Extrarenal and direct renal actions of atractyloside contribute to its acute nephrotoxicity in pentobarbital-anesthetized dogs.

Acute extrarenal and renal changes were noted following the intravenous administration of atractyloside (ATR) (12.97 and 32.40 mumol/kg) to spontaneously-respiring, pentobarbital-anesthetized dogs. Severe hypoglycemia, respiratory depression and hypoxemia developed within 2 h. These extrarenal changes were accompanied by adverse changes in renal function, ultrastructural damage to S1, S2 and S3 cells of the proximal tubule and to thick ascending limb cells and an impaired ability of the kidneys to respond to a known diuretic--ethacrynic acid (EA). Mechanical ventilation of ATR-treated pentobarbital-anesthetized dogs circumvented the development of hypoxemia and all but eliminated the toxicity to S3 and thick ascending limb cells, thereby establishing that ATR's extrarenal actions contributed to its nephrotoxicity. On the other hand, direct renal actions of ATR were evident following its administration into the renal artery; certain important extrarenal effects were minimized, while adverse changes in renal function and ultrastructure of S1 and S2 cells were noted primarily in the ipsilateral kidney. The high degree of variability associated with ATR's systemic toxicity was confirmed and a similar degree of variability in its renal toxicity was established. Our results emphasize the importance of evaluating the extrarenal effects produced by any toxicant when determining its nephrotoxic potential.