Role of the prostaglandin and kallikrein-kinin systems in aminoglycoside-induced acute renal failure.

The role of humoral factors in the pathogenesis of gentamicin and tobramycin aminoglycoside-induced acute renal failure was studied in rats. Renal function was evaluated after inhibition of prostaglandin synthesis with indomethacin and inhibition of the kallikrein-kinin system with aprotinin. Plasma and urinary kallikrein levels were measured in aminoglycoside-treated rats, as was in vitro effect of of these antibiotics on plasma kallikrein activity and prekallikrein activation by dextran sulfate. Indomethacin treatment (2 mg kg-1 day-1, ip, for 13 days) of rats which received gentamicin or tobramycin (40 mg kg-1 day-1, ip, for 10 days) caused a further fall in glomerular filtration rate (GFR) and renal blood flow and an impressive increase in renal resistance. The effect of indomethacin on GFR was more evident for gentamicin- than tobramycin-treated animals. Aprotinin administration had no additional effects on the renal function of antibiotic-treated rats. Plasma and urinary kallikrein levels in aminoglycoside-treated rats were significantly lower than in untreated controls. Both aminoglycosides at concentrations of 0.1 mg/ml inhibited dextran sulfate activation of plasma prekallikrein, and 2.0 micrograms/ml tobramycin, but not gentamicin, inhibited the hydrolysis of H-D-Pro-Phe-Arg-p-nitroanilide by rat plasma. These data suggest that prostaglandins may protect against aminoglycoside nephrotoxicity.