Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells.
Pulmonary hypertension due to long-term hypoxia occurs as a result of both chronic obstructive pulmonary disease and habitation at high altitudes. Studies in animal models of chronic hypoxia have demonstrated the development of a persistent depolarization of pulmonary artery (PA) smooth muscle cells (SMCs). In seeking to explain this effect, we compared under normoxic conditions the K+ currents in SMCs isolated from small PA of chronically hypoxic and normoxic rats. Chronic hypoxia was associated with a marked (40-50%) reduction in amplitude of a K+ current, which had the pharmacological and kinetic characteristics of a delayed rectifier. The resting potential of the isolated PA cells from chronically hypoxic animals was significantly more positive (-43.5 +/- 2 mV) than that of cells from normoxic animals (-54.3 +/- 2 mV), and this depolarization could be approximately mimicked in the cells from normoxic animals by application of 1 mM 4-aminopyridine, a blocker of the delayed rectifier K+ current. Glibenclamide (1 microM), a blocker of ATP-sensitive K+ (KATP) channels, also caused a substantial (14.5 +/- 2.2 mV) depolarization of the membrane. These results suggest that both delayed rectifier and ATP-dependent K+ currents contribute to setting the membrane potential in these cells and are consistent with the possibility that downregulation of the delayed rectifier K+ current contributes to the depolarization and altered responsiveness to vasoactive agents of PAs that occurs during long-term hypoxia.
Smirnov
S V
SV
Smooth Muscle Research Group, United Medical School, Guy's Hospital, London, United Kingdom.
Robertson
T P
TP
Ward
J P
JP
Aaronson
P I
PI
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D004553:Electric Conductivity; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology*; D011188:Potassium / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar
D015761:4-Aminopyridine; D011188:Potassium; D005905:Glyburide