Reduction of the drug-induced nephrotoxicity by ATP-MgCl2. 1. Effects on the cis-diamminedichloroplatinum-treated isolated perfused kidneys.
cis-Diamminedichloroplatinum (CDDP), a widely used cancer chemotherapeutic agent, has been shown to cause dose-dependent acute renal failure (ARF) probably secondary to a direct nephrotoxic effect on proximal tubule cells. The aim of this study was to determine whether administration of ATP-MgCl2 could ameliorate the deleterious effects of CDDP. Isolated rat kidneys were perfused for 2 hr with a 3.5 g % dextran T-110-Krebs HCO3 solution containing 100 micrograms/ml of CDDP. [3H]Inulin was added to measure GFR. Trace amounts of 14C-methylated cytochrome c (cyt) were added to the perfusate to determine the protein reabsorptive capacity (a sensitive indicator of tubular damage) of isolated perfused rat kidneys. Cyt, inulin radioactivity, and [Na+] were measured in the perfusate and urine in control and CDDP-treated kidneys. In additional experiments, ATP-MgCl2 was added simultaneously (0.3 mM) or 1 hr (2 mM) after CDDP treatment. The results indicate that after 2 hr of perfusion, CDDP treatment led to a marked inhibition of protein reabsorption with only a minimal decrease in Na+ and H2O absorption. Furthermore, GFR was not significantly altered despite a marked diuresis. Post-treatment with ATP-MgCl2 led to partial alleviation of the nephrotoxic effect of CDDP after 1 hr of perfusion. ATP-MgCl2 treatment simultaneously with CDDP, however, fully protected the protein reabsorptive capacity of CDDP-treated kidneys. The potential for administering ATP-MgCl2 simultaneously with CDDP suggests a new therapeutic modality in preventing ARF due to CDDP therapy.
D000255:Adenosine Triphosphate / Q000627:therapeutic use*; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D004338:Drug Combinations; D005919:Glomerular Filtration Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008297:Male; D009399:Nephrons / Q000187:drug effects*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D004338:Drug Combinations; D000255:Adenosine Triphosphate; D002945:Cisplatin