title: Endotoxin and tumor necrosis factor alpha exert a similar proinflammatory effect in neonatal rat cardiomyocytes, but have different cardiodepressant profiles.
abstract: Bolus application of endotoxin to healthy volunteers results in reversible hemodynamic alterations, such as observed in septic cardiomyopathy. Currently, endotoxin-induced cardiodepression is mainly attributed to the endotoxin-induced release of proinflammatory cytokines into the circulation, particularly of tumor necrosis factor alpha and interleukin-1, the serum levels of these cytokines being enhanced in sepsis and septic shock, and also in various heart diseases. In this study, we report a proinflammatory effect of endotoxin (1-10 micrograms/ml, 24-h incubation period) on neonatal rat cardiomyocytes in serum-free culture, evidenced by induction of inducible nitric oxide synthase, enhanced release of nitrite (protein synthesis-dependent) and interleukin-6 into the supernatant, as well as an increase in cell-associated interleukin-1 and a specific cardiodepressant profile: endotoxin disrupts beta-adrenoceptor-mediated increase in pulsation amplitude, but alpha-adrenoceptor-induced increase in pulsation amplitude and arrhythmias are not suppressed. In the presence of dexamethasone (0.1 microM), the endotoxin-mediated blockade of beta-adrenergic responsiveness, as well as induction of inducible nitric oxide synthase, enhanced nitrite release and interleukin-1/-6-production are inhibited. In contrast, tumor necrosis factor alpha at a low concentration (10 U/ml) depresses alpha- and beta-adrenergic responsiveness in the presence of dexamethasone in a nitric oxide-independent manner. These data suggest a stimulatory effect of endotoxin on the cardiomyocyte and a specific proinflammatory and nitric oxide-dependent cardiodepressant profile of endotoxin.
authors.affiliation: Department of Medicine III, Klinikum Kröllwitz, University of Halle-Wittenberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Müller-Werdan
authors.forename: H
authors.initials: H
authors.lastname: Schumann
authors.forename: H
authors.initials: H
authors.lastname: Loppnow
authors.forename: R
authors.initials: R
authors.lastname: Fuchs
authors.forename: D
authors.initials: D
authors.lastname: Darmer
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; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016895:Culture Media, Serum-Free; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat