Abstract Insulin and angiotensin II (Ang II) are involved in the regulation of endothelin-1 (ET-1). This study investigates their possible influence on plasma levels of ET-1 in humans. Twenty patients with essential hypertension were included in a randomized, double-blind, placebo-controlled crossover study of 4 weeks' treatment with losartan, a selective type 1 angiotensin (AT 1) receptor antagonist. The effect was evaluated in the fasting state and during acute hyperinsulinemia physiologically induced by oral glucose ingestion (OGTT) and by euglycemic glucose clamp. Losartan lowered blood pressure significantly, but did not influence plasma levels of ET-1 in the fasting condition (5.2 ± 0.2 fmol/mL on placebo and 5.6 ± 0.3 fmol/mL after losartan treatment). During both models of acute hyperinsulinemia, there was a significant decrease in plasma ET-1. In the OGTT the mean values after placebo treatment decreased from 5.2 ± 0.2 fmol/mL at time 0 to 4.7 ± 0.4 ( P = .001) and 4.0 ± 0.5 ( P = .001) at 60 and 120 minutes, respectively. During the clamp the mean ET-1 values decreased from 5.7 ± 0.4 fmol/mL at time 0 to 4.6 ± 0.2 ( P < .001) and 4.3 ± 0.3 ( P = .006) at 60 and 120 minutes, respectively. No differences in these profiles occurred after losartan treatment. Significant inverse correlation between fasting levels of ET-1 and insulin sensitivity index was found, r = −.51, P = .003. In conclusion, losartan did not influence the circulating levels of ET-1 in basal condition or during acute hyperinsulinemia, whereas a significant decrease in plasma ET-1 occurred during acute hyperinsulinemia. A significant inverse correlation demonstrated between basal levels of plasma ET-1 and the insulin-stimulated glucose uptake could point to a possible regulatory influence of ET-1 production on glucose metabolism or vice versa.