Inhibitory effects of a dihydropyridine calcium channel blocker on renal injury in aldosterone-infused rats
Inhibitory effects of a dihydropyridine calcium channel blocker on renal injury in aldosterone-infused rats
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DOI：
10.1097/hjh.0b013e32832dda6f
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发表时间：
2009-09-01
影响因子：
4.9
通讯作者：
Nishiyama, Akira
中科院分区：
文献类型：
--
作者：
Fan, Yu-Yan;Kohno, Masakazu;Nishiyama, Akira
目的体外研究表明二氢吡啶类钙通道阻滞剂具有直接的盐皮质激素受体拮抗活性。本研究旨在探讨二氢吡啶类钙通道阻滞剂阿折地平对醛固酮诱导的氧化应激和肾损伤的影响。方法和结果（0.75 μ g/h，皮下）和1% NaCl（饮水）显示收缩压（SBP）、尿蛋白排泄量（U蛋白V）、肾小球细胞增殖和肾间质纤维化。醛固酮诱导的肾损伤与肾皮质硫代巴比妥酸反应物质（TBARS）含量增加、NAD（P）H氧化酶复合物形成和NAD（P）H氧化酶膜组分（p22（phox）和gp 91（phox））mRNA表达增加相关。阿折地平给药[3 mg/kg/天，口服（p.o.）]显著减轻醛固酮引起的SBP、U蛋白V、肾皮质TBARS含量、NAD（P）H氧化酶复合物形成、p22（phox）和gp 91（phox）mRNA水平的升高以及形态学改变。在醛固酮输注大鼠中，用非特异性血管扩张剂肼苯哒嗪（5 mg/kg/天，溶于饮用水）治疗导致SBP降低，与阿折地平相似;然而，它不影响任何肾脏参数。结论二氢吡啶类钙通道阻滞剂可能通过抑制NAD（P）H氧化酶依赖的氧化应激而减轻醛固酮诱导的肾损伤。J Hypertens 27：1855-1862（C）2009 Wolters Kluwer Health vertical bar Lippincott威廉姆斯& Wilkins.
Objectives Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury.Methods and results Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 mu g/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P) H oxidase membrane components (p22(phox) and gp91(phox)). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22(phox) and gp91(phox), and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells.Conclusion These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P) H oxidase-dependent oxidative stress. J Hypertens 27:1855-1862 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.