Impaired voltage gated potassium channel responses in a fetal lamb model of persistent pulmonary hypertension of the newborn.
We investigated the hypothesis that oxidative stress in persistent pulmonary hypertension of the newborn (PPHN) impairs voltage gated potassium (Kv) channel function. We induced PPHN in fetal lambs by prenatal ligation of ductus arteriosus; controls had sham ligation. We studied changes in the tone of pulmonary artery (PA) rings and Kv channel current of freshly isolated PA smooth muscle cells (PASMC) using standard techniques. 4-Aminopyridine (4-AP), a Kv channel antagonist, induced dose-dependent constriction of control PA rings; this response was attenuated in PPHN pulmonary arteries. Exogenous superoxide and peroxynitrite inhibited the response to 4-AP in control rings. Tiron, a superoxide scavenger, improved the response to 4-AP in PPHN rings. 4-AP inhibited the NOS-independent relaxation response to ATP in control PA rings. Relaxation response to ATP was blunted in PPHN rings and was improved by NOS antagonist, N-nitro-L-arginine methyl ester (L-NAME). 4-AP attenuated this response in L-NAME-treated PPHN rings. Exogenous superoxide suppressed 4-AP sensitive Kv current in control PASMC. Kv channel current was attenuated in cells from PPHN lambs and was restored by tiron. Oxidative stress impairs Kv channel function in PPHN. Superoxide scavengers may improve pulmonary vasodilation in PPHN in part by restoring Kv channel function.
Konduri
Girija G
GG
Department of Pediatrics, Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, Wisconsin 53226, USA. gkonduri@mcw.edu
Bakhutashvili
Ivane
I
Eis
Annie
A
Gauthier
Kathryn M
KM
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000378:metabolism; D015761:4-Aminopyridine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000502:physiology* / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010547:Persistent Fetal Circulation Syndrome / Q000503:physiopathology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012756:Sheep; D013482:Superoxide Dismutase / Q000378:metabolism
D016166:Free Radical Scavengers; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000255:Adenosine Triphosphate; D015761:4-Aminopyridine; D013482:Superoxide Dismutase