The effect of endothelin antagonists on renal ischaemia-reperfusion injury and the development of acute renal failure in the rat.
BACKGROUND
It is recognized that endothelins are released in response to hypoperfusion and anoxia of the kidney and may be responsible for the consequent deterioration in renal function. This study examined the ability of a non-selective (SB209670) and ET(A)-selective (UK-350,926) endothelin antagonist to attenuate ischaemia-induced renal failure in unilaterally nephrectomized rats.


METHODS
The animals were anaesthetized, drug infusion commenced, and the renal artery occluded for 30 min. The endothelin antagonists were given for 30 min before, during, and 60 min after the ischaemic period, at 10, 30 and 100 micro g/kg/min or for 60 min after the start of reperfusion.


RESULTS
On day 1, following 30 min renal artery occlusion, there was a 95% reduction in glomerular filtration rate, an 8-10-fold increase in plasma creatinine, and 10-15-fold increases in fractional excretions of sodium and potassium, which were partially resolved on day 3 and normalized on day 8. The lowest dose of SB209670 was without effect on the renal functional responses but they were blunted (all P<0.05) by the highest dose. At 30 and 100 micro g/kg/min UK-350,926, the decreases in renal function subsequent to the ischaemic challenge were attenuated. Administration of UK-350,926 at 100 micro g/kg/min for 1 h starting 60 min after the start of reperfusion, had no effect on the magnitude of the renal disturbances over the first 3 days.


CONCLUSIONS
The data show that both the ET(A)/ET(B) and selective ET(A)-receptor antagonist ameliorated the ischaemia-reperfusion injury when given in the peri-ischaemic period but not when the ET(A)-receptor antagonist was given for 60 min at 100 micro g/kg/min after the ischaemic period.
Department of Physiology, The Medical School, Birmingham, UK.
Chunlong
C
Huang
Chunhua
C
Huang
Dominique
D
Hestin
Paul C
PC
Dent
Paul
P
Barclay
Michael
M
Collis
Edward J
EJ
Johns
D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology*; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-