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Rho GTPases in Lung Physiology and Disease

5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca²⁺ pools and Rho-kinase pathway

¹Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, J1H 5N4; ³Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada H2X 2P2; and ²Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901-6982

Submitted 12 January 2004 ; accepted in final form 14 April 2004

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 µM) 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 µM nifedipine (an L-type Ca²⁺ channel blocker) but relatively insensitive to 100 µM 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.

5-oxo-eicosatetraenoic acid; isometric tension; membrane potential; calcium entry; transient receptor potential; Rho-kinase

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