Schunkert H, Ingelfinger J R, Hirsch A T, Tang S S, Litwin S E, Talsness C E, Dzau V J
Cardiovascular Research Center, Stanford University School of Medicine, California 94305-5246.
J Clin Invest. 1992 Oct;90(4):1523-9. doi: 10.1172/JCI116020.
The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and they support the concept that the intrinsic renal RAS may contribute to the pathophysiology in this syndrome.
肾内肾素 - 血管紧张素系统（RAS）可能通过在肾脏局部位点生成血管紧张素II而参与心力衰竭的病理生理过程。血管紧张素II可能直接影响肾血流动力学、肾小球收缩性和肾小管钠重吸收，从而促进该综合征中的钠和液体潴留。在本研究中，我们检测了实验性心肌梗死后12周稳定代偿性心力衰竭（HF）大鼠循环RAS的成分以及肾内肾素和血管紧张素原mRNA的表达。与假手术对照组大鼠相比，载体处理的HF大鼠肾血管紧张素原mRNA水平增加了47%（P = 0.001）。与小梗死灶大鼠（31%，P =无显著性差异）相比，中等梗死灶（46%，P < 0.05）和大梗死灶（66%，P < 0.05）动物的血管紧张素原mRNA水平升高更为明显。假手术组和HFv组之间的肝血管紧张素原mRNA、循环血管紧张素原、血管紧张素II、血浆肾素浓度（PRC）、肾脏肾素含量（KRC）和肾肾素mRNA水平均无差异。此外，在另一组心力衰竭大鼠中，我们证明与年龄匹配的假手术对照组相比，肾血管紧张素II浓度增加了两倍（P < 0.05）。在进行这些测量前，一组平行的心力衰竭大鼠（HFe，n = 11）在饮水中给予依那普利（25 mg/kg每日）治疗6周。治疗期间血压显著下降（91 vs. 103 mmHg，P < 0.05）。HF大鼠的依那普利治疗使肾素mRNA水平增加（2.5倍，P < 0.005）、KRC增加（5.6倍，P = 0.005）和PRC增加（15.5倍，P < 0.005）。在依那普利治疗的HF大鼠中，HFv大鼠中观察到的肾血管紧张素原mRNA水平升高明显减弱（P < 0.001），提示血管紧张素II对肾血管紧张素原合成存在正反馈。这些发现表明在该实验性心力衰竭模型中肾内RAS被激活，但循环中的RAS无变化，并且支持肾内固有RAS可能参与该综合征病理生理过程的概念。
