Morin Caroline, Sirois Marco, Echave Vincent, Rizcallah Edmond, Rousseau Eric
Le Bilarium, Dept. of Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC, Canada J1H 5N4.
Am J Physiol Lung Cell Mol Physiol. 2009 Jan;296(1):L130-9. doi: 10.1152/ajplung.90436.2008. Epub 2008 Oct 31.
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 BK(Ca) and K(ATP) 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 muM Glyb. Complementary experiments performed on human bronchi, using the planar lipid bilayer reconstitution technique, demonstrated that 17(18)-EpETE activated reconstituted BK(Ca) channels at low free Ca(2+) concentration. Moreover, in bronchi, the relaxing responses induced by 17(18)-EpETE were also related to reduced Ca(2+) sensitivity of the myofilaments, since free Ca(2+) concentration-response curves, performed on beta-escin-permeabilized cultured explants, were shifted toward higher Ca(2+). 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.
人类细胞色素P-450环氧合酶可代谢二十碳五烯酸（EPA），一种ω-3多不饱和脂肪酸（PUFA），并产生17（18）-环氧二十碳四烯酸，即17（18）-EpETE。本研究的目的是阐明17（18）-EpETE对人肺动脉（HPA）和远端支气管的作用方式。等长张力测量表明，17（18）-EpETE在肺动脉和气道平滑肌中诱导浓度依赖性舒张作用。分别作为已知的大电导钙激活钾通道（BK（Ca））和ATP敏感性钾通道（K（ATP））抑制剂的iberiotoxin（IbTx）和格列本脲（Glyb），可逆转17（18）-EpETE对两种组织类型诱导的舒张作用。微电极测量表明，外源性添加17（18）-EpETE可使HPA和支气管平滑肌细胞的膜电位超极化。添加10 nM IbTx和10 μM Glyb可逆转这些诱导的电生理效应。使用平面脂质双层重建技术在人支气管上进行的补充实验表明，17（18）-EpETE在低游离Ca（2+）浓度下可激活重建的BK（Ca）通道。此外，在支气管中，17（18）-EpETE诱导的舒张反应也与肌丝对Ca（2+）的敏感性降低有关，因为在β-七叶皂苷通透的培养外植体上进行的游离Ca（2+）浓度-反应曲线向更高的Ca（2+）方向移动。总之，这些结果为17（18）-EpETE在肺组织中的作用方式提供了新的见解，并突出了这种类花生酸作为体外HPA和远端支气管张力的有效调节剂，这可能在肺动脉高压和气道疾病的病理生理学中具有临床相关性。
