Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats
Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats
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DOI：
10.1161/01.res.0000261658.12024.18
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发表时间：
2007-03-30
影响因子：
20.1
通讯作者：
McMurtry, Ivan F.
中科院分区：
文献类型：
--
作者：
Oka, Masahiko;Homma, Noriyuki;McMurtry, Ivan F.
人们认为，严重肺动脉高压（PAH）的高血管阻力是由血管重塑而非血管收缩引起的。我们之前发现，在没有闭塞性新内膜病变的慢性缺氧大鼠中，急性 Rho 激酶抑制几乎使 PAH 正常化。在这里，我们检查了 Rho 激酶介导的血管收缩在严重闭塞性 PAH 大鼠模型中是否也很重要。皮下注射血管内皮生长因子受体抑制剂 SUGEN 5416 后，成年大鼠处于慢性缺氧（约 10% O-2）。麻醉大鼠缺氧 2 周（早期组）和缺氧 3 周加常氧 2 周（晚期组）后进行血流动力学测量。两组均出现了 PAH，且晚期组更为严重。在早期组中，静脉注射法舒地尔在降低右心室收缩压方面比静脉注射缓激肽、吸入NO或静脉注射伊洛前列素更有效。尽管闭塞性血管病变较多，法舒地尔也显着降低了晚期大鼠的右心室收缩压。晚期大鼠的血液灌注肺部显示出自发的血管收缩，这种收缩可被内皮素 A 受体阻断剂 BQ123 部分逆转，并被法舒地尔或 Y-27632 完全逆转。两组大鼠肺部的 MYPT1（Rho 激酶下游靶标）磷酸化均增加，而法舒地尔（静脉注射）逆转了晚期组中增加的磷酸化。因此，除了结构闭塞之外，Rho激酶介导的血管收缩是SUGEN 5416/缺氧暴露大鼠中严重PAH的重要组成部分，并且如果使用非常规血管扩张剂，则在严重重塑肺循环的情况下可以显着减少PAH。
Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension ( PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase - mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximate to 10% O-2) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia ( early group) and 3 weeks of hypoxia plus 2 weeks of normoxia ( late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil ( intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase - mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.