© 1995 American Heart Association, Inc.
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Dithionite Increases Radical Formation and Decreases Vasoconstriction in the Lung
Evidence That Dithionite Does Not Mimic Alveolar Hypoxia
From the Minneapolis Veterans Affairs Medical Center and the University of Minnesota, Minneapolis.
Correspondence to Stephen Archer, MD (Associate Professor of Medicine), Minneapolis VA Medical Center, One Veterans Dr, Minneapolis, MN 55417.
Abstract Dithionite is a powerful reducing agent used to
deoxygenate hemoglobin and create anaerobic conditions in
vitro. Recently, dithionite has been used as a convenient means of
creating "hypoxia" in experiments studying the
O2 sensor in the pulmonary circulation and carotid body. We
evaluated the hypothesis that hypoxia created by hypoxic
ventilation and that created by dithionite have different effects on
the pulmonary circulation. In vitro, dithionite (10-5 to
10-3 mol/L), added to oxygenated Krebs' solution, rapidly
created superoxide anion in a dose-dependent manner. Dithionite
consumed O2 in parallel with the generation of superoxide
radical, with both processes peaking within seconds. Anoxia was
sustained only if resupply of O2 was prevented. In isolated
rat lungs (whether perfused with autologous blood or Krebs' solution),
hypoxic ventilation alone lowered perfusate
PO2 from 
140 to 40 mm Hg and decreased
lung levels of activated oxygen species (AOS), measured by
luminol-enhanced chemiluminescence, before the onset of hypoxic
pulmonary vasoconstriction. Constrictor responses to angiotensin II and
KCl were not impaired by intermittent hypoxic challenges, and lung
weight did not increase. In contrast, dithionite impaired constrictor
responses of the Krebs' solution–perfused lungs to all
vasoconstrictors tested and increased lung weight. When given as a
bolus (5x10-3 mol/L) into the pulmonary artery during
normoxic ventilation, dithionite caused no vasoconstriction and only
briefly lowered PO2 (because of constant
resupply of O2 from the alveoli). When superimposed on
hypoxic ventilation, dithionite further lowered
PO2 from 40 to 0 mm Hg and caused
additional constriction. Unlike hypoxic ventilation, dithionite
increased AOS production. Antioxidant enzymes diminished
dithionite-induced radical production and diminished the loss of
vascular reactivity and lung edema. In conclusion, unlike hypoxic
ventilation, dithionite causes edema and loss of vascular reactivity in
the lung by generating superoxide anion and hydrogen peroxide. Hypoxia
elicited by dithionite is not equivalent to authentic hypoxia
because of the obligatory associated generation of AOS. Dithionite
usage should not be substituted for authentic hypoxia in
studies of O2 sensing.
Key Words: dithionite • oxygen radicals • hypoxia • oxygen sensor • chemiluminescence
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