Division of Pulmonary and Critical Care, Department of Medicine, Loma Linda University Medical Center, Loma Linda, California, USA.
High Alt Med Biol. 2011 Fall;12(3):253-64. doi: 10.1089/ham.2010.1076.
Long-term hypoxia (LTH) can increase serotonin (5-HT) signaling as well as extracellular calcium entry in adult rodent pulmonary arteries (PA), and 5-HT is associated with pulmonary hypertension. Because LTH, 5-HT, and calcium entry are related, we tested the hypothesis that LTH increases 5-HT-mediated PA contractility and associated calcium influx through L-type Ca2+ channels, nonselective cation channels (NSCC), and reverse-mode sodium-Ca2+ exchange. We performed wire myography and confocal calcium imaging on pulmonary arteries from adult ewes that lived near sea level or were maintained at high-altitude (3801 m) for ∼110 days. LTH did not increase the arterial medial wall thickness, nor did it affect the potency or efficacy for 5-HT-induced PA contraction. Ketanserin (100 nM), a 5-HT2A antagonist, shifted the 5-HT potency to a far greater extent than 1 μM GR-55562, a 5-HT1B/D inhibitor. These influences were unaffected by LTH. The rank order for reducing 5-HT-induced PA contraction in normoxic animals was extracellular calcium removal≈10 mM Ni2+≈10 μM verapamil≈10 μM nifedipine with 50 μM SKF 96365>30 μM KB-R7943≈100 μM flufenamic acid≈10 μM nifedipine≈100 μM Gd3+> 100 μM La3+>500 μM Ni2+≈10 μM diltiazem≈50 μM 2-APB≈100 μM LOE 908. Contraction was not reduced by 100 μM spermine or 30 μM SN-6. LTH increased the effects of KB-R7943 and mitigated those of nifedipine but did not affect calcium responses in imaging studies. Overall, in adult sheep, arterial structure and 5-HT2A and 5HT1B/D functions are preserved following LTH while the role of NSCC-related calcium-dependent contraction is increased. These elements indicate preservation of PA contractility in LTH with minimal functional changes.
长期低氧（LTH）可增加成年啮齿动物肺动脉（PA）中的血清素（5-HT）信号和细胞外钙内流，并且 5-HT 与肺动脉高压有关。由于 LTH、5-HT 和钙内流有关，我们测试了以下假设：LTH 通过 L 型 Ca2+通道、非选择性阳离子通道（NSCC）和反向模式钠钙交换增加 5-HT 介导的 PA 收缩性和相关的钙内流。我们对生活在海平面附近或在高海拔（3801 m）维持约 110 天的成年绵羊的肺动脉进行了线描和共聚焦钙成像。LTH 并未增加动脉中膜壁的厚度，也未影响 5-HT 诱导的 PA 收缩的效力或功效。酮色林（100 nM），一种 5-HT2A 拮抗剂，使 5-HT 的效力转移到远远大于 1 μM GR-55562（一种 5-HT1B/D 抑制剂）的程度。这些影响不受 LTH 影响。在常氧动物中，降低 5-HT 诱导的 PA 收缩的顺序是：去除细胞外钙≈10 mM Ni2+≈10 μM 维拉帕米≈10 μM 硝苯地平，用 50 μM SKF 96365>30 μM KB-R7943≈100 μM 氟芬那酸≈10 μM 硝苯地平≈100 μM Gd3+>100 μM La3+>500 μM Ni2+≈10 μM 地尔硫卓≈50 μM 2-APB≈100 μM LOE 908。100 μM 精胺或 30 μM SN-6 不能减少收缩。LTH 增加了 KB-R7943 的作用并减轻了硝苯地平的作用，但在成像研究中并未影响钙反应。总体而言，在成年绵羊中，LTH 后动脉结构和 5-HT2A 和 5-HT1B/D 功能得以保留，而与 NSCC 相关的钙依赖性收缩的作用增加。这些因素表明 LTH 中 PA 收缩性得以保留，而功能变化最小。
