Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs
Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs
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DOI：
10.1152/ajplung.1999.276.2.l358
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发表时间：
1999-02-01
影响因子：
4.9
通讯作者：
Fukuchi, Y
中科院分区：
文献类型：
--
作者：
Muramatsu, M;Oka, M;Fukuchi, Y
为了研究慢性缺氧是否影响内皮素B（ETB）受体介导的肺血管舒张，我们比较了血管舒张反应IRL-1620，一种选择性ETB受体激动剂，在离体灌注肺常氧和慢性缺氧的成年雄性大鼠。IRL-1620引起剂量依赖性血管舒张，其在高血压肺中比在正常血压肺中更大。在血压正常的肺中，一氧化氮（NO）合酶抑制剂N-ω-硝基-L-精氨酸（L-NNA; 300 μ M）和ATP敏感性钾（K-ATP）通道抑制剂格列本脲（Glib; 10 μ M）均降低了对IRL-1620（1 nM）的血管扩张反应，但L-NNA和Glib联合使用比单独使用任何一种药物更有效地抑制了这种反应。相比之下，L-NNA单独，而不是单独Glib，完全阻断IRL-1620诱导的高血压肺血管舒张。在高血压肺中，对K-ATP通道开放剂NIP-121（1 μ M）的血管舒张反应增强，但对硝普钠（1 μ M）的反应不增强。我们还发现缺氧暴露后肺组织中ETB受体mRNA的表达增加。此外，半定量免疫组化显示，低氧大鼠肺动脉远段内皮ETB受体表达水平高于常氧大鼠。这些结果表明，ETB受体介导的肺血管舒张增强慢性缺氧暴露后，NO的释放可能是这种血管舒张在高血压肺的唯一机制，而NO的释放和激活的K-ATP通道参与在正常血压的肺。我们推测，这种增强的潜在机制可能部分与高血压肺阻力动脉内皮ETB受体的上调有关。
To investigate whether chronic hypoxia affects endothelin-B (ETB) receptor-mediated pulmonary vasodilation, we compared the vasodilator responses to IRL-1620, a selective ETB-receptor agonist, in isolated perfused lungs from normoxic and chronically hypoxic adult male rats. IRL-1620 caused a dose-dependent vasodilation that was greater in the hypertensive lungs than in the normotensive lungs. In normotensive lungs, a nitric oxide (NO) synthase inhibitor, N-omega-nitro-L-arginine (L-NNA; 300 mu M), and an ATP-sensitive potassium (K-ATP)-channel inhibitor, glibenclamide (Glib; 10 mu M), each reduced the vasodilator response to IRL-1620 (1 nM), but the combination of L-NNA and Glib inhibited it more effectively than either drug alone. In contrast, L-NNA alone, but not Glib alone, completely blocked IRL-1620-induced vasodilation in hypertensive lungs. The vasodilator response to a K-ATP- channel opener, NIP-121 (1 mu M), but not the response to sodium nitroprusside (1 mu M), was enhanced in hypertensive lungs. We also found increased expression of mRNA for the ETB receptor in lung tissue after hypoxic exposure. In addition, semiquantitative immunohistochemistry demonstrated higher expression levels of ETB receptors in the endothelium of distal segments of the pulmonary artery in hypoxic than in normoxic rats. These results suggest that ETB receptor-mediated pulmonary vasodilation is augmented after chronic hypoxic exposure and that release of NO may be the sole mechanism of this vasodilation in hypertensive lungs, whereas both release of NO and activation of K-ATP channels are involved in normotensive lungs. We speculate that the underlying mechanism responsible for this augmentation may partly be related to upregulation of ETB receptors in the endothelium of pulmonary resistance arteries in hypertensive lungs.