Tumor necrosis factor α (TNFα) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity

Ursula Müller-Werdan, Heike Schumann, Ralph Fuchs, Christopher Reithmann, Harald Loppnow, Susanne Koch, Ursula Zimny-Arndt, Chang He, Dorothea Darmer, Peter Jungblut, Josef Stadler, Jürgen Holtz, Karl Werdan

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac hypertrophy and heart failure are frequently accompanied by elevated plasma levels of tumor necrosis factor α (TNFα), the pathogenetic relevance of this finding being a matter of debate. In human acute septic cardiomyopathy, on the other hand, the negative inotropic impact of TNFα on the heart is well documented and frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS) and an enhanced production of NO in the heart. Yet the present study presents evidence that in cardiomyocytes TNFα in non-toxic concentrations specifically depresses contractile performance independent of NO. In spontaneously beating neonatal rat cardiomyocytes, TNFα in low, pathophysiologically relevant concentration (10 U/ml, 1-3 days) does not alter basal pulsation amplitude, but blocks α- and β-adrenoceptor-stimulated increase in contractility and beating irregularity and impairs the impact of high extracellular calcium on contractile performance. However, this low TNFα-concentration does not suffice to induce iNOS - documented by reverse transcriptase polymerase chain reaction - or enhance nitrite concentrations in the cell culture supernatants as a measure of cellular NO production, neither in the presence nor absence of dexamethasone (0.1 μM). Only in high concentration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNFα (1000 U/mol; 6, 24 h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production. TNFα-incubation (10-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity.

Original languageEnglish (US)
Pages (from-to)2915-2923
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume29
Issue number11
DOIs
StatePublished - Nov 1997

Keywords

  • Cardiodepression
  • Cardiomyocytes
  • Catecholamines
  • Contractility
  • Inducible nitric oxide synthase
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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