Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans.
BACKGROUND
In patients with renal or cardiac failure, renal function may be endangered by elevated plasma concentrations of the vasoconstrictor endothelin-1 (ET-1). To mimic effects of pathologically increased plasma ET-1, we gave intravenous ET-1 in healthy subjects and examined whether simultaneous infusion of the ETA-receptor antagonist VML 588 would prevent the effects of ET-1 on the kidney.


METHODS
Nine healthy men received on four separate days intravenous infusion of ET-1 (2.5 ng/kg/min) superimposed on vehicle (saline) or on VML 588 infusion (0.05, 0.20 and 0.40 mg/kg/h) in randomized order to assess the effects on renal function and renal haemodynamics.


RESULTS
At resting plasma ET-1, infusion of VML 588 alone had no significant effects on renal function. Infusion of ET-1 alone decreased glomerular filtration rate by 11% and this reduction was not reversed by co-infusion of VML 588. ET-1 reduced renal blood flow by 35% and VML 588 reduced this decrease by one-third, in a dose-independent fashion. ET-1 increased the filtration fraction by 34% and VML 588 reduced this increase dose-independently by one-half. ET-1 increased renal vascular resistance by 59% and VML 588 reduced this increase dose-independently by one-half. Finally, ET-1 decreased sodium excretion by 58% and VML 588 reduced this decrease dose-independently by two-thirds.


CONCLUSIONS
ET-1-induced reductions in renal function were partially but not completely prevented in a dose-independent manner by the ETA-receptor antagonist VML 588.
Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.
J L Tycho
JL
Vuurmans
Peter
P
Boer
Hein A
HA
Koomans
D000293:Adolescent; D000328:Adult; D004146:Dioxanes / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides; D013777:Tetrazoles
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan