• C Stamm, D B Cowan, I Friehs, S Noria, P J del Nido, and F X McGowan.
• Department of Anesthesia and Cardiac Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
• Anesthesiology. 2001 Dec 1;95(6):1396-405.

BackgroundBacterial endotoxin (lipopolysaccharide [LPS]) induces septic shock and depressed myocardial contractility. The mechanism of LPS-mediated cardiac dysfunction remains controversial. We hypothesized that LPS exerts significant effects on myocardial excitation-contraction coupling by rapid stimulation of tumor necrosis factor alpha (TNF-alpha) expression in the heart.MethodsIsolated rat hearts were studied with and without recirculation of cell-free perfusate. The effects of LPS, exogenous TNF-alpha, anti-TNF-alpha antibody, and ceramidase inhibition were examined. Measurements included myocardial uptake of LPS, left ventricular contractility, myocardial oxygen consumption, intracellular calcium [Ca2+] cycling, and TNF-alpha concentrations in coronary perfusate and myocardium.ResultsLipopolysaccharide was rapidly taken up by the perfused heart. With non-recirculating perfusion, LPS had no effect on contractility, oxygen consumption, coronary vascular resistance, or intracellular free calcium concentration ([Ca2+]i). However, with recirculating perfusion contractility was significantly impaired after 30 min of LPS, associated with lower [Ca2+]i levels and attenuated systolic rise in [Ca2+]i. Significant amounts of TNF-alpha accumulated in recirculating perfusate and myocardial tissue from LPS-perfused hearts. Ceramidase inhibition or neutralizing anti-TNF-alpha antibody inhibited the effects of LPS on contractility and [Ca2+]i. Recombinant rat TNF-alpha mimicked the LPS effects with faster onset.ConclusionsLipopolysaccharide exerts rapid, negative inotropic effects on the isolated whole rat heart. The reduction in contractility is associated with depressed intracellular calcium cycling. In response to LPS, TNF-alpha is rapidly released from the heart and mediates the effects of LPS via the sphingomyelinase pathway. The present study for the first time directly links LPS-stimulated TNF-alpha production, abnormal calcium cycling, and decreased contractility in intact hearts.

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