Endothelin-induced increased nitric oxide mediates augmented distal nephron acidification as a result of dietary protein.
Tested was the hypothesis that enhanced nitric oxide (NO) production that is stimulated by increased renal endothelin activity mediates decreased distal nephron HCO(3) secretion that is induced by dietary protein. Munich-Wistar rats that ate minimum electrolyte diets with 50% casein-provided protein (HiPro) compared with controls that ate 20% protein for 3 wk had higher urine excretion of endothelin-1 (80 +/- 15.7 versus 29 +/- 3.9 fmol/kg body wt per d; P < 0.02) and of the NO metabolites NO(2)/NO(3) (21.2 +/- 1.9 versus 14.9 +/- 0.8 mumol/kg body wt per d; P < 0.03). Bosentan, an endothelin A/B receptor antagonist, reduced HiPro rats' urine excretion of net acid (5859 +/- 654 versus 8017 +/- 1103 micromol/d; P < 0.03, paired t test) and NO(2)/NO(3) (18.1 +/- 1.1 versus 22.9 +/- 2.0 micromol/kg body wt per d; P < 0.05, paired t test). N-nitro-l-arginine methyl ester (L-NAME), an NO synthase inhibitor, also decreased urine net acid excretion (6621 +/- 717 versus 8449 +/- 1086 micromol/d; P < 0.05, paired t test) but was not additive to bosentan. L-NAME increased in situ late distal nephron HCO(3) delivery in HiPro rats (18.8 +/- 1.7 versus 9.6 +/- 1.4 pmol/mm per min; P < 0.001) that was mediated by increased distal nephron HCO(3) secretion (-7.2 +/- 0.7 versus -3.5 +/- 0.4 pmol/mm per min; P < 0.001) without changes in distal nephron transtubule HCO(3) permeability or H(+) secretion. Bosentan decreased H(+) secretion and increased HCO(3) secretion in the distal nephron of HiPro rats, but L-NAME had no additive effect on either component. The data support that dietary protein augments distal nephron acidification through decreased HCO(3) secretion that is mediated through endothelin-stimulated NO.
Wesson
Donald E
DE
Texas Tech University Health Sciences Center, Renal Section, 3601 4th Street, Lubbock, TX 79430, USA. donald.wesson@ttuhsc.edu
Simoni
Jan
J
Prabhakar
Sharma
S
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D000077300:Bosentan; D002245:Carbon Dioxide / Q000097:blood; D004032:Diet; D004044:Dietary Proteins / Q000008:administration & dosage*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D005260:Female; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology
D001639:Bicarbonates; D004044:Dietary Proteins; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D013449:Sulfonamides; D002245:Carbon Dioxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester