Beneficial effect of ETA receptor blockade in a rat model of radiocontrast-induced nephropathy.
Endothelin has been implicated in the pathogenesis of acute renal failure associated with radiocontrast media. The current study was designed to determine the effect of endothelin receptor blockade in a model of radiocontrast-induced nephropathy. Inhibition of prostanoids and nitric oxide with indomethacin and L-nitroarginine methyl ester (L-NAME) predisposes rats to the nephrotoxic effects of radiocontrast media and, therefore, has been proposed as a clinically relevant model. Separate groups of conscious rats were given the ETA receptor antagonist, A-127722 (3, 10, or 30 mg/kg), or water (1 mL/kg) by oral gavage. All rats were then given indomethacin (10 mg/kg), L-NAME (10 mg/kg), and the contrast agent, diatrizoate (6 mL/kg), by intravenous injection at 15-min intervals. Urine was collected for the subsequent 24 h by placing rats in metabolism cages. When indomethacin, L-NAME, and diatrizoate were administered without A-127722, rats displayed typical signs of renal failure; protein excretion was increased from a baseline of 13 +/- 2 to 33 +/- 8 mg/day (p < 0.05) and plasma creatinine increased from 0.52 +/- 0.01 to 0.62 +/- 0.04 mg/dL (p < 0.05). ETA receptor blockade prevented the rise in protein excretion and plasma creatinine in a dose-dependent manner. In separate series of clearance experiments, A-127722 completely inhibited the renal effects of exogenous ET-1. These results suggest that endothelin plays a role in the hemodynamic events in this model and that ETA receptor antagonists should be investigated as potential therapeutic agents for radiocontrast-induced nephropathy.
Pollock
D M
DM
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA. DPollock@mail.mcg.edu
Polakowski
J S
JS
Wegner
C D
CD
Opgenorth
T J
TJ
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000517:prevention & control*; D000818:Animals; D000077868:Atrasentan; D003287:Contrast Media / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D003973:Diatrizoate / Q000009:adverse effects*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011507:Proteinuria / Q000652:urine; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D003287:Contrast Media; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011448:Prostaglandin Antagonists; D011759:Pyrrolidines; D003973:Diatrizoate; D009569:Nitric Oxide; D003404:Creatinine; D019331:NG-Nitroarginine Methyl Ester; D000077868:Atrasentan; D007213:Indomethacin