title: Modulation of the renal effects of contrast media by endothelium-derived nitric oxide in the rat.
abstract: OBJECTIVE
  A possible involvement of endothelium derived relaxing nitric oxide (NO) in the pathogenesis of iodinated contrast media (CM)-induced nephrotoxicity was investigated in the rat.
  
  
  METHODS
  Male rats (6 to 12 per group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery and a low-osmolar contrast medium (CM), ioxaglate, was injected (1 mL/min; 3 minutes) via an aortic puncture in the single remaining kidney. Contrast medium was injected with or without the NO-synthase inhibitor L-NAME (100 mg/kg intravenously [i.v.] 5 minutes before CM). One group received L-Arginine, the physiological precursor of NO (100 mg/kg i.v.), 5 minutes before L-NAME. Phenylephrine (300 micrograms/kg; 30 min) was used as a vasoconstrictive NO-independent control. The effects of iohexol, another low-osmolar CM, on creatinine clearance (CrCl) were also studied with and without pretreatment with L-NAME. A control group was subjected to a 3-minute renal ischemia only. Creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion were determined before, and 24 and 48 hours after CM administration. Blinded histologic analysis was carried out after completion of the study.
  
  
  RESULTS
  When administered alone, neither L-NAME nor L-arginine modified CrCl. Ioxaglate mildly but significantly decreased CrCl at 24 hours (-26.5% of preinjection value). This was similar to the effect observed in the control group subjected to ischemia only. When associated with L-NAME, ioxaglate markedly decreased CrCl (-58 + 11% at 24 hours, P < .05 vs. ioxaglate alone). A similar interaction was noted in the case of iohexol. L-NAME also markedly increased ioxaglate-induced urinary NAG excretion. Phenylephrine had a similar impact on renal function. L-arginine pretreatment reduced the increase in serum creatinine induced by L-NAME+ioxaglate (68 + 17 mumol/L vs. 175 + 59 mumol/L for L-NAME+ioxaglate; P < .05) and urinary NAG excretion. Ioxaglate alone induced only tubular epithelial vacuolization. When associated with L-NAME, this CM induced tubular and vascular lesions, as well as necrosis in the outer medulla. Such histologic effects were clearly inhibited by L-arginine.
  
  
  CONCLUSIONS
  These data indicate that L-NAME, a specific inhibitor of NO-synthase, and phenylephrine, accentuate the nephrotoxicity of CM in the rat. This is consistent with results from the literature showing that CM-toxicity is enhanced by renal ischemia.
authors.affiliation: Laboratoire GUERBET, Roissy Charles de Gaulle, France.
authors.forename: C
authors.initials: C
authors.lastname: Touati
authors.forename: J M
authors.initials: JM
authors.lastname: Idee
authors.forename: G
authors.initials: G
authors.lastname: Deray
authors.forename: R
authors.initials: R
authors.lastname: Santus
authors.forename: C
authors.initials: C
authors.lastname: Balut
authors.forename: H
authors.initials: H
authors.lastname: Beaufils
authors.forename: C
authors.initials: C
authors.lastname: Jouanneau
authors.forename: R
authors.initials: R
authors.lastname: Bourbouze
authors.forename: D
authors.initials: D
authors.lastname: Doucet
authors.forename: B
authors.initials: B
authors.lastname: Bonnemain
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D058186:Acute Kidney Injury / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D007472:Iohexol / Q000633:toxicity*; D007485:Ioxaglic Acid / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010656:Phenylephrine; D009569:Nitric Oxide; D007472:Iohexol; D001120:Arginine; D003404:Creatinine; D000118:Acetylglucosaminidase; D019331:NG-Nitroarginine Methyl Ester; D007485:Ioxaglic Acid