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Acute hypoxia increases intracellular [Ca²⁺] in pulmonary arterial smooth muscle by enhancing capacitative Ca²⁺ entry

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 4 December 2004 ; accepted in final form 19 January 2005

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca²⁺ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca²⁺ entry (CCE) through store-operated Ca²⁺ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca²⁺-sensitive dye fura-2 to measure effects of 4% O₂ on intracellular [Ca²⁺] ([Ca²⁺]_i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca²⁺-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca²⁺ stores in sarcoplasmic reticulum and nifedipine to prevent Ca²⁺ entry through L-type voltage-operated Ca²⁺ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca²⁺]_i caused by restoration of extracellular [Ca²⁺] and the rate at which extracellular Mn²⁺ quenched fura-2 fluorescence. These effects, as well as the increased [Ca²⁺]_i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl₂, and LaCl₃ at concentrations that inhibited CCE >80% but did not alter [Ca²⁺]_i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca²⁺]_i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca²⁺]_i caused by hypoxia was completely reversed by perfusion with Ca²⁺-free KRBS. LaCl₃ increased basal [Ca²⁺]_i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca²⁺]_i. SOCCs and CCE may play important roles in HPV.

vascular smooth muscle; calcium; ion channels; pulmonary artery; rat

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