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Capsazepine, a vanilloid antagonist, abolishes tonic responses induced by 20-HETE on guinea pig airway smooth muscle

Department of Physiology and Biophysics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Submitted 6 July 2004 ; accepted in final form 15 November 2004

The aim of this study was to delineate the mode of action of 20-hydroxy-eicosatetraenoic acid (20-HETE) in airway smooth muscle (ASM) cells. ASM metabolizes arachidonic acid by various enzymatic pathways, including the cytochrome P-450 (CYP-450) -hydroxylase, which leads to the production of 20-HETE, a bronchoconstrictive eicosanoid. The present study demonstrated that 20-HETE induced concentration-dependent tonic responses in ASM, whereas transient responses were recorded in Ca²⁺-free solution, suggesting an intracellular Ca²⁺ release process. 20-HETE inotropic responses were abolished by 36 µM 2-aminoethoxydiphenyl borate or 1 µM thapsigargin but were insensitive to 10 µM ryanodine, indicating that inositol triphosphate receptors likely control the release of intracellular Ca²⁺. Sustained tension, which required Ca²⁺ entry, was partially blocked by 1 µM nifedipine (an L-type) and 100 µM Gd³⁺ (a nonselective cationic channel blocker). Moreover, in the absence of selective 20-HETE receptor antagonists, 20-HETE tonic responses were inhibited in a concentration-dependent manner (0.1–10 µM) by capsazepine, a well-characterized vanilloid receptor antagonist. Capsazepine was also observed to reverse cumulative responses to 20-HETE and capsaicin, a TRPV1 agonist. In addition, capsazepine pretreatment largely modified the sustained inotropic responses to 20-HETE, suggesting that 20-HETE cross-reacted with TRPV1 receptors with a low affinity (µM) or that its specific receptor was inhibited by the vanilloid antagonist. Data obtained using RHC-80267, ONO-RS-082, and eicosatetraynoic acid, respective inhibitors of diacylglycerol-lipase, phospholipase A₂, and CYP-450 -hydroxylase, reveal that intracellular arachidonic acid production and its 20-HETE metabolite may be responsible for the activation of nonselective cationic channels and tonic responses.

20-hydroxyeicosatetraenoic acid; contraction; lung; TRPV channel

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