Primary Prevention of Hypertension in Obese Adolescents

描述（由申请人提供）： 高血压影响着世界人口的25%。它是中风和心力衰竭的头号原因，也是终末期肾病的第二大常见原因。在美国，高血压的患病率超过5000万。不到一半的人接受治疗，只有30%的人达到正常血压。最好的方法是确定导致高血压发展的因素，然后消除或治疗这些因素，以便预防高血压。我们发现血尿酸升高与青少年原发性高血压的发病密切相关，降低血尿酸可以降低这一人群的血压。在我们的动物模型中，高尿酸血症诱导大鼠高血压，具有原发性高血压的所有临床病理特征。在大鼠中，其机制是由内皮功能障碍、肾素血管紧张素系统（RAS）的激活和考克斯-2的刺激介导的，导致肾血管收缩。最初，高血压是耐盐的，不依赖于肾脏;然而，持续的高尿酸血症导致肾小球前小动脉病变（小动脉硬化）。一旦小动脉硬化发展，高血压是盐敏感的，由肾脏驱动。肥胖的青少年人群尿酸升高的比例很高，患高血压的风险也明显增加。因此，我们建议招募肥胖青少年受试者（BMI > 30 Kg/m2）参加一项研究，检查血清尿酸降低至< 5.0 mg/dl对随后发生高血压风险的影响。在R21可行性阶段，年龄为11-18岁且尿酸> 5.0mg/dl的受试者将被随机分配至安慰剂、别嘌呤醇或丙磺舒，持续2个月，并筛选内皮功能（总硝酸盐、SVR、肱动脉反应性）的改善、RAS的下调和炎症（MCP-1、hs-CRP）的减少。选择这些终点是因为它们参与大鼠模型中尿酸介导的高血压。如果高尿酸血症的改善至少在三个途径中的两个方面得到改善，我们将继续进行R33期，这是一项安慰剂对照试验，旨在确定降低血清尿酸对3年原发性高血压发病率、收缩压变化和代谢综合征特征的影响。

DESCRIPTION (provided by applicant): Hypertension affects 25% of the world population. It is the number one cause of stroke and heart failure and the second most common cause of end stage renal disease. In the USA the prevalence of hypertension exceeds 50 million. Less than half receive treatment and only 30% achieve normal blood pressures. The best approach would be to identify the factors responsible for the development of hypertension and then to eliminate or treat these factors so that hypertension can be prevented. We have found that elevated serum uric acid is closely related to the onset of essential hypertension in adolescents and that lowering serum uric acid can lower blood pressure in this population. In our animal model, hyperuricemia induces hypertension in rats that has all of the clinico-pathologic characteristics of essential hypertension. The mechanism, in rats is mediated by endothelial dysfunction, activation of the renin angiotensin system (RAS), and stimulation of COX-2, resulting in renal vasoconstriction. Initially, the hypertension is salt resistant and renal independent; however, persistent hyperuricemia causes a pre-glomerular arteriolar lesion (arteriolosclerosis). Once arteriolosclerosis develops, the hypertension is salt-sensitive and driven by the kidney. The obese adolescent population has a high rate of elevated uric acid as well as a markedly increased risk of hypertension. We thus propose to enlist obese adolescent subjects (BMI >30Kg/m2) into a study examining the effect of lowering serum uric acid to < 5.0 mg/dl on the subsequent risk of hypertension. In the R21 feasibility phase, subjects age 11-18 with uric acid > 5.0mg/dl will be randomized to placebo, allopurinol or probenecid, for 2 months and screened for improvements in endothelial function (total nitrates, SVR, brachial artery reactivity), down-regulation of the RAS, and reduction of inflammation (MCP-1, hs-CRP). These endpoints have been selected because of their involvement in uric acid mediated hypertension in the rat model. If amelioration of hyperuricemia yields improvement in at least two of the three pathways, we will proceed with the R33 phase, a placebo controlled trial determine the effect of lowering serum uric acid on the 3 yr incidence of essential hypertension, change in systolic blood pressure, and features of metabolic syndrome.