Redox control of oxygen sensing in the rabbit ductus arteriosus

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Abstract
How the ductus arteriosus (DA) closes at birth remains unclear. Inhibition of O2‐sensitive K+ channels may initiate the closure but the sensor mechanism is unknown. We hypothesized that changes in endogenous H2O2 could act as this sensor. Using chemiluminescence measurements with luminol (50 μm) or lucigenin (5 μm) we showed significantly higher levels of reactive O2 species in normoxic, compared to hypoxic DA. This increase in chemiluminescence was completely reversed by catalase (1200 U ml−1). Prolonged normoxia caused a significant decrease in K+ current density and depolarization of membrane potential in single fetal DA smooth muscle cells. Removal of endogenous H2O2 with intracellular catalase (200 U ml−1) increased normoxic whole‐cell K+ currents (IK) and hyperpolarized membrane potential while intracellular H2O2 (100 nm) and extracellular t‐butyl H2O2 (100 μm) decreased IK and depolarized membrane potential. More rapid metabolism of O2−· with superoxide dismutase (100 U ml−1) had no significant effect on normoxic K+ currents. N‐Mercaptopropionylglycine (NMPG), duroquinone and dithiothreitol all dilated normoxic‐constricted DA rings, while the oxidizing agent 5,5′‐dithiobis‐(2‐nitrobenzoic acid) constricted hypoxia‐dilated rings. NMPG also increased IK. We conclude that increased H2O2 levels, associated with a cytosolic redox shift at birth, signal K+ channel inhibition and DA constriction.