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Porter, Valerie A., Michael T. Rhodes, Helen L. Reeve, and David N. Cornfield. Oxygen-induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of [K.sub.ca] channels. Am J Physiol Lung Cell Mol Physiol 281: L1379-L1385, 2001.--[O.sub.2] sensing in fetal pulmonary artery smooth muscle is critically important in the successful transition to air breathing at birth. However, the mechanism by which the fetal pulmonary vasculature senses and responds to an acute increase in [O.sub.2] tension is not known. Isolated fetal pulmonary artery smooth muscle cells were kept in primary culture for 5-14 days in a hypoxic environment (20-30 mmHg). These cells showed a 25.1 [+ or -] 1.7% decrease in intracellular calcium in response to an acute increase in [O.sub.2] tension. Low concentrations of caffeine (0.5 mM) and diltiazem also decreased intracellular calcium. The decrease in intracellular calcium concentration in response to increasing [O.sub.2] was inhibited by iberiotoxin and ryanodine. Freshly isolated fetal pulmonary artery smooth muscle cells exhibited 'spontaneous transient outward currents,' indicative of intracellular calcium spark activation of calcium-sensitive potassium channels. The frequency of spontaneous transient outward currents increased when [O.sub.2] tension was increased to normoxic levels. Increasing fetal pulmonary [O.sub.2] tension in acutely instrumented fetal sheep increased fetal pulmonary blood flow. Ryanodine attenuated [O.sub.2]-induced pulmonary vasodilation. This study demonstrates that fetal pulmonary vascular smooth muscle cells are capable of responding to an acute increase in [O.sub.2] tension and that this [O.sub.2] response is mediated by intracellular calcium activation of calcium-sensitive potassium channels. smooth muscle cells; spontaneous transient outward current; calcium-sensitive potassium channel Received 31 October 2000; accepted in final form 1 August 2001

To address developmental regulation of pulmonary vascular [O.sub.2] sensing, we tested the hypotheses that 1) fetal but not adult pulmonary artery smooth muscle cells (PASMCs) can directly sense an acute increase in [O.sub.2], 2) [Ca.sup.2+]-sensitive [K.sup.+] ([K.sub.Ca]) channel activity decreases with maturation, and 3) PASMC [K.sub.Ca] channel expression decreases with maturation. We used fluorescence microscopy to confirm that fetal but not adult PASMCs are able to sense an acute increase in [O.sub.2] tension. Acute normoxia induced a 22 [+ or -] 2% decrease in cytosolic [Ca.sup.2+] concentration ([[[Ca.sup.2+].sub.i]) in fetal PASMCs and no change in [[[Ca.sup.2+].sub.i] in adult PASMCs (P [is less than] 0.01). The effects of [K.sup.+] channel antagonists were studied on fetal and adult PASMC [[[Ca.sup.2+].sub.i]. Iberiotoxin ([10.sup.-9] M) caused PASMC [[[Ca.sup.2+].sub.i] to increase by 694 [+ or -] 22% in the fetus and caused no change in adult PASMCs. [K.sub.Ca] channel expression and mRNA levels in distal pulmonary arteries from fetal and adult sheep were examined. Both [K.sub.Ca] channel protein and mRNA expression in the distal pulmonary vasculature decreased with maturation. We conclude that maturation-dependent changes in PASMC [O.sub.2] sensing render the fetal PASMCs uniquely sensitive to an acute increase in [O.sub.2] tension at a biologically critical time point. ontogeny; smooth muscle cells; ion channel; cytosolic calcium

Tests the hypothesis that maturation-related changes in the ability of the pulmonary vasculature to respond to an acute increase in oxygen tension are intrinsic to the pulmonary artery smooth muscle cells (PASMC). Indication that maturation-dependent changes in PASMC oxygen sensing render the fetal PASMC uniquely sensitive to an acute increase in oxygen tension at a biologically critical time point.