Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat
Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat
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DOI：
10.1152/ajplung.00042.2008
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发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Kadowitz, Philip J.
中科院分区：
文献类型：
--
作者：
Badejo, Adeleke M., Jr.;Dhaliwal, Jasdeep S.;Kadowitz, Philip J.
Badejo AM Jr，Dhaliwal JS，凯西DB，加伦TB，Greco AJ，Kadowitz PJ。麻醉大鼠对Rho激酶抑制剂法舒地尔的肺血管舒张反应分析。美国生理学杂志肺细胞分子生理学295：L 828-L 836，2008年。首次发表于2008年8月8日; doi：10.1152/ajplung.00042.2008。小GTP结合蛋白Rho及其下游效应物Rho激酶是血管收缩张力的重要调节剂。Rho激酶在实验性肺动脉高压模型中上调，Rho激酶抑制剂可降低患有野百合碱和慢性缺氧诱导的肺动脉高压的啮齿动物的肺动脉压。然而，当肺血管阻力在急性基础上通过血管收缩剂和呼吸性缺氧升高时，对法舒地尔的反应知之甚少。在本研究中，静脉注射法舒地尔逆转了静脉输注血栓烷受体激动剂U-46619和10%O-2气体混合物通气引起的肺动脉高压反应，并抑制了静脉注射血管紧张素II、BAY K 8644和U-46619引起的肺血管收缩反应，而无需事先暴露于激动剂，这可以上调Rho激酶活性。钙通道阻滞剂伊拉地平和法舒地尔具有相似的作用，小剂量时在钝化血管收缩反应方面具有累加作用，表明肺中的平行和串联机制。当肺血管阻力增加与U-46619，法舒地尔产生类似的降低肺动脉压和体循环动脉压，而伊拉地平产生更大的降低体循环动脉压。iv硝基精氨酸甲酯（L-NAME）5-10 mg/kg可增强缺氧性升压反应，法舒地尔或伊拉地平可逆转对照组和L-NAME处理组的缺氧性肺动脉高压反应，提示该反应是由Rho激酶和L型Ca ~（2+）通道介导的。这些结果表明，Rho-激酶在生理条件下调节肺中的基线张力和血管收缩反应中是组成性活性的，并且Rho-激酶抑制减弱肺血管收缩反应，所述肺血管收缩反应对通过不同机制起作用的药剂起作用，而无需预先暴露于激动剂。
Badejo AM Jr, Dhaliwal JS, Casey DB, Gallen TB, Greco AJ, Kadowitz PJ. Analysis of pulmonary vasodilator responses to the Rho- kinase inhibitor fasudil in the anesthetized rat. Am J Physiol Lung Cell Mol Physiol 295: L828-L836, 2008. First published August 8, 2008; doi:10.1152/ajplung.00042.2008.- The small GTP-binding protein Rho and its downstream effector, Rho-kinase, are important regulators of vasoconstrictor tone. Rho-kinase is upregulated in experimental models of pulmonary hypertension, and Rho-kinase inhibitors decrease pulmonary arterial pressure in rodents with monocrotaline and chronic hypoxia-induced pulmonary hypertension. However, less is known about responses to fasudil when pulmonary vascular resistance is elevated on an acute basis by vasoconstrictor agents and ventilatory hypoxia. In the present study, intravenous injections of fasudil reversed pulmonary hypertensive responses to intravenous infusion of the thromboxane receptor agonist, U-46619 and ventilation with a 10% O-2 gas mixture and inhibited pulmonary vasoconstrictor responses to intravenous injections of angiotensin II, BAY K 8644, and U-46619 without prior exposure to agonists, which can upregulate Rho-kinase activity. The calcium channel blocker isradipine and fasudil had similar effects and in small doses had additive effects in blunting vasoconstrictor responses, suggesting parallel and series mechanisms in the lung. When pulmonary vascular resistance was increased with U-46619, fasudil produced similar decreases in pulmonary and systemic arterial pressure, whereas isradipine produced greater decreases in systemic arterial pressure. The hypoxic pressor response was enhanced by 5-10 mg/kg iv nitro-Larginine methyl ester ( L-NAME), and fasudil or isradipine reversed the pulmonary hypertensive response to hypoxia in control and in L-NAME- treated animals, suggesting that the response is mediated by Rho-kinase and L-type Ca2+ channels. These results suggest that Rho-kinase is constitutively active in regulating baseline tone and vasoconstrictor responses in the lung under physiological conditions and that Rho-kinase inhibition attenuates pulmonary vasoconstrictor responses to agents that act by different mechanisms without prior exposure to the agonist.