TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) IS CARDIODEPRESSANT IN PATHOPHYSIOLOGICALLY RELEVANT CONCENTRATIONS WITHOUT INDUCING INDUCIBLE NITRIC OXIDE-(NO)-SYNTHASE (INOS) OR TRIGGERING SERIOUS CYTOTOXICITY

Cardiac hypertrophy and heart failure are frequently accompanied by el evated plasma levels of tumor necrosis factor alpha (TNF alpha), the p athogenetic relevance of this finding being a matter of debate. In hum an acute septic cardiomyopathy, on the other hand, the negative inotro pic impact of TNF alpha on the heart is well documented and frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iN OS) and an enhanced production of NO in the heart, Yet the present stu dy presents evidence that in cardiomyocytes TNF alpha in non-toxic con centrations specifically depresses contractile performance independent of NO, In spontaneously beating neonatal rat cardiomyocytes, TNF alph a 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 irr egularity and impairs the impact of high extracellular calcium on cont ractile performance, However, this low TNF alpha-concentration does no t suffice to induce iNOS - documented by reverse transcriptase polymer ase chain reaction - or enhance nitrite concentrations in the cell cul ture supernatants as a measure of cellular NO production, neither in t he presence nor absence of dexamethasone (0.1 mu M). Only in high conc entration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNF alpha (10 00 U/mol; 6, 24h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production, TNF alpha-incubation (1 0-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity. (C ) 1997 Academic Press Limited.