title: Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase.
abstract: In patients with septic shock or inflammatory cardiac diseases like myocarditis myocardial contractility is depressed. These patients have elevated circulating levels of bacterial endotoxins (lipopolysaccharides, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alpha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear, whether LPS and/or cytokines have direct inotropic effects on cardiomyocytes and whether these effects are mediated via the L-arginine-nitric oxide synthase (NOS) pathway as demonstrated in vascular smooth muscle cells. Therefore, we examined the direct effects of LPS. IL-1 beta and TNF-alpha on contractility and cGMP content in isolated guinea-pig ventricular cardiomyocytes. Furthermore, the influence of the NOS inhibitor NG-nitro-L-arginine (L-NNA) and dexamethasone on these effects was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decreased contractility by 48%, 55% and 65% and augmented cGMP content by 135%, 88% or 70% after long-term treatment (18 h) in cardiomyocytes, without altering contractility or cGMP content after short-term treatment (30 min). These effects were blocked by L-NNA (100 microM) and dexamethasone (3 microM). Furthermore iNOS protein was expressed in LPS- and cytokine-treated cardiomyocytes. These findings demonstrate that LPS. IL-1 beta and TNF-alpha have direct negative inotropic effects on cardiomyocytes, which are accompanied by an increase in cGMP content. These effects are mediated via de novo synthesis of a myocardial iNOS. The direct negative inotropic effects of endotoxins and cytokines on cardiomyocytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases.
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, FRG.
authors.forename: B
authors.initials: B
authors.lastname: Stein
authors.forename: P
authors.initials: P
authors.lastname: Frank
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.forename: H
authors.initials: H
authors.lastname: Scholz
authors.forename: M
authors.initials: M
authors.lastname: Thoenes
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019335:Nitroarginine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D005938:Glucocorticoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP