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)-α into the perfusate and preceded by myocardial TNF-α mRNA upregulation as quantified by real-time polymerase chain reaction. The cardiodepression was abrogated when LPS was perfused with a TNF-α 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) A 2 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-α 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-α 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 TxA 2 appears to facilitate TNF-α synthesis in response to LPS.
CITATION STYLE
Grandel, U., Fink, L., Blum, A., Heep, M., Buerke, M., Kraemer, H.-J., … Sibelius, U. (2000). Endotoxin-Induced Myocardial Tumor Necrosis Factor-α Synthesis Depresses Contractility of Isolated Rat Hearts. Circulation, 102(22), 2758–2764. https://doi.org/10.1161/01.cir.102.22.2758
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