Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade.
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 humans, yet peritubular 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 randomized, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15-152 ml/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 [-4.7 pg/min (SD 5.5), 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% (SD 26%), P < 0.01] or in combination with BQ-123 [-40% (SD 29%), 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.
Goddard
Jane
J
Centre for Cardiovascular Science, Univ. of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Johnston
Neil R
NR
Cumming
Allan D
AD
Webb
David J
DJ
D000328:Adult; D000368:Aged; D002908:Chronic Disease; D004311:Double-Blind Method; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000652:urine*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000503:physiopathology / Q000652:urine*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology
D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)