In situ demonstration of angiotensin-dependent and independent pathways for hyperaldosteronism during chronic extracellular fluid volume depletion.

在野生型小鼠中，服用血管紧张素Ⅱ1型(AT1)受体拮抗剂氯沙坦2周后，与仅限钠组相比，饮食限钠组的皮质酮升高幅度更大(2.75±0.35 vs.1.38±0.16 ng/ml，P&lt；0.01)。限钠、氯沙坦治疗的小鼠血钾升高(6.0±0.2EQM/L)，而仅限钠的小鼠血钾保持不变。为了研究Ang II对肾小球细胞的影响，这些细胞可能在原位不依赖于血浆钾，我们使用了由带有或不带有完整AT1A基因(Agtrla)的细胞组成的嵌合小鼠。当饲喂正常饲料或长期灌流血管紧张素Ⅱ时，仅在Agtr1a+/+区的肾小球细胞中检测到醛固酮合成酶的mRNA，而在Agtr1a-/-区的肾小球细胞中检测不到。限钠2wk后，血浆醛固酮水平升高(1.51±0.27 ng/ml)，血钾浓度维持在4.5±0.2mEq/L，醛固酮合成酶基因在Agtr1a+/+细胞中表达较强，而在Agtr1a-/-细胞中检测不到。同时加用钠限制和氯沙坦治疗后，血浆钾(5.5±0.1mEq/L)和醛固酮(1.84±0.38 ng/ml)均升高，Agtr1a-/-和Agtr1a+/+细胞均高表达醛固酮合成酶基因。因此，当血浆钾维持在正常范围时，在细胞外液容量的慢性变化过程中，肾上腺中的醛固酮的产生受到血管紧张素II的调节。根据先前的观察，限钾和限钠可消除血管紧张素原缺失突变小鼠的继发性醛固酮增多症，本研究结果表明，当肾素-血管紧张素系统受损时，血浆钾通过诱导高醛固酮增多症的能力，作为容量平衡的有效替代机制。

In wild-type mice, a 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of piasma aldosterone greater than that seen with sodium restriction alone (2.75±0.35 vs. 1.38±0.16 ng/ml, P<0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 ±0.2 Eqm/liter), while potassium remained unchanged in mice with sodium restriction alone. To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtrla). When animals were fed a normal diet or chrontcally infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 ±0.27 ng/ml) and potassium remained on average at 4.5±0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5±0.1 mEq/liter) and aldosterone (1.84±0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.