Redox control of oxygen sensing in the rabbit ductus arteriosus

Helen L. Reeve, Simona Tolarova, Daniel P. Nelson, Stephen Archer, Edward K Weir

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

1. How the ductus arteriosus (DA) closes at birth remains unclear. Inhibition of O 2-sensitive K + channels may initiate the closure but the sensor mechanism is unknown. We hypothesized that changes in endogenous H 2O 2 could act as this sensor. 2. Using chemiluminescence measurements with luminol (50 μM) or lucigenin (5 μM) we showed significantly higher levels of reactive O 2 species in normoxic, compared to hypoxic DA. This increase in chemiluminescence was completely reversed by catalase (1200 U ml -1). 3. 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 H 2O 2 with intracellular catalase (200 U ml -1) increased normoxic whole-cell K + currents (I K) and hyperpolarized membrane potential while intracellular H 2O 2 (100 nM) and extracellular t-butyl H 2O 2 (100 μM) decreased I K and depolarized membrane potential. More rapid metabolism of O 2 -· with superoxide dismutase (100 U ml -1) had no significant effect on normoxic K + currents. 4. 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 I K. We conclude that increased H 2O 2 levels, associated with a cytosolic redox shift at birth, signal K + channel inhibition and DA constriction.

Original languageEnglish (US)
Pages (from-to)253-261
Number of pages9
JournalJournal of Physiology
Volume533
Issue number1
DOIs
StatePublished - Mar 15 2001

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