Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet
Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet
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DOI：
10.1080/080370599438392
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发表时间：
1999-01-01
期刊：
影响因子：
1.8
通讯作者：
Karppanen, H
中科院分区：
文献类型：
--
作者：
Mervaala, E;Lassila, M;Karppanen, H
环孢霉素A（CsA）诱导的高血压已被证明是依赖于饮食中的盐的水平。本研究评估了高钠饮食的自发性高血压大鼠（SHR）中肾素-血管紧张素系统在CsA诱导的高血压和肾毒性发展中的作用。此外，我们还研究了ACE抑制剂是否能阻止CsA对高钠摄入SHR血压、肾功能和血管形态的不利影响。将8周龄SHR分为3组（每组n = 8）：（i）SHR对照组接受高钠饮食（Na为食物干重的2.6%），（ii）CsA组（5 mg/kg s.c.）接受高钠饮食，（iii）CsA +依那普利组（30 mg/kg p.o.）高钠饮食在6周实验期结束时，CsA组的收缩压显著高于对照组（分别为245 +/- 6 vs 208 +/- 9 mmHg，p < 0.05）。CsA治疗使血浆肾素活性增加20倍（与对照组相比p < 0.05）。CsA使血清肌酐增加22%，24小时尿蛋白排泄量增加190%，24小时尿钙、磷和镁排泄量分别增加150%、25%和140%（与对照组相比，p < 0.05）。组织学上，CsA处理的SHR的肾脏表现出严重的中膜增厚和纤维素样坏死的小动脉壁的传入小动脉。有趣的是，CsA诱导的血管损伤也在小心肌动脉。依那普利治疗预防CsA诱导的高血压和肾功能恶化以及CsA诱导的肾脏和心肌血管损伤。依那普利还降低左心室重量与体重的比值，并防止CsA诱导的尿钙和磷排泄增加。我们的研究结果表明CsA对高钠摄入的SHR的血压、肾功能和血管形态有不利影响。ACE抑制剂可预防CsA引起的高血压、肾毒性和血管损伤。因此，我们的研究结果表明，肾素-血管紧张素系统的活性增加参与CsA诱导的高血压和高钠饮食的SHR肾毒性的发病机制。
Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the level of dietary salt. The present study assessed the role of the renin-angiotensin system in the development of CsA-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In addition, we examined whether ACE inhibition prevents the detrimental effects of CsA on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. Eight-week-old SHR were divided into three different groups (n = 8 in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of the dry weight of the chow), (ii) CsA group (5 mg/kg s.c,) on a high-sodium diet and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end of the six-week experimental period, systolic blood pressure in the CsA group was significantly higher compared to the control group (245 +/- 6 vs 208 +/- 9 mmHg, respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%, the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05 compared to controls). Histologically, the kidneys of CsA treated SHR showed severe thickening of the media of the afferent arteriole and fibrinoid necrosis of the arteriolar wall. Interestingly, CsA induced vascular injury also in the small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension and deterioration of kidney function as well as CsA-induced vascular injuries in the kidneys and myocardium. Enalapril also decreased left ventricular weight-to body weight ratio and prevented CsA-induced increases in urinary calcium and phosphorus excretions. Our findings indicate that CsA has a detrimental effect on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and vascular injuries. Our findings thus suggest that increased activity of the renin-angiotensin system is involved in the pathogenesis of CsA-induced hypertension and nephrotoxicity in SHR on a high-sodium diet.