Alterations in a redox oxygen sensing mechanism in chronic hypoxia.
The mechanism of acute hypoxic pulmonary vasoconstriction (HPV) may involve the inhibition of several voltage-gated K+ channels in pulmonary artery smooth muscle cells. Changes in PO2 can either be sensed directly by the channel(s) or be transmitted to the channel via a redox-based effector mechanism. In control lungs, hypoxia and rotenone acutely decrease production of activated oxygen species, inhibit K+ channels, and cause constriction. Two-day and 3-wk chronic hypoxia (CH) resulted in a decrease in basal activated oxygen species levels, an increase in reduced glutathione, and loss of HPV and rotenone-induced constriction. In contrast, 4-aminopyridine- and KCl-mediated constrictions were preserved. After 3-wk CH, pulmonary arterial smooth muscle cell membrane potential was depolarized, K+ channel density was reduced, and acute hypoxic inhibition of whole cell K+ current was lost. In addition, Kv1.5 and Kv2.1 channel protein was decreased. These data suggest that chronic reduction of the cytosol occurs before changes in K+ channel expression. HPV may be attenuated in CH because of an impaired redox sensor.
Reeve
H L
HL
Department of Medicine, University of Minnesota, Minneapolis 55455, USA.
Michelakis
E
E
Nelson
D P
DP
Weir
E K
EK
Archer
S L
SL
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002908:Chronic Disease; D004594:Electrophysiology; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D015640:Ion Channel Gating / Q000502:physiology; D008163:Luminescent Measurements; D008168:Lung / Q000378:metabolism / Q000502:physiology; D008297:Male; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012402:Rotenone; D005978:Glutathione