Primary Prevention of Hypertension in Obese Adolescents

点击翻译按钮获取中文摘要

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.