Recent data indicate that insulin stimulates synthesis of the vasoconstrictor peptide endothelin-1 (ET-1) by cultured vascular endothelial cells in vitro. To determine whether insulin modulates ET levels in vivo and whether this effect is important in the pathogenesis of obesity-associated hypertension, we measured circulating immunoreactive ET-1 levels during euglycemic hyperinsulinemic clamps (20 mU/m2.min-1 for 120 minutes) in eight obese women (body mass index, 36 +/- 1 kg/m2) before and after 10 weeks on an 800-kcal/d protein-sparing liquid diet. During the clamp that preceded weight loss, insulin levels were increased from 17 +/- 2 to 51 +/- 3 mU/L and this was associated with an increment in ET-1 level from 28 +/- 3 to 33 +/- 3 pg/mL (P < .05). After weight loss, insulin levels were increased from 10 +/- 2 to 47 +/- 3 mU/L during the clamp, and there was a corresponding increase in ET-1 levels from 24 +/- 3 to 30 +/- 3 pg/mL (P < .025). The reduction in basal ET-1 level (from 28 +/- 3 to 24 +/- 3 pg/mL) with weight loss correlated strongly with the reduction in fasting immunoreactive insulin level (from 17 +/- 2 to 10 +/- 2 mU/L; r = .92, P < .01). The decrease in blood pressure with weight loss (from 130 +/- 6/73 +/- 3 to 118 +/- 4/72 +/- 3 mm Hg) did not correlate with the corresponding reduction in circulating ET-1 levels. These results indicate that insulin modulates ET-1 levels in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)