Acute effects of alkylating agents on canine renal function and ultrastructure: high-dose ethacrynic acid vs. dihydroethacrynic acid and ticrynafen.

Ethacrynic acid (EA) is unique among diuretics in that it is both an avid alkylating agent and is actively secreted by renal proximal tubular cells. EA might therefore be expected to produce detrimental proximal tubular changes at elevated doses. Because of this possibility, we examined the renal effects of two relatively high doses of EA (i.e., 66 and 151 mumol/kg i.v.) and an equivalent high dose (i.e., 151 mumol/kg) of two nonalkylating relatives of EA [dihydro-EA (EA-H2) and ticrynafen]. Twelve renal function parameters were monitored in pentobarbital-anesthetized dogs for a period of 2 hr after administration of EA, EA-H2 and ticrynafen and renal tissue was acquired at the end of the 2 hr of study for light and electron microscopic evaluation. Both doses of EA produced a profound diuresis of similar magnitude. However, only the larger dose was associated with a concomitant reduction in the glomerular filtration rate, a downward trend in the renal blood flow, a proteinuric response in four of the seven dogs in the treatment group and a reproducible vacuolation of the initial portion of the proximal convoluted tubules (i.e., the S1 cells). EA-H2 induced a small, transient increase in the excretion rates of sodium, chloride and potassium, but failed to elicit a proteinuric response or alter proximal tubular ultrastructure. Ticrynafen, a far more efficacious diuretic agent than EA-H2, likewise failed to trigger a proteinuric response or changes in renal ultrastructure. The combination of acidic (anionic) and alkylating properties of EA is thought to be responsible for the proximal tubular effects observed in this study.