We investigated the possible role of losartan on insulin-mediated glucose uptake, substrate oxidation and blood flow in insulin-resistant hypertensive patients. Sixteen newly diagnosed patients with mild-to-moderate hypertension were studied. The study design was a single-blind, randomised, placebo-controlled trial. After a 1 week run-in period, each patient was randomly assigned to placebo (n = 7) and losartan (n = 9). Both treatment periods lasted 4 weeks. At baseline, and at the end of the placebo and losartan treatment periods, euglycaemic hyperinsulinaemic glucose clamp and indirect calorimetry were performed. Before and along each glucose clamp, blood flow was also determined in the femoral artery by image-directed duplex ultrasonography combining B-mode imaging and pulse Doppler beams. Losartan vs placebo lowered systolic blood pressure by 163 +/- 3.5 and 147 +/- 4.1 mm Hg (P < 0.001), and diastolic blood pressure by 95 +/- 3.2 and 85 +/- 3.2 mm Hg (P < 0.001). Losartan enhanced glucose metabolic clearance rate by 5.1 +/- 0.3 and 6.3 +/- 0.4 mg/kg x min (P < 0.05), and whole body glucose disposal (WBGD) by 29.2 +/- 0.5 and 38.1 +/- 0.4 mumol/kg free fatty mass (FFM) x min (P < 0.01) but did not affect heart rate. Insulin-mediated change in blood flow was greater after losartan than placebo administration (111 +/- 4 vs 84 +/- 3%, P < 0.01). Per cent change in insulin-mediated stimulation of blood flow and WBGD were also correlated (r = 0.76, P < 0.01). Analysis of substrate oxidation revealed that losartan administration improved insulin action and non-oxidative glucose metabolism (NOGM) (30.8 +/- 2.2 vs 22.8 +/- 2.8 mumol/kg FFM x min, P < 0.05). In conclusion losartan improves insulin-mediated glucose uptake through an increase in NOGM and blood flow in hypertensive patients.