Becker Silke, Moir Lyn M, Snetkov Vladimir A, Aaronson Philip I
Division of Asthma, Allergy, and Lung Biology, King's College London, London, United Kingdom.
Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L982-90. doi: 10.1152/ajplung.00361.2006. Epub 2007 Jul 6.
It has been proposed that a hypoxia-induced inhibition of the Na(+)-Ca(2+) exchanger (NCX) contributes to hypoxic pulmonary vasoconstriction (HPV). By recording isometric tension development in rat intrapulmonary arteries (IPA), we examined the effect on HPV of maneuvers that reduce the ability of NCX to regulate intracellular Ca(2+) concentration (Ca(2+)). In some experiments, fura pentakis(acetoxymethyl) ester-3 (fura PE-3) was also used to monitor Ca(2+). HPV was elicited in IPA that were pretreated with 10 microM diltiazem and slightly preconstricted with PGF(2alpha), which enhances the hypoxic response. Substitution of Na(+) with Li(+) increased HPV and the associated rise in Ca(2+). Pretreatment with ouabain (100 microM) to diminish the Na(+) gradient or with the reverse-mode NCX inhibitor KB-R7943 (3 or 10 microM) had no significant effect on HPV. Combined treatment with ouabain and low-[Na(+)] (24 mM) solution enhanced HPV strongly. The role of NCX in Ca(2+) extrusion was examined by assessing the decrease in Ca(2+) in Ca(2+)-free physiological saline solution either containing or lacking Na(+) following a high K(+)-induced loading of cellular [Ca(2+)]. Although the large initial rapid fall in [Ca(2+)] was Na(+) independent, final recovery of [Ca(2+)] to its basal level was delayed in the absence of Na(+). Therefore, HPV persisted or was increased under conditions in which forward-mode NCX was already attenuated or prevented, demonstrating that inhibition of NCX by hypoxia is unlikely to initiate HPV. Instead, NCX appears to act to inhibit HPV as would be expected if it is functioning to extrude Ca(2+).
有人提出，缺氧诱导的钠钙交换体（NCX）抑制作用有助于缺氧性肺血管收缩（HPV）。通过记录大鼠肺内动脉（IPA）的等长张力发展情况，我们研究了降低NCX调节细胞内钙浓度（[Ca²⁺]i）能力的操作对HPV的影响。在一些实验中，还使用了五乙酰氧基甲基酯-3（fura PE-3）来监测[Ca²⁺]i。在用10微摩尔/升地尔硫䓬预处理并稍用前列腺素F₂α（PGF₂α）预收缩以增强缺氧反应的IPA中引发HPV。用Li⁺替代Na⁺增加了HPV以及相关的[Ca²⁺]i升高。用哇巴因（100微摩尔/升）预处理以降低Na⁺梯度或用反向模式NCX抑制剂KB-R7943（3或10微摩尔/升）对HPV无显著影响。哇巴因与低[Na⁺]（24毫摩尔/升）溶液联合处理强烈增强了HPV。通过评估在高钾诱导细胞内[Ca²⁺]负载后，含或不含Na⁺的无钙生理盐溶液中[Ca²⁺]i的降低情况，研究了NCX在Ca²⁺外排中的作用。尽管最初[Ca²⁺]的大幅快速下降不依赖于Na⁺，但在无Na⁺时[Ca²⁺]最终恢复到基础水平的过程延迟。因此，在正向模式NCX已经减弱或被阻止的情况下，HPV持续存在或增加，这表明缺氧对NCX的抑制不太可能引发HPV。相反，NCX似乎起到抑制HPV的作用，这与如果它起到外排Ca²⁺的作用时预期的情况相符。
