Therapeutic administration of an endothelin-A receptor antagonist after acute ischemic renal failure dose-dependently improves recovery of renal function.
Endothelin (ET) is known to reduce glomerular filtration rate and renal blood flow and is a possible mediator of acute renal failure (ARF). We recently demonstrated that the administration of a very high dose of the ET(A)-receptor antagonist LU 135252 (LU) accelerates recovery from postischemic acute renal failure by an improvement of renal perfusion in a rat model. The aim of this study was to investigate whether this effect of LU is dose dependent. ARF was induced in rats by clamping both renal arteries. Serum creatinine was measured and endogenous creatinine clearance and fractional sodium excretion were calculated up to 4 days after acute ischemia. Rats were treated either with the selective ET(A)-receptor antagonist LU or with vehicle only after reperfusion. LU in doses of 0.5, 1, or 5 mg/kg per day was infused via a femoral vein using an osmotic minipump. Serum creatinine was increased approximately eightfold after induction of ARF. Creatinine clearance decreased from 4.35 +/- 0.26 ml/min before acute renal failure to 0.15 +/- 0.02, 0.54 +/- 0.1, and 1.49 +/- 0.19 ml/min on days 1, 2, and 4 after ischemia (p < 0.05). Fractional sodium excretion increased from baseline 0.77 +/- 0.05% to 7.5 +/- 1.21 % on day 1 and 8.53 +/- 1.34% on day 2 (p < 0.05). Treatment with LU improved kidney function dose relatedly. There was no significant change in creatinine clearance, but compared with controls, with doses of 0.5 mg/kg per day and 1 mg/kg per day (0.28 +/- 0.1, 0.88 +/- 0.22, and 1.93 +/- 0.24 ml/min on days 1, 2, and 4), we noted a significant increase under 5 mg/kg per day (day 1: 0.62 +/- 0.17 ml/min; day 2: 1.38 +/- 0.26 ml/min; and day 4: 2.45 +/- 0.21 ml/min; p < 0.05). Fractional sodium excretion decreased dose-relatedly to a maximally 2.48 +/- 0.58% on day 1 and 2.25 +/- 0.71 % on day 2 after treatment with the highest dose when compared with untreated control rats (p < 0.05). Our data support the hypothesis that ET plays a major role in ARF. It can be concluded from these results that recovery from ischemic ARF is significantly and dose-dependently enhanced by treatment with a selective ET(A)-receptor antagonist.
Knoll
T
T
Department of Urology, University Hospital Mannheim, Faculty of Clinical Medicine of the University of Heidelberg, Germany. thomas.knoll@uro.ma.uni-heidelberg.de
Schult
S
S
Birck
R
R
Braun
C
C
Michel
M S
MS
Bross
S
S
Juenemann
K P
KP
Kirchengast
M
M
Rohmeiss
P
P
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D007511:Ischemia; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012964:Sodium / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D012964:Sodium; D003404:Creatinine