MODULATION OF THE RENAL EFFECTS OF CONTRAST-MEDIA BY ENDOTHELIUM-DERIVED NITRIC-OXIDE IN THE RAT

RATIONALE AND OBJECTIVES. A possible involvement of endothelium derive d relaxing nitric oxide (NO) in the pathogenesis of iodinated contrast media (CM)-induced nephrotoxicity was investigated in the rat. METHOD S. Male rats (6 to 12 per group) were uninephrectomized. Six days late r, the aorta was clamped above the renal artery and a low-osmolar cont rast medium (CM), ioxaglate, was injected (1 mL/min; 3 minutes) via an aortic puncture in the single remaining kidney. Contrast medium was i njected with or without the NO-synthase inhibitor L-NAME (100 mg/kg in travenously [IV] 5 minutes before CM). One group received L-Arginine, the physiological precursor of NO (100 mg/kg IV), 5 minutes before L-N AME. Phenylephrine (300 mug/kg; 30 min) was used as a vasoconstrictive NO-independent control. The effects of iohexol, another low-osmolar C M, on creatinine clearance (CrCl) were also studied with and without p retreatment with L-NAME. A control group was subjected to a 3-minute r enal ischemia only. Creatinine clearance and urinary N-acetyl-beta-D-g lucosaminidase (NAG) excretion were determined before, and 24 and 48 h ours after CM administration. Blinded histologic analysis was carried out after completion of the study. RESULTS. When administered alone, n either L-NAME nor L-arginine modified CrCl. Ioxaglate mildly but signi ficantly decreased CrCl at 24 hours (-26.5% of preinjection value). Th is was similar to the effect observed in the control group subjected t o ischemia only. When associated with L-NAME, ioxaglate markedly decre ased CrCl (-58 + 11% at 24 hours, P < .05 vs. ioxaglate alone). A simi lar 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 th e 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 urin ary NAG excretion. Ioxaglate alone induced only tubular epithelial vac uolization. When associated with L-NAME, this CM induced tubular and v ascular lesions, as well as necrosis in the outer medulla. Such histol ogic effects were clearly inhibited by L-arginine. CONCLUSION. These d ata indicate that L-NAME, a specific inhibitor of NO-synthase, and phe nylephrine, accentuate the nephrotoxicity of CM in the rat. This is co nsistent with results from the literature showing that CM-toxicity is enhanced by renal ischemia.