5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca2+ pools and Rho-kinase pathway.
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a proinflammatory mediator, but its effects on airway smooth muscle (ASM) have never been assessed. Tension measurements performed on guinea pig ASM showed that 5-oxo-ETE induced sustained concentration-dependent positive inotropic responses (EC50 = 0.89 microM) of somewhat lower amplitude than those induced by carbamylcholine and the thromboxane A2 (TXA2) agonist U-46619. Transient inotropic responses to 5-oxo-ETE were recorded in Ca2+-free medium, suggesting mobilization of intracellular Ca2+. Meanwhile, the sustained contraction, which required Ca2+ entry, was partially blocked by 1 microM nifedipine (an L-type Ca2+ channel blocker) but relatively insensitive to 100 microM Gd3+. The 5-oxo-ETE responses were also inhibited by indomethacin and SC-560 [a cyclooxygenase (COX-1) inhibitor] pretreatments but not by NS-398 (a selective COX-2 inhibitor). The contractile effects of 5-oxo-ETE on ASM were inhibited by the selective TXA2 receptor (TP receptor) antagonist SQ-29548 (-75%) and by 2-(p-amylcinnamoyl) amino-4-chlorobenzoic acid pretreatment, a phospholipase A2 inhibitor (-66%), suggesting that the major part of its effect is mediated by the release of TXA2. ASM responses to 5-oxo-ETE were also blocked by the Rho-kinase inhibitor Y-27632, which also partially inhibited the response to the TP receptor agonist U-46619, suggesting that the contractile response is due in part to Ca2+ sensitization of ASM cell myofilaments.
Mercier
Frederic
F
Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada.
Morin
Caroline
C
Cloutier
Martin
M
Proteau
Sonia
S
Rokach
Joshua
J
Powell
William S
WS
Rousseau
Eric
E
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D047908:Intracellular Signaling Peptides and Proteins; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
D001095:Arachidonic Acids; D047908:Intracellular Signaling Peptides and Proteins; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases