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Humans genetically predisposed to hypertension tend to develop at a prehypertensive stage subtle metabolic and hormonal dysregulations, and certain of these could potentially be angiotensin II dependent. Therefore the aim of this study was to investigate the effects of the angiotensin II-receptor antagonist losartan on insulin sensitivity, lipid profile, and plasma endothelin-1 (ET-1) levels in normotensive offspring of hypertensive parents with a randomized, double-blind, placebo- controlled, crossover design. Insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total and HDL cholesterol, serum triglycerides, and plasma ET-1 levels were assessed in 19 young (26.2 +/- 0.7 years, mean +/- SEM), healthy, lean [body mass index (BMI), 22.6 +/- 0.7 kg/m2] normotensive male offspring of essential hypertensive parents after 14 days of losartan, 50 mg, and 14 days of placebo, respectively. Compared with placebo, losartan administration did not significantly modify SI (12.2 +/- 1.7 vs. 12.7 +/- 1.5 x 10(-4)/min/microU/ml on placebo), fasting plasma insulin and glucose, as well as the areas under the insulin and glucose curves. Plasma ET-1 levels also did not differ significantly between the placebo and losartan administration phases (1.1 +/- 0.06 vs. 1.2 +/- 0.06 pg/ml). However, serum total cholesterol and triglycerides decreased significantly with losartan treatment (3.8 +/- 0.2 vs. 4.1 +/- 0.2 mM and 0.9 +/- 0.1 vs. 1.1 +/- 0.1 mM, respectively; p < 0.01). Body weight, BMI, heart rate (HR), blood pressure (BP), and 24-h urinary sodium, potassium, and creatinine values were stable throughout the study. These findings demonstrate that angiotensin II-receptor blockade with losartan, administered in the therapeutic dose of 50 mg daily, does not alter insulin sensitivity determined by the Minimal Model Method of Bergman and does not affect ET-1 in normotensive offspring of essential hypertensive parents. The normal insulin sensitivity in the subjects studied might explain why losartan did not improve it. However, losartan significantly reduced serum total cholesterol and total triglyceride levels.