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Cited by 362Pulmonary Hypertension Research and TreatmentsNitric Oxide and Endothelin EffectsMitochondrial Function and Pathology

A redox-based O2 sensor in rat pulmonary vasculature.

Archer, S L, Huang, J, Henry, T, Peterson, D, Weir, E K·1993·Circulation Research
DOI 10.1161/01.res.73.6.1100
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Abstract

The effector mechanism of hypoxic pulmonary vasoconstriction (HPV) involves K+ channel inhibition with subsequent membrane depolarization. It remains uncertain how hypoxia modulates K+ channel activity. The similar effects of hypoxia and mitochondrial electron transport chain (ETC) inhibitors on metabolism and vascular tone suggest a common mechanism of action. ETC inhibitors and hypoxia may alter cell redox status by causing an accumulation of electron donors from the Krebs cycle and by decreasing the production of activated O2 species (AOS) by the ETC. We hypothesized that this shift toward a more reduced redox state elicits vasoconstriction by inhibition of K+ channels. Pulmonary artery pressure and AOS, measured simultaneously using enhanced chemiluminescence, were studied in isolated perfused rat lungs during exposure to hypoxia, proximal ETC inhibitors (rotenone and antimycin A), and a distal ETC inhibitor (cyanide). Patch-clamp measurements of whole-cell K+ currents were made on freshly isolated rat pulmonary vascular smooth muscle cells during exposure to hypoxia and ETC inhibitors. Hypoxia, rotenone, and antimycin A decreased lung chemiluminescence (-62 +/- 12, -46 +/- 7, and -148 +/- 36 counts/0.1 s, respectively) and subsequently increased pulmonary artery pressure (+14 +/- 2, +13 +/- 3, and +21 +/- 3 mm Hg, respectively). These agents reversibly inhibited an outward, ATP-independent, K+ current in pulmonary vascular smooth muscle cells. Antimycin A and rotenone abolished subsequent HPV. In contrast, cyanide increased AOS and did not alter K+ currents or inhibit HPV. The initial effect of rotenone, antimycin A, and hypoxia was a change in redox status (evident as a decrease in production of AOS). This was associated with the reversible inhibition of an ATP-independent K+ channel and vasoconstriction. These findings are consistent with the existence of a redox-based O2 sensor in the pulmonary vasculature.

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Authors
Archer, S. L., Huang, J., Henry, T., Peterson, D., & Weir, E. K.
Affiliations
  • United States Department of Veterans Affairs (US)
  • Veterans Administration Medical Center, Minneapolis, MN 55417.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1993-12
Volume
73
Issue
6
Pages
1100-1112
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/01.res.73.6.1100
OpenAlex
W2003831717
Cited by
362
References
37
Citations by year
2026: 2 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 14 · 2016: 8 · 2015: 12 · 2014: 7 · 2013: 6 · 2012: 8
FWCI
10.21
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r29hl045735-04)
  • National Heart, Lung, and Blood Institute (1R29-HL-45735-1)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
hypoxic pulmonary vasoconstriction, redox signaling, oxygen sensing, rotenone, antimycin A, cyanide, potassium channel inhibition, pulmonary vascular smooth muscle cells, reactive oxygen species, pulmonary artery pressure, hypoxia
MeSH terms
Animals, Antimycin A, Chemoreceptor Cells, Cyanides, Electrophysiology, Luminescent Measurements, Lung, Male, Muscle, Smooth, Vascular, Oxidation-Reduction, Oxygen, Potassium, Pulmonary Circulation, Rotenone, Reactive Oxygen Species, Rats, In Vitro Techniques

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