title: Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans.
abstract: 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(4)Cl 2.1 mmol·kg body weight (BW)(-1)·day(-1)] 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(-1)·day(-1)). 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 ± 0.8 to 20.1 ± 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.
authors.affiliation: Univ. Dept. of Medicine, Kantonsspital Bruderholz, CH-4101 Bruderholz/Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pallini
authors.forename: Henry N
authors.initials: HN
authors.lastname: Hulter
authors.forename: Jurgen
authors.initials: J
authors.lastname: Muser
authors.forename: Reto
authors.initials: R
authors.lastname: Krapf
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects / Q000502:physiology*; D000138:Acidosis / Q000139:chemically induced / Q000378:metabolism*; D000328:Adult; D000077300:Bosentan; D004032:Diet; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017673:Sodium Chloride, Dietary / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides; D000077300:Bosentan