Long-term high-altitude hypoxia influences pulmonary arterial L-type calcium channel-mediated Ca2+ signals and contraction in fetal and adult sheep.
Long-term high-altitude hypoxia influences pulmonary arterial L-type calcium channel-mediated Ca2+ signals and contraction in fetal and adult sheep.
复制标题
DOI：
10.1152/ajpregu.00154.2017
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Christine P Shen;M. Romero;Alexander Brunelle;C. Wolfe;A. Dobyns;Michael Francis;M. Taylor;J. Puglisi;L. Longo;Lubo Zhang;Christopher G. Wilson;S. Wilson
中科院分区：
文献类型：
--
作者：
Christine P Shen;M. Romero;Alexander Brunelle;C. Wolfe;A. Dobyns;Michael Francis;M. Taylor;J. Puglisi;L. Longo;Lubo Zhang;Christopher G. Wilson;S. Wilson
长期缺氧（LTH）对胎儿和成人的肺动脉血管收缩具有深远的影响。 Ca2+ 信号传导失调在 LTH 诱导的肺动脉高压的发生过程中非常重要。在本研究中，我们测试了这样的假设：L 型 Ca2+ 通道 (CaL) 具有电压依赖性，存在于平滑肌、骨骼肌和心肌中，对于出生后成熟过程中肺动脉收缩的适应和对 LTH 的反应非常重要。从在低海拔或高海拔 (3,801 m) 维持 > 100 天的胎儿或成年羊中分离出肺动脉。在存在或不存在抑制剂硝苯地平 (NIF) 的情况下，使用 L 型 Ca2+ 通道开放剂 FPL 64176 (FPL) 测量对动脉收缩、细胞内 Ca2+ 振荡和兰尼碱受体驱动的 Ca2+ 火花的影响。所有组中 FPL 诱导的肺动脉收缩对 NIF 均敏感。然而，与 125 mM K+ 相比，胎儿的 FPL 收缩比成人更大。 FPL 减少成人肌细胞中的 Ca2+ 振荡，但不减少胎儿动脉，与海拔无关。 FPL 对 Ca2+ 振荡的影响在缺氧成人的肌细胞中被 NIF 逆转，但在常氧成人的肌细胞中却没有逆转。 FPL未能提高Ca2+火花频率，对时空点火特性影响不大。这些数据表明，CaL 依赖性收缩在很大程度上与细胞内 Ca2+ 振荡和 Ca2+ 火花的发展无关。这就提出了关于肺动脉收缩力与膜去极化、伴随的 CaL 促进以及与 Ca2+ 振荡和 Ca2+ 火花激活的相关关联的问题。
Long-term hypoxia (LTH) has a profound effect on pulmonary arterial vasoconstriction in the fetus and adult. Dysregulation in Ca2+ signaling is important during the development of LTH-induced pulmonary hypertension. In the present study, we tested the hypothesis that L-type Ca2+ channels (CaL), which are voltage dependent and found in smooth, skeletal, and cardiac muscle, are important in the adaptation of pulmonary arterial contractions in postnatal maturation and in response to LTH. Pulmonary arteries were isolated from fetal or adult sheep maintained at low or high altitude (3,801 m) for >100 days. The effects were measured using an L-type Ca2+ channel opener FPL 64176 (FPL) in the presence or absence of an inhibitor, Nifedipine (NIF) on arterial contractions, intracellular Ca2+ oscillations, and ryanodine receptor-driven Ca2+ sparks. FPL induced pulmonary arterial contractions in all groups were sensitive to NIF. However, when compared with 125 mM K+, FPL contractions were greater in fetuses than in adults. FPL reduced Ca2+ oscillations in myocytes of adult but not fetal arteries, independently of altitude. The FPL effects on Ca2+ oscillations were reversed by NIF in myocytes of hypoxic but not normoxic adults. FPL failed to enhance Ca2+ spark frequency and had little impact on spatiotemporal firing characteristics. These data suggest that CaL-dependent contractions are largely uncoupled from intracellular Ca2+ oscillations and the development of Ca2+ sparks. This raises questions regarding the coupling of pulmonary arterial contractility to membrane depolarization, attendant CaL facilitation, and the related associations with the activation of Ca2+ oscillations and Ca2+ sparks.