Aldosterone synthase inhibitor ameliorates angiotensin II - Induced organ damage
Aldosterone synthase inhibitor ameliorates angiotensin II - Induced organ damage
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DOI：
10.1161/circulationaha.104.521625
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发表时间：
2005-06-14
期刊：
影响因子：
37.8
通讯作者：
Muller, DN
中科院分区：
文献类型：
--
作者：
Fiebeler, A;Nussberger, JR;Muller, DN
背景-醛固酮和血管紧张素（Ang） II都可能引起器官损伤。循环醛固酮在肾上腺中产生；然而，局部心脏合成也有报道。醛固酮浓度取决于醛固酮合成酶（CYP11B2）的活性。我们检验了通过抑制CYP11B2或肾上腺切除术（ADX）减少醛固酮可能改善器官损伤的假设。此外，我们研究了多少局部心脏醛固酮来源于肾上腺。方法和结果-我们研究了CYP11B2抑制剂FAD286、氯沙坦对过度表达人肾素和血管紧张素原基因（dTGR）的转基因大鼠的影响，以及ADX的后果。dTGR-ADX给予地塞米松和1%盐。在ADX方案中，地塞米松处理的dtgr盐作为对照组。未经治疗的dTGR出现高血压、心脏和肾脏损害，7周死亡率为40%（5/13）。FAD286将死亡率降低至10%(1/10)，并改善心脏肥厚、蛋白尿、细胞浸润和心脏和肾脏基质沉积。FAD286对第5周和第6周的血压没有影响，但在第7周的血压略有降低（dTGR +/- FAD286组为177 +/- 6mmhg， dTGR组为200 +/- 5mmhg）。在整个研究过程中，氯沙坦使血压恢复正常。FAD286或氯沙坦治疗的dTGR组循环和心脏醛固酮水平降低。ADX联合地塞米松和盐治疗将循环和心脏醛固酮降低到几乎无法检测到的水平。在第7周，adx - dtgr -地塞米松盐的死亡率为22%，而dtgr -地塞米松盐的死亡率为73%。两组高血压相似（190 +/- 9和187 +/- 4毫米汞柱）。ADX后心肌肥厚指数、蛋白尿、细胞浸润、基质沉积均显著降低（P < 0.05）。结论-醛固酮在Ang II诱导的器官损伤的发病机制中起关键作用。FAD286和ADX均可降低循环和心脏醛固酮水平。结果表明，肾上腺产生的醛固酮是心脏醛固酮的主要来源。
Background - Aldosterone and angiotensin (Ang) II both may cause organ damage. Circulating aldosterone is produced in the adrenals; however, local cardiac synthesis has been reported. Aldosterone concentrations depend on the activity of aldosterone synthase (CYP11B2). We tested the hypothesis that reducing aldosterone by inhibiting CYP11B2 or by adrenalectomy (ADX) may ameliorate organ damage. Furthermore, we investigated how much local cardiac aldosterone originates from the adrenal gland.Methods and Results - We investigated the effect of the CYP11B2 inhibitor FAD286, losartan, and the consequences of ADX in transgenic rats overexpressing both the human renin and angiotensinogen genes (dTGR). dTGR-ADX received dexamethasone and 1% salt. Dexamethasone-treated dTGR-salt served as a control group in the ADX protocol. Untreated dTGR developed hypertension and cardiac and renal damage and had a 40% mortality rate (5/13) at 7 weeks. FAD286 reduced mortality to 10% (1/10) and ameliorated cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in the heart and kidney. FAD286 had no effect on blood pressure at weeks 5 and 6 but slightly reduced blood pressure at week7 (177 +/- 6 mm Hg in dTGR +/- FAD286 and 200 +/- 5 mm Hg in dTGR). Losartan normalized blood pressure during the entire study. Circulating and cardiac aldosterone levels were reduced in FAD286 or losartan- treated dTGR. ADX combined with dexamethasone and salt treatment decreased circulating and cardiac aldosterone to barely detectable levels. At week 7, ADX-dTGR-dexamethasone-salt had a 22% mortality rate compared with 73% in dTGR-dexamethasone-salt. Both groups were similarly hypertensive (190 +/- 9 and 187 +/- 4 mm Hg). In contrast, cardiac hypertrophy index, albuminuria, cell infiltration, and matrix deposition were significantly reduced after ADX ( P < 0.05).Conclusions - Aldosterone plays a key role in the pathogenesis of Ang II - induced organ damage. Both FAD286 and ADX reduced circulating and cardiac aldosterone levels. The present results show that aldosterone produced in the adrenals is the main source of cardiac aldosterone.