title: Tumor necrosis factor alpha (TNF alpha) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity.
abstract: Cardiac hypertrophy and heart failure are frequently accompanied by elevated plasma levels of tumor necrosis factor alpha (TNF alpha), 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 TNF alpha 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 TNF alpha in non-toxic concentrations specifically depresses contractile performance independent of NO. In spontaneously beating neonatal rat cardiomyocytes, TNF alpha in a low, pathophysiologically relevant concentration (10 U/ml, 1-3 days) does not alter basal pulsation amplitude, but blocks alpha- and beta-adrenoceptor-stimulated increase in contractility and beating irregularity and impairs the impact of high extracellular calcium on contractile performance. However, this low TNF alpha-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 micro M). Only in high concentration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNF alpha (1000 U/mol; 6, 24 h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production. TNF alpha-incubation (10-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity.
authors.affiliation: Department of Medicine III, Klinikum Kröllwitz, University of Halle-Wittenberg, Ernst-Grube-Strasse 40, Halle, D-06097, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Müller-Werdan
authors.forename: H
authors.initials: H
authors.lastname: Schumann
authors.forename: R
authors.initials: R
authors.lastname: Fuchs
authors.forename: C
authors.initials: C
authors.lastname: Reithmann
authors.forename: H
authors.initials: H
authors.lastname: Loppnow
authors.forename: S
authors.initials: S
authors.lastname: Koch
authors.forename: U
authors.initials: U
authors.lastname: Zimny-Arndt
authors.forename: C
authors.initials: C
authors.lastname: He
authors.forename: D
authors.initials: D
authors.lastname: Darmer
authors.forename: P
authors.initials: P
authors.lastname: Jungblut
authors.forename: J
authors.initials: J
authors.lastname: Stadler
authors.forename: J
authors.initials: J
authors.lastname: Holtz
authors.forename: K
authors.initials: K
authors.lastname: Werdan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D003864:Depression, Chemical; D004790:Enzyme Induction; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat