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Published ahead of print on January 19, 2007, doi:10.1165/rcmb.2006-0281OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 5, May 2007, 633-641

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Submitted on August 2, 2006
Revised on January 17, 2007

EET Relaxing Effects Involve BKCa Channel Activation and CPI-17 Dephosphorylation in Human Bronchi

Caroline Morin1, Marco Sirois2, Vincent Echave2, Marcio M Gomes3, and Eric Rousseau1*

1 Le Bilarium, Department of Physiology and Biophysics, Universite de Sherbrooke, Sherbrooke, QC, Canada, 2 Service of Thoracic Surgery, Universite de Sherbrooke, Sherbrooke, QC, Canada, 3 Department of Pathology, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, QC, Canada

* To whom correspondence should be addressed. E-mail: eric.rousseau{at}usherbrooke.ca.

The aim of the present study was to provide a mechanistic insight into how 14,15-EET relaxes organ-cultured human bronchi. Tension measurements, performed on either fresh or 3-day cultured bronchi, revealed that the contractile responses to 1 µM methacholine, and 10 µM arachidonic acid were largely relaxed by the eicosanoid regioisomer in a concentration-dependent manner (0.01-10 µM). Pretreatments with 14,15-EEZE, a specific 14,15-EET antagonist, prevented the relaxing effect while IbTx pretreatments (10 nM) partially abolished EET-induced relaxations. In contrast, pretreatments with 1 µM indomethacin amplified relaxations in explants as well as membrane hyperpolarizations triggered by 14,15-EET on ASM cells. The relaxing responses induced by 14,15-EET were likely related to reduced Ca2+ sensitivity of the myofilaments since free Ca2+ concentration-response curves performed on {beta}-escin permeabilized cultured explants were shifted toward higher [Ca2+] (lower pCa2+ values). 14,15-EET also abolished the tonic responses induced by PDBu (a PKC-sensitizing agent), on both fresh (intact) and {beta}-escin permeabilized explants. Western blot analyses, using two specific primary antibodies against CPI-17 and its PKC-dependent phosphorylated isoform (P-CPI-17), confirmed that the eicosanoid interferes with this intracellular process. These data indicate that 14,15-EET hyperpolarizes ASM cells and relaxes pre-contracted human bronchi, while reducing Ca2+ sensitivity of fresh and cultured explants. The intracellular effects are related to a PKC-dependent process involving a lower phosphorylation level of CPI-17.




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Copyright © 2007 American Thoracic Society. 		  2009/2010 ATS Fellows Career Development Awards