EFFECT OF NA AND K INTAKE ON ALDOSTERONE IN HYPERTENSION

描述：（根据具体目标改编）目前的建议侧重于 钠和钾摄入量改变对肾上腺肾小球（ZG）的作用 合成醛固酮。 在大鼠和人类中，Na减少或K增加 摄入增强肾上腺肾小球反应性。 然而，在某些形式中， 人高血压（非调节剂）和自发性高血压 高血压大鼠（SHR）饮食摄入产生不太明显的影响。 的 导致肾上腺对饮食反应性改变的正常机制 摄入量和SHR中效果降低的原因尚不清楚。 两 主要的假设是要测试：（1）增强醛固酮输出与 日粮钾负荷或钠限制是次要的增加ZG产生 它可以激活许多第二信使系统， β羟化酶（P450 cII）酶，其参与了 醛固酮合成 (2)SHR对AII的反应性降低 在低钠摄入量是继发于（a）局部AII缺陷 形成，（B）AII信号系统或（c）AII不能上调 P450 c11 mRNA水平的表达。 测试这些的具体目的 假设包括：（1）确定ZG对饮食的反应性 操纵是由晚期途径mRNA水平的变化介导的 酶系统 这些研究将涉及测量mRNA水平和酶 活动期间慢性操纵饮食钠和钾。额外 还将使用培养的牛ZG细胞进行研究。 研究 将对SHR大鼠进行检测，以确定该模型中的缺陷是否是由于 Na对P450 c11 mRNA的调节作用减弱。 具体目标2 局部产生的AII作为基因改变的介质的作用 将研究由饮食Na/K操纵诱导的活化。 的时间 将评估Na/K操作后肾上腺AII的过程变化， 正常血压和SHR大鼠。 此外，在培养的细胞中，CEI和 将在研究中研究血浆蛋白原酶抑制剂对mRNA水平和P450 cll活性的影响 在高K+培养基中孵育的细胞。 (3)另一个目标是确定 外源性AII是否诱导肾上腺AII，以及AII是否可以 在用CEI和肾素处理的细胞中恢复P450 cII水平和活性 抑制作用 (4)最后，本地生产的AII是否与细胞 将评价表面AII受体。 具体目标3是评估 蛋白激酶C（PKC）的激活是否是改变 局部AII的产生和晚期途径的基因激活。 具体来说，膳食钠和钾对磷脂酶C的作用 包括磷酸肌醇、Ca ~（2+）和DAG在内的信使系统， 研究了 研究将在正常和SHR大鼠中进行。 两个“控” 将在研究中使用。 束状带细胞及其早期信号通路 系统侧链裂解（SCC）。

DESCRIPTION: (Adapted from Specific Aims) The current proposal focuses on the role of altered Na and K intake on the adrenal zona glomerulosa (ZG) synthesis of aldosterone. In rats and humans reduced Na or increased K intake enhances adrenal glomerulosa responsiveness. However, in some forms of human hypertension (non-modulators) and in the spontaneously hypertensive rat (SHR) dietary intake produces less marked effects. The normal mechanisms leading to changes in adrenal responsiveness to dietary intake and the reason for reduced effects in the SHR are not known. Two major hypotheses are to be tested: (1) enhanced aldosterone output with dietary K loading or Na restriction is secondary to increased ZG generation of AII which can activate a number of second messenger systems and new 11 Beta hydroxylase (P450cll) enzyme which is involved in the last step of aldosterone synthesis. (2) The reduced responsiveness of the SHR to AII during low Na intake is secondary to either a defect in (a) local AII formation, (b) AII signalling systems or (c) failure of AII to upregulate expression of P450cll mRNA levels. The Specific Aims to test these hypothesis include: (1) To determine whether ZG responsiveness to dietary manipulation is mediated by changes in mRNA levels for the late pathway enzyme system. These studies will involve measuring mRNA levels and enzyme activity during chronic manipulations of dietary Na and K. Additional studies will also be performed using cultured bovine ZG cells. Studies in SHR rat will be performed to determine if the defect in this model is due to an impairment of Na modulation of P450cll mRNA. In Specific Aim 2, the role of locally generated AII as the mediator of the change in gene activation induced by dietary Na/K manipulation will be studied. The time course changes of adrenal AII after Na/K manipulations will be evaluated in normotensive and SHR rats. Also, in cultured cells the effect of CEI and renin inhibitors on mRNA levels and activity of P450cll will be studied in cells incubated in high K+ media. (3) Another goal will be to determine whether exogenously added AII induces adrenal AII and whether AII can restore P450cII levels and activity in cells treated with CEI and renin inhibition. (4) Finally, whether locally produced AII works with cell surface AII receptors will be evaluated. Specific Aim 3 is to evaluate whether activation of protein kinase C (PKC) is the link between the change in local AII production and gene activation of the late pathway. Specifically, the effort of dietary Na and K on the phospholipase C messenger system including inositol phosphates Ca2+ and DAG will be studied. Studies will be conducted in normal and SHR rats. Two "Controls" in the studies will be used. Zona fasciculata cells and the early pathway system side chain cleavage (SCC).