IODINATED CONTRAST INDUCED RENAL INJURY IS DUE TO THE DOWN-REGULATION OF RENAL CORTICAL AND MEDULLARY NO SYNTHESIS

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Li Wang, B.S., Fang Liu, B.S., Lori Bartula, B.S., Stuart I. Myers, MD.
Virginia Commonwealth University, Richmond, VA, USA.

OBJECTIVES: The loss of renal function continues to be a frequent complication of the iodinated contrast agents used to perform diagnostic angiography and endovascular procedures. The mechanism of this loss in renal function has been hypothesized to be secondary to an oxygen radical injury to the medulla. This study examines the hypothesis that contrast-induced renal injury is due to loss of cortical and medullary microvascular blood flow following the down-regulation of endogenous renal cortical and medullary NO synthesis.
METHODS:Anesthetized male Sprague Dawley rats (350g) either had micro-dialysis probes or Laser Doppler fibers inserted into the renal cortex (depth of 2mm) and into the renal medulla (depth of 4mm). Laser Doppler blood flow (BF) was continuously monitored (Data reported as percent change compared to basal) and the microdialysis probes were connected to a syringe pump and perfused in vivo at 3 μl/min with lactated ringer’s solution. Dialysate fluid was collected following at time zero (Basal), following infusion of either saline or Conray 400 (6 mls/kg, Mallinckrodt Chem). Both groups were treated with either saline carrier, L-Name (30 mg/kg, NOS inhibitor), L-Arginine (400 mg/kg, NO precursor) or Superoxide dismutase (SOD, 10,000 u/kg, ODFR scavenger) Dialysate was analyzed for total NO (uM) and PGE₂, 6-keto-PGF_1a (PGI₂ metabolite) and thromboxane B₂ (TxB₂) (pg/ml) synthesis. The renal cortex (Co) and medulla (Me) were analyzed for iNOS, COX-2, Prostacyclin Synthase (PS) and PGE₂ synthase content by Western Blot. All data is converted to percent of Basal (Mean ± SEM, N≥5, p< 0.05 by ANOVA compared to the Sham group (a), contrast alone (b), L-NAME group (c) and L-Arginine group (d).
RESULTS:Conray decreased renal cortical iNOS content by 70% (p<0.05) and renal medulla iNOS content by 20% (NS). Only minor changes were noticed in the content of PS, COX-2 and PGE₂ synthase following Conray treatment. No change in PGI₂ release (as measured by 6-ketoPG_1a) was found.
CONCLUSION: Conray caused a marked decrease in medullary and cortical blood flow with a concomitant decrease in endogenous medullary and cortical NO synthesis. Cortical and medullary blood flow was further decreased by L-NAME but returned to normal levels by L-Arginine treatment. SOD further worsened medullary blood flow suggesting that oxygen radicals were not involved in the contrast-induced decrease in medullary blood flow. These data suggest that the down-regulation of renal cortical and medullary NO synthesis (and cortical iNOS content) contribute to the contrast-induced loss of renal cortical and medullary microvascular blood flow. Preservation of normal levels of renal cortical and medullary NO synthesis may help prevent or lessen the contrast-induced renal injury found following diagnostic and therapeutic endovascular procedures.