TY - JOUR
T1 - Tumor necrosis factor α (TNFα) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity
AU - Müller-Werdan, Ursula
AU - Schumann, Heike
AU - Fuchs, Ralph
AU - Reithmann, Christopher
AU - Loppnow, Harald
AU - Koch, Susanne
AU - Zimny-Arndt, Ursula
AU - He, Chang
AU - Darmer, Dorothea
AU - Jungblut, Peter
AU - Stadler, Josef
AU - Holtz, Jürgen
AU - Werdan, Karl
N1 - Funding Information:
This study was supported by the Deutsche For-schungsgemeinschaft (Mu 1010/1-4,-5, Sta 311/
Funding Information:
2-1) and by Bundesministerium für Bildung und Forschung (BMBF, grant no. 01ZZ9512).
PY - 1997/11
Y1 - 1997/11
N2 - 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.
AB - 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.
KW - Cardiodepression
KW - Cardiomyocytes
KW - Catecholamines
KW - Contractility
KW - Inducible nitric oxide synthase
KW - Tumor necrosis factor α
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U2 - 10.1006/jmcc.1997.0526
DO - 10.1006/jmcc.1997.0526
M3 - Article
C2 - 9405166
AN - SCOPUS:0031282192
SN - 0022-2828
VL - 29
SP - 2915
EP - 2923
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 11
ER -