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a Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain b Research Institute of Growth and Development (GROW), University of Maastricht, 6202 AZ Maastricht, The Netherlands
Key Words: voltage-gated potassium channels • thromboxane A2 • cyclooxygenases
Address for correspondence: F. Perez-Vizcaino, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Voice: 34-913941477; fax: 34-913941465. e-mail: fperez{at}med.ucm.es
Voltage-gated potassium channels (Kv) and thromboxane A2 (TXA2) have been involved in several forms of human and experimental pulmonary hypertension. We have reported that the TXA2 analog U46619, via activation of TP receptors and PKC
 , inhibited Kv currents in rat pulmonary artery smooth muscle cells (PASMC), increased cytosolic calcium, and induced a contractile response in isolated rat and piglet pulmonary arteries (PA). Herein, we have analyzed the role of reactive oxygen species (ROS) in this signaling pathway. In rat PA, U46619 increased dichlorofluorescein fluorescence, an indicator of intracellular hydrogen peroxide, and this effect was prevented by the NADPH oxidase inhibitor apocynin and by polyethyleneglycol-catalase (PEG-catalase, a membrane-permeable form of catalase). U46619 inhibited Kv currents in native PASMC and these effects were strongly inhibited by apocynin. The contractile responses to U46619 in isolated PA were inhibited by PEG-catalase and the NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin. A membrane permeable of hydrogen peroxide, t-butyl hydroperoxide, also inhibited Kv currents and induced a contractile response. Activation of NADPH oxidase and the subsequent production of hydrogen peroxide are involved in the Kv channel inhibition and the contractile response induced by TP receptor activation in rat PA.
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