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1 Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
2 Division of Pediatric Pulmonary and Critical Care Medicine, Physiology, University of Minnesota, Minneapolis, MN, USA
3 Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Pulmonary and Critical Care Medicine, Physiology, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Pulmonary and Critical Care Medicine, Surgery, University of Minnesota, Minneapolis, MN, USA
4 Division of Pediatric Pulmonary and Critical Care Medicine, Surgery, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Pulmonary and Critical Care Medicine, Physiology, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
* To whom correspondence should be addressed. E-mail: cornf001{at}umn.edu.
In utero, blood shunts away from the lungs via the ductus arteriosus (DA) and the foramen ovale. After birth, the DA closes concomitant with increased oxygen tension. The present experimental series tests the hypothesis that oxygen directly increases DA smooth muscle cell (SMC) cytosolic calcium ([Ca2+]i) through inactivation of a K+ channel, membrane depolarization, and entry of extracellular calcium. To test the hypothesis, DA SMC were isolated from late-gestation fetal lambs and grown to subconfluence in primary culture in low oxygen tension (25 torr.). DA SMC were loaded with the calcium sensitive fluorophore, fura-2, under low oxygen tension conditions and studied using microfluorimetry while oxygen tension was acutely increased (120 torr.). An acute increase in oxygen tension progressively increased DA SMC [Ca2+]i by 11.7% ± 1.4% over 40 minutes. The effect of acute normoxia on DA SMC [Ca2+]i was mimicked by pharmacologic blockade of the voltage-sensitive K+ channel. Neither removal of extracellular calcium nor voltage-operated calcium channel blockade prevented the initial increase in DA SMC [Ca2+]i. Manganese quenching experiments demonstrated that acute normoxia initially decreases the rate of extracellular calcium entry. Pharmacologic blockade of inositol triphosphate-sensitive, but not ryanodine-sensitive, intracellular calcium stores prevented the oxygen-induced increase in [Ca2+]i. Endothelin increased [Ca2+]i in acutely normoxic, but not hypoxic, DA SMC. Thus, acute normoxia increases DA SMC [Ca2+]i via: (i) release of calcium from intracellular calcium stores, and subsequent entry of extracellular calcium; and (ii) potentiates the effect of contractile agonists. Prolonged patency of the DA may result from disordered intracellular calcium homeostasis.
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