Zou L X, Imig J D, von Thun A M, Hymel A, Ono H, Navar L G
Department of Physiology, Tulane University School of Medicine, New Orleans, La. 70112, USA.
Hypertension. 1996 Oct;28(4):669-77. doi: 10.1161/01.hyp.28.4.669.
Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.
持续13天低剂量输注血管紧张素II（Ang II）可模拟二肾一夹型戈德布拉特高血压，并增加肾内Ang II水平。我们进行了研究，以确定肾内Ang II水平升高的时间进程，以及肾内Ang II升高是否是组织特异性事件，是否需要受体介导的步骤。将雄性Sprague-Dawley大鼠进行单侧肾切除，通过皮下渗透微型泵输注载体或Ang II（40 ng/分钟）。在微型泵植入后3、7、10和13天测量血浆和肾内Ang II水平。与对照组（126±2 mmHg）相比，输注Ang II的大鼠收缩压在第6天出现可检测到的升高（146±2 mmHg），并在第12天持续升高至189±5 mmHg。血浆Ang II水平在第3天升高，而肾内Ang II水平直到输注Ang II 10天后才显著升高。输注Ang II 13天后，以局灶性和节段性肾小球硬化为特征的肾损伤明显。氯沙坦（每天30 mg/kg）在输注期间可防止输注Ang II的大鼠发生高血压（125±1 mmHg），并减轻肾小球损伤程度。输注Ang II组的血浆肾素活性受到抑制，但在两个氯沙坦治疗组中均显著升高。输注Ang II的大鼠血浆Ang II水平升高，在氯沙坦治疗期间甚至更高。输注Ang II的大鼠肾内Ang II水平显著升高（354±60对164±23 fmol/g）。然而，氯沙坦治疗可防止Ang II输注引起的肾内Ang II升高。输注Ang II的大鼠心脏和肾上腺Ang II水平没有显著升高，但在氯沙坦治疗期间显著升高。这些结果表明慢性Ang II输注引起的肾内Ang II水平的组织特异性升高是由1型血管紧张素受体激活介导的，这导致Ang II的受体介导内化、肾内Ang II形成增强或两者兼有。
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