Effect of chronic hypoxia on ca2&-activated k& channels:
regulation in human pulmonary vascular smooth muscle cells.
Peng, Wei, John R. Hoidal, Sv Karwande, and Imad S. Farrukh.
Division of Respiratory, Critical Care and Occupational Pulmonary
Medicine, Department of Internal Medicine, and Division of
Cardiothoracic Surgery, Department of Surgery, University of Utah
Health Science Center, and The Veterans Affairs Medical Center Salt
Lake City, Utah 84132
APStracts 3:0375C, 1996.
We investigated the effects of chronic hypoxia on the major outward
potassium currents (IKo) in early cultured main human 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
(IBTX)-sensitive and a Ca2&-dependent K& channel (KCa). The
4-aminopyridine (4-AP)-sensitive and CTX-insensitive channel or the
delayed rectifier K& channel (Kdr) was unaffected by chronic
hypoxia. Chronic hypoxia caused a &33 to &53 mV right shift
in voltage-dependent activation of KCa, and an e-fold decrease in KCa
activity at all cytosolic Ca2& concentrations ([Ca2&]i) in
the range of 0.1 - 10 _M. Thus the hypoxia-induced decrease in KCa
activity was most likely due to a decrease in KCa sensitivity to Em
and [Ca2&]i. Chronic hypoxia reduced the ability of nitric oxide
(NO_) and cGMP to activate KCa. The cGMP-dependent protein kinase
(cGMP-PK)-induced activation of KCa was significantly inhibited by
chronic hypoxia. In addition, inhibiting channel dephosphorylation
with calyculin A caused significantly less increase in KCa activity
in membrane patches excised from chronically hypoxic HPSMC compared
to normoxic control. This suggests that the mechanism by which
hypoxia modulates NO_-induced KCa activation is by decreasing the
NO_/cGMP-mediated phosphorylation of the channel.
Received 19 June 1996; accepted in final form 7 November 1996.
APS Manuscript Number C352-6.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996