Evidence suggests that urinary excretion of endothelin-1 (ET-1) reflects renal ET-1 production, and is independent of systemic ET-1 activity. The influence of ET receptors on urinary ET-1 excretion has not been studied in man, yet peri-tubular ETB receptors are abundant within the kidney. We have studied the effects of acute ETA and ETB receptor blockade with BQ-123 and BQ-788 respectively on urinary ET-1 excretion in a randomised, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15-152ml/min). Plasma ET-1 concentrations (pET-1) and urinary ET-1 excretion rate (uET-1) at baseline correlated inversely with GFR (R²=0.18 and 0.36 respectively, P<0.01). However, changes in pET-1 after ET receptor antagonism were not related to changes in uET-1 (R²=0.007, P=0.18). pET-1 increased only after BQ-788, alone or in combination with BQ-123, consistent with ETB receptor mediated clearance of ET-1 from the circulation. uET-1 was reduced only after BQ-788 alone (-4.7pg/min (SD5.5), P<0.01). Because BQ-788 also reduced GFR, fractional excretion of ET-1 (FeET-1) was calculated. FeET-1 fell after BQ-788 alone (-41% (SD26%), P<0.01) or in combination with BQ-123 (-40% (SD29%), P<0.01). FeET-1 was not altered by placebo or BQ-123 alone. In conclusion, urinary ET-1 excretion does not appear to relate to the pool of plasma ET-1. Because of the short duration of this study, it is unlikely that ET receptor blockade had significant effects on renal ET-1 production. Therefore, the reduction in FeET-1 after ETB blockade appears to indicate that renal excretion of ET-1 is at least partly facilitated by ETB receptor activation.