Contribution of the K(Ca) channel to membrane potential and O2 sensitivity is decreased in an ovine PPHN model.
Ca2+-sensitive K+ (K(Ca)) channels play an important role in mediating perinatal pulmonary vasodilation. We hypothesized that lung K(Ca) channel function may be decreased in persistent pulmonary hypertension of the newborn (PPHN). To test this hypothesis, pulmonary artery smooth muscle cells (PASMC) were isolated from fetal lambs with severe pulmonary hypertension induced by ligation of the ductus arteriosus in fetal lambs at 125-128 days gestation. Fetal lambs were killed after pulmonary hypertension had been maintained for at least 7 days. Age-matched, sham-operated animals were used as controls. PASMC K+ currents and membrane potentials were recorded using amphotericin B-perforated patch-clamp techniques. The increase in whole cell current normally seen in response to normoxia was decreased (333.9 +/- 63.6% in control vs. 133.1 +/- 16.0% in hypertensive fetuses). The contribution of the K(Ca) channel to the whole cell current was diminished in hypertensive, compared with control, fetal PASMC. In PASMC from hypertensive fetuses, a change from hypoxia to normoxia caused no change in membrane potential compared with a -14.6 +/- 2.8 mV decrease in membrane potential in PASMC from control animals. In PASMC from animals with pulmonary hypertension, 4-aminopyridine (4-AP) caused a larger depolarization than iberiotoxin, whereas in PASMC from control animals, iberiotoxin caused a larger depolarization than 4-AP. These data confirm the hypothesis that the contribution of the K(Ca) channel to membrane potential and O2 sensitivity is decreased in an ovine model of PPHN, and this may contribute to the abnormal perinatal pulmonary vasoreactivity associated with PPHN.
Olschewski
Andrea
A
Department of Anesthesiology, Justus Liebig University, 35392 Giessen, Germany.
Hong
Zhigang
Z
Linden
Bradley C
BC
Porter
Valerie A
VA
Weir
E Kenneth
EK
Cornfield
David N
DN
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D005865:Gestational Age; D006976:Hypertension, Pulmonary / Q000196:embryology / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D013779:Tetrodotoxin / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology
D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D013779:Tetrodotoxin; C064719:iberiotoxin; D015761:4-Aminopyridine