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Articles in PresS, published online ahead of print January 30, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00471.2001
Submitted on October 4, 2001
Accepted on January 25, 2002
1 Unite 99, INSERM, CRETEIL, 94010, France
* To whom correspondence should be addressed. E-mail: francoise.pecker{at}im3.inserm.fr.
Tumor necrosis factor 
(TNF) induces a biphasic effect on heart contractility in conscious animals. It has also been reported that TNF stimulates phospholipase A2 in isolated cardiomyocytes. Since arachidonic acid (AA) exerts a dual effect on [Ca2+]i transients, the aim of the present study was to investigate the possible role of AA as a mediator of the contractile effects of TNF. We examined the effects of both AA and TNF on [Ca2+]i transients and contraction of electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/mL) TNF produced a 40% increase in the amplitude of both [Ca2+]i transients and contraction within 40 min . At high concentration (50 ng/mL), in two third of isolated cardiomyocytes, TNF evoked a biphasic effect comprising an initial positive effect peaking at 5 min, followed by a sustained negative effect leading to 50-40% decreases in [Ca2+]i transients and contraction after 30 min. Both the positive and negative effects of TNF were blocked by AACOCF3, an inhibitor of cytosolic Ca2+-dependent phospholipase A2 (cPLA2). AA added to the cell medium reproduced the concentration-dependent effect of TNF: at low concentrations (5 µmol/L), AA caused an increase in [Ca2+]i transients and contraction, while at higher concentrations (10 - 25 µmol/L) it produced a biphasic effect. Lipoxygenase and cyclooxygenase inhibitors reproduced the high-dose effects of TNF and AA. The negative effects of TNF and AA were also reproduced by sphingosine and abrogated by blocking sphingosine production using an inhibitor of ceramidase, n-oleoylethanolamine. These results point out the key role of the cPLA2/AA pathway in mediating the contractile effects of TNF.
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