Endotoxin and tumor necrosis factor alpha exert a similar proinflammatory effect in neonatal rat cardiomyocytes, but have different cardiodepressant profiles.
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.
Müller-Werdan
U
U
Department of Medicine III, Klinikum Kröllwitz, University of Halle-Wittenberg, Germany.
Schumann
H
H
Loppnow
H
H
Fuchs
R
R
Darmer
D
D
Stadler
J
J
Holtz
J
J
Werdan
K
K
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*
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