Uric Acid and Hypertension in African-Americans

非裔美国人的尿酸和高血压

• 批准号: 7105071
• 负责人: Richard Joseph Johnson
• 金额: $ 70.42万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105071
• 关键词: African American; allopurinol; blood flow measurement; chlorothiazide; clinical research; data collection methodology /evaluation; disease /disorder prevention /control; dosage; drug adverse effect; glomerular filtration; glucose tolerance; glucose tolerance test; high performance liquid chromatography; human subject; human therapy evaluation; hyperinsulinism; hypertension; hypertriglyceridemia; hyperuricemia; inflammation; kidney circulation; liquid chromatography mass spectrometry; medical complication; metabolic syndrome; patient oriented research; radioimmunoassay; therapy adverse effect

DESCRIPTION (provided by applicant): Thiazide diuretics are associated with many metabolic side effects including hyperuricemia, gout, insulin resistance, and hyperlipidemia. These very conditions are already highly prevalent in African-Americans. We and others have generated a large body of epidemiologic, animal model, cell culture, and preliminary data in patients that suggests that uric acid is itself a mediator of hypertension, endotheliai dysfunction, and systemic inflammation. In our animal models elevated uric acid leads to increased blood pressure (BP) and lowering uric acid decreases BP. Furthermore, our study of hypertensive young adults suggests that allopurinol treatment leads to a decrease in uric acid associated with a lower BP. Our hypothesis is that thiazide-induced hyperuricemia decreases the efficacy of thiazides in controlling BP, leads to endothelial dysfunction, and increases the incidence of insulin resistance and impaired glucose tolerance. This hypothesis will be tested in a randomized double-blind placebo-controlled 2x2 factorial clinical trial of 8- week duration in which a total of 300 African-Americans patients with stage 1 hypertension (BP: 140-159/90- 99 mm Hg) will be assigned to one of four regimens: 1) a thiazide-like diuretic, chlorthalidone 25 mg/day, and a xanthine oxidase inhibitor, allopurinol; 2) chlorthalidone 25 mg/day and placebo; 3) placebo or 4) allopurinol. All subjects will receive a low-sodium diet. Our hypothesis predicts that lowering uric acid will enhance BP control, prevent endothelial dysfunction, reduce systemic inflammation, improve g.ucose tolerance and reduce hyperinsulinemia. In Aim 1 we test the hypothesis that prevention of chlorthalidone - induced hyperuricemia with allopurinol results in improved BP control. In Aim 2 we test the hypothesis that prevention of chlorthalidone-induced increase in serum uric acid by allopurinol improves endothelial function and reduces systemic inflammation. In Aim 3 we test the hypothesis that prevention of chlorthalidone induced hyperuricemia with allopurinol improves renal blood flow and GFR and prevents microalbumineria.

描述（由申请人提供）：噻嗪类利尿剂与许多代谢副作用相关，包括高尿酸血症、痛风、胰岛素抵抗和高脂血症。这些情况在非洲裔美国人中已经非常普遍。我们和其他人已经产生了大量的流行病学、动物模型、细胞培养和患者的初步数据，这些数据表明尿酸本身是高血压、内皮功能障碍和全身炎症的介质。在我们的动物模型中，尿酸升高会导致血压升高（BP），而降低尿酸会降低BP。此外，我们对年轻高血压患者的研究表明，别嘌呤醇治疗可导致尿酸降低，血压降低。我们的假设是噻嗪类药物诱导的高尿酸血症降低了噻嗪类药物控制血压的效果，导致内皮功能障碍，并增加胰岛素抵抗和糖耐量受损的发生率。将在一项为期8周的随机双盲安慰剂对照2x2析因临床试验中检验这一假设，该试验共纳入300例1期高血压非洲裔美国人患者，（BP：140-159/90- 99 mm Hg）将被分配到四种方案之一：1）噻嗪类利尿剂，氯噻酮25 mg/天，和黄嘌呤氧化酶抑制剂，别嘌呤醇; 2）氯噻酮25 mg/天和安慰剂; 3）安慰剂或4）别嘌呤醇。所有受试者将接受低钠饮食。我们的假设预测，降低尿酸将加强血压控制，防止内皮功能障碍，减少全身炎症，改善葡萄糖耐受性和减少高胰岛素血症。在目的1中，我们检验了用别嘌呤醇预防氯噻酮诱导的高尿酸血症可改善血压控制的假设。在目的2中，我们检验了别嘌呤醇预防氯噻酮诱导的血清尿酸升高改善内皮功能并减少全身炎症的假设。在目标3中，我们检验了用别嘌呤醇预防氯噻酮诱导的高尿酸血症可改善肾血流量和GFR并预防微量白蛋白血症的假设。