Arachidonic acid mediates dual effect of TNF- on Ca transients and contraction of adult rat cardiomyocytes

Amadou, Aı̈ssata, Artur Nawrocki, Martin Best-Belpomme, Catherine Pavoine, and Françoise Pecker. Arachidonic acid mediates dual effect of TNFon Ca2 transients and contraction of adult rat cardiomyocytes. Am J Physiol Cell Physiol 282: C1339–C1347, 2002. First published January 30, 2002; 10.1152/ajpcell.00471.2001.—Tumor necrosis factor (TNF)has a biphasic effect on heart contractility and stimulates phospholipase A2 (PLA2) in cardiomyocytes. Because arachidonic acid (AA) exerts a dual effect on intracellular Ca2 concentration ([Ca2 ]i) transients, we investigated the possible role of AA as a mediator of TNFon [Ca2 ]i transients and contraction with electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/ml) TNFproduced a 40% increase in the amplitude of both [Ca2 ]i transients and contraction within 40 min. At a high concentration (50 ng/ml) TNFevoked 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 TNFwere reproduced by AA and blocked by arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of cytosolic PLA2. Lipoxygenase and cyclooxygenase inhibitors reproduced the highdose effects of TNFand AA. The negative effects of TNFand AA were also reproduced by sphingosine and were abrogated by the ceramidase inhibitor n-oleoylethanolamine. These results point out the key role of the cytosolic PLA2/AA pathway in mediating the contractile effects of TNF.