Inhibition of mitochondrial function is not the diuretic mechanism of ethacrynic acid in the dog.

Kidney metabolites were studied in five anesthetized dogs before and after 5 mg/kg i.v. of ethacrynic acid, followed by 3 mg X kg-1 X hr-1. This dose, which inhibits most of the reabsorption of sodium and chloride in the diluting segment, improved the energy state in biopsies from the outer medulla and caused an increase in ATP and a decrease in ADP and AMP levels and the lactate/pyruvate ratio. This was probably related to ongoing rapid metabolism in the control biopsies (with improved results after ethacrynic acid due to a primary reduction in an ATP requiring process) before they were completely frozen in liquid nitrogen. No changes occurred in ATP, ADP or phosphocreatine levels or the lactate/pyruvate ratio in cortical biopsies, which was in agreement with the previously shown lack of effect on proximal tubular reabsorption at this dosage of ethacrynic acid. These results indicate that the saluretic effect and parallel reduction in outer medullary metabolic rate with ethacrynic acid cannot be due to a direct inhibition of mitochondrial ATP production as suggested by others from in vitro experiments. The reduced rate of ATP production in vivo must be secondary to a reduced ATP demand.