Pioglitazone abrogates cyclosporine-evoked hypertension via rectifying abnormalities in vascular endothelial function
Pioglitazone abrogates cyclosporine-evoked hypertension via rectifying abnormalities in vascular endothelial function
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DOI：
10.1016/j.bcp.2010.11.013
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发表时间：
2011-02-15
影响因子：
5.8
通讯作者：
Abdel-Rahman, Abdel A.
中科院分区：
文献类型：
--
作者：
El-Mas, Mahmoud M.;El-Gowelli, Hanan M.;Abdel-Rahman, Abdel A.
除了胰岛素增敏外，噻唑二酮类药物吡格列酮也具有良好的循环作用。在这里，我们假设吡格列酮可以预防由免疫抑制剂环孢素（CSA）引起的高血压和相关血管紊乱。与对照组（橄榄油）相比，CSA （20 mg/kg/天s.c，持续14天）慢性治疗大鼠血压升高（BP），降低主动脉磷酸化eNOS （p-eNOS）蛋白表达，并损害离体主动脉对乙醇诱导的内皮依赖性血管松弛的反应性。同时给予吡格列酮（2.5 mg/kg/天）后，CSA对血压、主动脉p-eNOS和碳醇舒张的影响被消除。脂联素（一种脂肪组织来源的脂肪因子）的血清水平没有被CSA改变，但在吡格列酮或吡格列酮加CSA治疗的大鼠中显示出显著升高。研究了抗氧化和/或脂质谱改变导致csa -吡格列酮BP相互作用的可能性。吡格列酮消除了CSA的氧化（主动脉超氧化物歧化酶）、脂质过氧化（主动脉丙二醛）和血脂异常（血清LDL水平和LDL/HDL比值）效应。组织学上，CSA引起主动脉内皮层局灶性破坏，而在与吡格列酮共同治疗的大鼠中，这种影响消失。综上所述，吡格列酮通过改善CSA引起的血管内皮NOS/NO通路以及氧化和脂质谱的有害变化，消除了CSA的高血压作用。(C) 2010爱思唯尔公司版权所有。
In addition to insulin sensitization, the thiazolidenedione drug pioglitazone exhibits favorable circulatory effects. Here, we hypothesized that pioglitazone protects against the hypertension and related vascular derangements caused by the immunosuppressant drug cyclosporine (CSA). Compared with vehicle (olive oil)-treated rats, chronic treatment with CSA (20 mg/kg/day s.c., for 14 days) increased blood pressure (BP), reduced the aortic protein expression of phosphorylated eNOS (p-eNOS), and impaired responsiveness of isolated aortas to endothelium-dependent vasorelaxations induced by carbachol. The effects of CSA on BP, aortic p-eNOS, and carbachol relaxations were abolished upon concurrent administration of pioglitazone (2.5 mg/kg/day). Serum levels of adiponectin, an adipose tissue-derived adipokine, were not altered by CSA but showed significant elevations in rats treated with pioglitazone or pioglitazone plus CSA. The possibility that alterations in the antioxidant and/or lipid profile contributed to the CSA-pioglitazone BP interaction was investigated. Pioglitazone abrogated the oxidative (aortic superoxide dismutase), lipid peroxidation (aortic malondialdyde), and dyslipidemic (serum LDL levels and LDL/HDL ratio) effects of CSA. Histologically, CSA caused focal disruption in the endothelial lining of the aorta and this effect disappeared in rats co-treated with pioglitazone. Collectively, pioglitazone abrogates the hypertensive effect of CSA via ameliorating detrimental changes in vascular endothelial NOS/NO pathway and oxidative and lipid profiles caused by CSA. (C) 2010 Elsevier Inc. All rights reserved.