Role of reactive oxygen species in Kv channel inhibition and vasoconstriction induced by TP receptor activation in rat pulmonary arteries.
Voltage-gated potassium channels (Kv) and thromboxane A(2) (TXA(2)) have been involved in several forms of human and experimental pulmonary hypertension. We have reported that the TXA(2) analog U46619, via activation of TP receptors and PKCzeta, 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.
Cogolludo
Angel
A
Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
Frazziano
Giovanna
G
Cobeño
Laura
L
Moreno
Laura
L
Lodi
Federica
F
Villamor
Eduardo
E
Tamargo
Juan
J
Perez-Vizcaino
Francisco
F
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D008297:Male; D026902:Potassium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid