Low-Renin Hypertension in African Americans

描述（来自申请的逐字）：低肾素高血压是常见的 在非洲裔美国人中，许多人未能达到正常的血压， 尽管有各种各样的抗高血压药物可供使用。的 低肾素状态与增加的钠潴留一致。我们有 有证据表明，黑人有较高的整体活性的上皮钠 通道（ENaC），肾脏内钠重吸收的主要部位 某些分子突变导致钠潴留， 低肾素高血压（Liddle综合征）。ENaC被醛固酮上调。 在目前的建议中，我们将研究两种药物的有效性， ENaC活性、醛固酮拮抗剂螺内酯和阿米洛利 ENaC的直接抑制剂，在患有低肾素高血压的黑人中， 抵抗治疗。我们将遵循一个简单的协议，我们将研究 服用最佳降压药物方案的患者，包括 全剂量利尿剂，但在谁的正常血压尚未 办妥了一批患者将随机接受螺内酯25 mg/ 阿米洛利10 mg/天，螺内酯25 mg和 阿米洛利10 mg/天或安慰剂治疗9周。在具体目标#1中，我们将 检验耐药低肾素高血压黑人 通过小剂量的药物治疗使血压正常化 降低ENaC功能的药物。我们还将测试协同效应， 安体舒通和阿米洛利降低血压。在具体目标#2中， 将检验这样的假设，即抗ENaC药物降低 血压是通过降低固有的较高水平的ENaC功能， 如基线时较低的肾素和醛固酮水平以及基线时较高的 在治疗期间增加。在具体目标#3中，我们将测试 假设对螺内酯的血压反应与 ENaC亚基中存在分子变体，已经显示的变体 以前与血压水平有关。总之，我们探索 治疗黑人低肾素高血压的独特而简单的方法， 一种治疗方式，可以证明是有用的许多患者目前 不受控制的血压。

DESCRIPTION (Verbatim from the application): Low-renin hypertension is common in African Americans, with many failing to achieve a normal blood pressure despite the availability of a wide variety of antihypertensive agents. The low-renin state is consistent with increased retention of sodium. We have evidence that blacks have higher overall activity of the epithelial sodium channel (ENaC), a principal site for reabsorption of sodium within the kidney and where certain molecular mutations result in retention of sodium and severe low-renin hypertension (Liddle's syndrome). ENaC is upregulated by aldosterone. In the present proposal, we will study the usefulness of two drugs that inhibit ENaC activity, spironolactone, an antagonist of aldosterone, and amiloride, a direct inhibitor of ENaC, in blacks with low-renin hypertension who have shown resistance to treatment. We will follow a simple protocol wherein we will study patients taking an optimal regimen of antihypertensive medication including a full dose of diuretic but in whom a normal blood pressure has not been achieved. The patients will be randomized to either spironolactone 25 mg per day, amiloride 10 mg per day, the combination of spironolactone 25 mg and amiloride 10 mg per day, or placebo for 9 weeks. In Specific Aim #1, we will test the hypothesis that drug-resistant, low-renin hypertensive blacks normalize their blood pressure in response to treatment with small doses of agents that reduce ENaC function. We will also test for a synergistic effect of spironolactone with amiloride to lower blood pressure. In Specific Aim #2, we will test the hypothesis that the mechanism whereby the anti-ENaC drugs lower blood pressure is by reducing an intrinsically higher level of ENaC function, as evidenced by lower levels of renin and aldosterone at baseline and greater increments during treatment in responders. In Specific Aim #3, we will test the hypothesis that blood pressure responses to spironolactone are related to the presence of molecular variants in ENaC subunits, variants that have been shown previously to associate with level of blood pressure. In summary, we explore unique but simple approaches to treatment of low-renin hypertension in blacks, a treatment modality that could prove useful to many patients currently with uncontrolled blood pressure.