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Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor α attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations

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Abstract

The main purpose of this study was to determine the subchronic effects of low concentrations of tumor necrosis factor α (TNFα) on the inotropic response and on the cellular level of high energy phosphates of cardiomyocytes. Therefore, the inotropic response of cultured neonatal rat heart cells to 10−5 M isoproterenol-, 10−6 M ouabain-, 10−5 M forskolin- and 2,4 mM calcium-perfusion was studied 24 h after exposure to TNFα (0.01/0.1/1/10/100 U/ml). In parallel experiments high energy phosphates (CP, ATP, ADP, AMP) were determined by high performance liquid chromatography. Furthermore, the reversibility of TNFα-induced changes was studied after washout of TNFα or after administration of anti-TNFα-antibody. Whereas control cells showed an increase of cell wall motion to 150 ± 5% of baseline value during 10-5 M isoproterenol-perfusion respectively 180 ± 7% during 2,4 mM calcium-perfusion, 24 h exposure of the cells to 1 U/ml up to 100 U/ml TNFα resulted in an inhibition of the inotropic response. Almost complete inhibition was observed 12 h after exposure to TNFα and was reversible 12 h after administration of the anti-TNFa-antibody. If the cells were perfused with 10−6 M ouabain or 10−5 M forskolin, a similar inhibition of the inotropic response was observed 24 h after TNFα-exposure. Determination of high energy phosphates showed that 24 h TNFα-exposure resulted in a reversible decrease of ATP, ADP, AMP and CP by 30–40% (p < 0.05). However, a similar reduction of cellular high energy phosphate levels using a TNFα independent mechanism (2,5 mM 2-deoxy-D-glucose) did not inhibit the inotropic response of the cardiomyocytes. From our results we conclude that subchronic exposure to low concentrations of TNFα resulted in an almost complete but reversible inhibition of the response of cardiomyocytes to different inotropic agents suggesting that a common final step of the inotropic cascade might be altered by TNFα. Though energy metabolism of TNFα exposed cells was affected also, reduction of high energy phosphate levels alone did not explain the observed inhibition of the inotropic response of the cardiomyocytes.

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Authors and Affiliations

  1. Department of Internal Medicine I, Klinikum Grofßhadern, University of Munich, Germany

    Peter Boekstegers, Iris Kainz, Wolfgang Giehrl, Wolfgang Peter & Karl Werdan

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  1. Peter Boekstegers
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  2. Iris Kainz
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Boekstegers, P., Kainz, I., Giehrl, W. et al. Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor α attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations. Mol Cell Biochem 156, 135–143 (1996). https://doi.org/10.1007/BF00426336

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  • DOI: https://doi.org/10.1007/BF00426336

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