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Oxidant Signaling in Lung Cells

Opposite effects of redox status on membrane potential, cytosolic calcium, and tone in pulmonary arteries and ductus arteriosus

¹Justus Liebig University, 35385 Giessen, Germany; ²Minneapolis Veterans Affairs Medical Center; and ³Department of Pediatrics, Division of Pulmonary and Critical Care, and ⁴Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55417

Submitted 1 November 2002 ; accepted in final form 24 June 2003

At birth, associated with the rise in oxygen tension, the pulmonary arteries (PA) dilate and the ductus arteriosus (DA) constricts. Both PA and DA constrict with vasoconstrictors and dilate with vasodilators. They respond in a contrary manner only to changes in oxygen tension. We hypothesized that the effects of changes in oxygen are mediated by changes in redox status. Consequently, we tested whether a reducing agent, DTT, and an oxidizing agent, dithionitrobenzoic acid (DTNB), would have opposite effects on a major oxygen signaling pathway in the PA and DA smooth muscle cells (SMCs), the sequence of change in potassium current (I_K), membrane potential (E_m), cytosolic calcium, and vessel tone. Under normoxic conditions, DTT constricted adult and fetal resistance PA rings, whereas in DA rings DTT acted as a potent vasodilator. In normoxia, voltage-clamp measurements showed inhibition of I_K by DTT in PASMCs and, in contrast, activation in DASMCs. Consequently, DTT depolarized fetal and adult PASMCs and hyperpolarized DASMCs. [Ca²⁺]_i was increased by DTT in fetal and adult PASMCs and decreased in DASMCs. Under hypoxic conditions, DTNB constricted DA rings and caused vasodilatation in fetal PA rings. DTNB inhibited I_K and depolarized the cell membrane in DASMCs. In contrast, activation of I_K and hyperpolarization was seen in PASMCs. Thus the same redox signal can elicit opposite effects on I_K, E_m, cytosolic calcium, and vascular tone in resistance PA and the DA. These observations support the concept that redox changes could signal the opposite effects of oxygen in the PA and DA.

hypoxia; potassium channels; resting membrane potential; pulmonary vasoconstriction

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