title: Beneficial effect of ETA receptor blockade in a rat model of radiocontrast-induced nephropathy.
abstract: 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.
authors.affiliation: Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA. DPollock@mail.mcg.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Pollock
authors.forename: J S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: C D
authors.initials: CD
authors.lastname: Wegner
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: 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
chemical_list: 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