(Circulation. 2000;102:2758.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Endotoxin-Induced Myocardial Tumor Necrosis Factor-
Synthesis Depresses Contractility of Isolated Rat Hearts
Evidence for a Role of Sphingosine and Cyclooxygenase-2–Derived Thromboxane Production
From the Department of Internal Medicine (U.G., L.F., A.B., M.H., H.-J.K., K.M., W.S., F.G., U.S.) and the Department of Pathology (L.F., R.M.B.), Justus-Liebig-University, Giessen, Germany; and the Second Department of Internal Medicine (M.B.), Johannes-Gutenberg-University, Mainz, Germany.
Correspondence to Ulf Sibelius, MD, Department of Internal Medicine, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail ulf.sibelius{at}innere.med.uni-giessen.de
Background—Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated.
Methods and Results—Perfusion of isolated rat hearts with LPS for
180 minutes resulted in a decline of left ventricular
contractility after 90 minutes, whereas
coronary perfusion pressure remained unaffected. This
cardiodepression was paralleled by a release of tumor necrosis
factor (TNF)-
into the perfusate and preceded by myocardial
TNF- mRNA upregulation as quantified by real-time polymerase chain
reaction. The cardiodepression was abrogated when LPS was perfused with
a TNF- antiserum or the ceramidase inhibitor
N-oleoylethanolamine. In contrast, the cardiac release
of nitric oxide (NO) was not augmented by LPS. Immunohistochemical
studies of LPS-perfused hearts revealed a positive staining for the
constitutive (NOSIII) but not for the inducible NO synthase (NOSII).
Accordingly, NOSII mRNA levels commenced to increase only at the very
end of the LPS perfusion period. Progressive liberation of
thromboxane (Tx) A2 and prostacyclin was
induced by LPS together with myocardial
cyclooxygenase (Cox)-2 mRNA expression. Both
nonselective inhibition of Cox by indomethacin and
selective inhibition of the inducible Cox-2 by NS-398 abolished
prostanoid release. Interestingly, the generation of TNF- and the
associated cardiodepression caused by LPS were reduced by
indomethacin, NS-398 and the Tx-receptor
antagonist daltroban.
Conclusions—LPS depresses contractility of
isolated rat hearts by inducing TNF- synthesis and subsequently
activating the sphingomyelinase pathway, whereas no evidence for a role
of NOSII- or NOSIII-generated NO was found. Moreover, Cox-2–derived
TxA2 appears to facilitate TNF- synthesis in response to
LPS.
Key Words: contractility • nitric oxide • nitric oxide synthase • perfusion • heart failure • shock
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