Voltage-gated K+-channel activity in ovine pulmonary vasculature is developmentally regulated

1 Division of Pediatric Pulmonology and Critical Care Medicine, Department of Pediatrics, and 2 Department of Physiology, University of Minnesota, Minneapolis 55455; and 3 Department of Medicine, Department of Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota 55417 To examine mechanisms underlying developmental changes in pulmonary vascular tone, we tested the hypotheses that 1 ) maturation-related changes in the ability of the pulmonary vasculature to respond to hypoxia are intrinsic to the pulmonary artery (PA) smooth muscle cells (SMCs); 2 ) voltage-gated K + (K v )-channel activity increases with maturation; and 3 ) O 2 -sensitive Kv2.1 channel expression and message increase with maturation. To confirm that maturational differences are intrinsic to PASMCs, we used fluorescence microscopy to study the effect of acute hypoxia on cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in SMCs isolated from adult and fetal PAs. Although PASMCs from both fetal and adult circulations were able to sense an acute decrease in O 2 tension, acute hypoxia induced a more rapid and greater change in [Ca 2+ ] i in magnitude in PASMCs from adult compared with fetal PAs. To determine developmental changes in K v -channel activity, the effects of the K + -channel antagonist 4-aminopyridine (4-AP) were studied on fetal and adult PASMC [Ca 2+ ] i . 4-AP (1 mM) caused PASMC [Ca 2+ ] i to increase by 94 ± 22% in the fetus and 303 ± 46% in the adult. K v -channel expression and mRNA levels in distal pulmonary arteries from fetal, neonatal, and adult sheep were determined through the use of immunoblotting and semiquantitative RT-PCR. Both Kv2.1-channel protein and mRNA expression in distal pulmonary vasculature increased with maturation. We conclude that there are maturation-dependent changes in PASMC O 2 sensing that may render the adult PASMCs more responsive to acute hypoxia. potassium channels; oxygen sensing; fetus; pulmonary artery; hypoxic pulmonary vasoconstriction; cytosolic calcium