Arachidonic acid mediates dual effect of TNF-alpha on Ca2+ transients and contraction of adult rat cardiomyocytes.
Tumor necrosis factor (TNF)-alpha 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 TNF-alpha on [Ca2+]i transients and contraction with electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/ml) TNF-alpha produced a 40% increase in the amplitude of both [Ca2+]i transients and contraction within 40 min. At a high concentration (50 ng/ml) TNF-alpha 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-alpha were reproduced by AA and blocked by arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of cytosolic PLA2. Lipoxygenase and cyclooxygenase inhibitors reproduced the high-dose effects of TNF-alpha and AA. The negative effects of TNF-alpha and 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-alpha.
Amadou
Aïssata
A
Institut National de la Santé et de la Recherche Médicale Unité 99, Hôpital Henri Mondor, 94010 Créteil, France.
Nawrocki
Artur
A
Best-Belpomme
Martin
M
Pavoine
Catherine
C
Pecker
Françoise
F
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002469:Cell Separation; D055572:Ceramidases; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D063388:Endocannabinoids; D004789:Enzyme Activation / Q000502:physiology; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009829:Oleic Acids; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D000581:Amidohydrolases; D055572:Ceramidases; D002118:Calcium