1. Acute tubular necrosis (ATN) with acute renal failure (ARF) was induced in rats with (a) a combination of subcutaneous (s.c.) cephaloridine 500 mg/kg, frusemide 50 mg/kg and 4 ml/kg of 50% (v/v) glycerol in sterile water, (b) s.c. cephaloridine 1500 mg/kg, (c) s.c. mercuric chloride 2·0 and 4·7 mg/kg and (d) both s.c. and intramuscular glycerol (10 ml/kg in sterile water).
2. Pretreatment of rats with varying doses of frusemide protected against both the ATN and ARF of all the models except for glycerol where the ATN and ARF was aggravated. The protection against the ATN of cephaloridine alone and the ATN and ARF of the cephaloridine-glycerol-frusemide combination was almost complete if the last (or only) frusemide pretreatment injection was given 5–12 h before the challenge. Frusemide administered together with cephaloridine makes the ATN and ARF more severe.
3. The pretreatment regime results in moderate dehydration, a lowered serum potassium, a markedly elevated plasma renin activity and a reduced glomerular filtration rate. All these factors would be expected to increase the damage resulting from the nephrotoxic challenges, rather than to protect against it.
4. The possible mechanism of this protection conferred by frusemide pretreatment on the ‘toxic’ type of ARF is discussed. With this type of nephrotoxic insult the resulting ATN involves mainly the proximal convoluted tubules. The potentiation of the ‘circulatory’ type of ARF by frusemide pretreatment probably results from the effects of dehydration.