EFFECT OF NA AND K INTAKE ON ALDOSTERONE IN HYPERTENSION

描述：(改编自特定目标)当前提案的重点是 钠、钾摄入量改变对肾上腺球状带(ZG)的影响 醛固酮的合成。在大鼠和人类中减少钠或增加钾 摄取可增强肾上腺小球的反应性。然而，在某些形式下， 人类高血压(非调节剂)和自发性高血压 高血压大鼠(SHR)饮食摄入产生的影响较小。这个 导致肾上腺对饮食反应性改变的正常机制 自发性高血压患者的摄入量和减少影响的原因尚不清楚。二 主要假设将被检验：(1)增强醛固酮产量 饮食中钾负荷或钠限制是ZG生成增加的次要因素 在所有可以激活一些第二信使系统和新11 β-羟基酶(P450Cl1)，参与最后一步 醛固酮合成。(2)SHR对AII的反应性降低 在低钠摄入量期间，局部AII的缺陷是继发性的 形成，(B)所有信号系统或(C)所有信号系统未能上调 P450cl1基因表达水平。具体的目的是测试这些 假设包括：(1)确定ZG对饮食的反应性 调控是通过改变晚期通路的mRNA水平来实现的 酶系统。这些研究将包括测量信使核糖核酸水平和酶 长期控制饮食中钠和钾的活动 研究还将使用培养的牛ZG细胞进行。研究项目： 将对SHR大鼠进行检查，以确定该模型中的缺陷是否 Na对P450cl1基因表达的调节作用。在具体目标2中， 局部产生的AII在基因改变中的中介作用 将研究饮食中Na/K操作所引起的激活。时间 Na/K操作后肾上腺AII的病程变化将在 正常血压和自发性高血压大鼠。此外，在培养的细胞中，CEI和 肾素抑制剂对P450Cl1基因表达水平和活性的影响 细胞在高K+培养液中孵育。(3)另一个目标将是确定 外源性加入AII是否会诱导肾上腺AII以及AII是否可以 CEI和肾素处理的细胞恢复P450cII水平和活性 抑制力。(4)最后，本地生产的ALI是否与细胞一起工作 将对表面AII受体进行评估。具体目标3是评估 蛋白激酶C(PKC)的激活是否是这种变化之间的联系 在局部AII的产生和基因激活的晚期途径。 具体地说，饮食中钠和钾对磷脂酶C的作用 包括肌醇磷酸盐、钙离子和DAG在内的信使系统将 学习。研究将在正常大鼠和自发性高血压大鼠身上进行。两个“控制” 将在研究中使用。束带细胞及其早期途径 系统侧链断裂(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).