Relaxing effects of 17(18)-EpETE on arterial and airway smooth muscles in human lung

Morin C, Sirois M, Echave V, Rizcallah E, Rousseau E. Relaxing effects of 17(18)-EpETE on arterial and airway smooth muscles in human lung. Am J Physiol Lung Cell Mol Physiol 296: L130-L139, 2009. First published October 31, 2008; doi:10.1152/ajplung.90436.2008.-Human cytochrome P-450 epoxygenase enzymes metabolize eicosapentaenoic acid (EPA), an omega-3-polyunsaturated fatty acid (PUFA), and leads to the production of 17(18)-epoxyeicosatetraenoic acid, or 17(18)-EpETE. The aim of the present study was to delineate the mode of action of 17(18)-EpETE on human pulmonary artery (HPA) and distal bronchi. Isometric tension measurements demonstrated that 17(18)-EpETE induced concentration-dependent relaxing effects in pulmonary artery and airway smooth muscles. Iberiotoxin (IbTx) and glyburide (Glyb), known BKCa and KATP channel inhibitors, respectively, reversed the relaxation induced by 17(18)-EpETE on both tissues types. Microelectrode measurements showed that exogenous addition of 17(18)-EpETE hyperpolarized the membrane potential of HPA and bronchial smooth muscle cells. These induced electrophysiological effects were reversed by the addition of 10 nM IbTx and 10 mu M Glyb. Complementary experiments performed on human bronchi, using the planar lipid bilayer reconstitution technique, demonstrated that 17(18)-EpETE activated reconstituted BKCa channels at low free Ca2+ concentration. Moreover, in bronchi, the relaxing responses induced by 17(18)-EpETE were also related to reduced Ca2+ sensitivity of the myofilaments, since free Ca2+ concentration-response curves, performed on beta-escinpermeabilized cultured explants, were shifted toward higher Ca2+. Together, these results provide new insight into the mode of action of 17(18)-EpETE in lung tissues and highlight this eicosanoid as a potent modulator of tone on both HPA and distal bronchi in vitro, which may be of clinical relevance in the pathophysiology of pulmonary hypertension and airway diseases.