-Endothelin-1 inhibits collecting duct sodium reabsorption and stimulates proximal and distal tubule acidification in experimental animals both directly and indirectly via increased mineralocorticoid activity. Diet-induced acid loads have been shown to increase renal endothelin-1 activity, and it is hypothesized that increased dietary acid-induced endothelin-1 activity may be a causative progression factor in human renal insufficiency and that this might be reversed by provision of dietary alkali. We sought to clarify, in normal human volunteers, the role of endothelin-1 in renal acidification and to determine whether the effect is dependent on dietary sodium chloride. Acid-base equilibrium was studied in seven normal human volunteers with experimentally induced metabolic acidosis [NH 4Cl 2.1 mmol·kg body weight (BW) Ϫ1·day Ϫ1 ] with and without inhibition of endogenous endothelin-1 activity by the endothelin A/B-receptor antagonist bosentan (125 BID p.o./day) both during dietary NaCl restriction (20 mmol/day) and NaCl repletion (2 mmol NaCl·kg BW Ϫ1 ·day Ϫ1 ). During NaCl restriction, but not in the NaCl replete state, bosentan significantly increased renal net acid excretion in association with stimulation of ammoniagenesis resulting in a significantly increased plasma bicarbonate concentration (19.0 Ϯ 0.8 to 20.1 Ϯ 0.9 mmol/l) despite a decrease in mineralocorticoid activity and an increase in endogenous acid production. In pre-existing human metabolic acidosis, endothelin-1 activity worsens acidosis by decreasing the set-point for renal regulation of plasma bicarbonate concentration, but only when dietary NaCl provision is restricted. metabolic acidosis; endothelin-1; bosentan; renal acidification; mineralocorticoids OF THE THREE REPORTED ENDOTHELINS (ET-1-3), ET-1 is most important for renal function with expression in renal endothelial cells, mesangium, proximal tubule, and collecting duct (13). The biologic effects of ET-1 are mediated by ET-receptors (ET-A and ET-B). ET-A is present throughout the renal and systemic vasculature (27) and also in collecting duct and proximal tubule (6,7,13). ET-B is expressed in renal endothelial cells and throughout the nephron.While known chiefly as vasoconstrictors, ETs are also reported to modulate renal sodium reabsorption and renal proton secretion (25). ET-1, through activation of ET-B, inhibits collecting duct sodium and water reabsorption. The finding that collecting duct-specific knockout of ET-1 causes hypertension and sodium retention (1) provides strong evidence that renal ET-1 is an important physiological regulator of renal Na excretion and systemic blood pressure.ET-1, through activation of ET-B, has also been shown to stimulate proximal tubule acidification by enhancing proximaltubular Na/H exchange (NHE3, via c-src activation). Distal tubule acidification in rats is also stimulated by systemic administration of ET-1, and the effect of ETs is mediated both by increased proton secretion and decreased HCO 3 Ϫ secretion (10, 11, 31, 32). Both indirect and dir...