took an integrative approach to simultaneously measure [Ca²⁺]_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 [Ca²⁺]_i was reduced by 31% and systolic shortening by 19%. Diastolic [Ca²⁺]_i, myocyte length and relaxation rate were not affected, nor were the activity of the [Ca²⁺]_i removal mechanisms. The reduction in systolic [Ca²⁺]_i was associated with a 14% reduction in sarcoplasmic reticulum (SR) content and a 11% decrease in peak L-type Ca current (I_Ca-L). Ca influx was decreased by 7% associated with a more rapid I_Ca-L inactivation. These data show that at the level of the myocyte, TNF-α reduces SR Ca which underlies a reduction in systolic [Ca²⁺]_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.

【 授权许可】

CC BY   
© 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.