Effect of chronic hypoxia on K+ channels: regulation in human pulmonary vascular smooth muscle cells.
We investigated the effects of chronic hypoxia on the major outward K+ currents in early cultured human main pulmonary arterial smooth muscle cells (HPSMC). Unitary currents were measured from inside-out, outside-out, and cell-attached patches of HPSMC. Chronic hypoxia depolarized resting membrane potential (Em) and reduced the activity of a charybdotoxin (CTX)- and iberiotoxin-sensitive, Ca2+-dependent K+ channel (KCa). The 4-aminopyridine-sensitive and CTX-insensitive channel or the delayed rectifier K+ channel was unaffected by chronic hypoxia. Chronic hypoxia caused a +33- to +53-mV right shift in voltage-dependent activation of K(Ca) and a decrease in K(Ca) activity at all cytosolic Ca2+ concentrations ([Ca2+]i) in the range of 0.1-10 microM. Thus the hypoxia-induced decrease in K(Ca) activity was most likely due to a decrease in K(Ca) sensitivity to Em and [Ca2+]i. Chronic hypoxia reduced the ability of nitric oxide (NO.) and guanosine 3',5'-cyclic monophosphate (cGMP) to activate K(Ca). The cGMP-dependent protein kinase-induced activation of K(Ca) was also significantly inhibited by chronic hypoxia. In addition, inhibiting channel dephosphorylation with calyculin A caused significantly less increase in K(Ca) activity in membrane patches excised from chronically hypoxic HPSMC compared with normoxic controls. This suggests that the mechanism by which hypoxia modulates NO.-induced K(Ca) activation is by decreasing the NO./cGMP-mediated phosphorylation of the channel.
Peng
W
W
Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah Health Science Center and The Veterans Affairs Medical Center, Salt Lake City 84132, USA.
Hoidal
J R
JR
Karwande
S V
SV
Farrukh
I S
IS
D001808:Blood Vessels / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002908:Chronic Disease; D006152:Cyclic GMP / Q000502:physiology; D004594:Electrophysiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011652:Pulmonary Circulation
D015221:Potassium Channels; D009569:Nitric Oxide; D011494:Protein Kinases; D006152:Cyclic GMP; D002118:Calcium