RT Journal Article
SR Electronic
T1 Inhibition of mitochondrial function is not the diuretic mechanism of ethacrynic acid in the dog.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 594
OP 597
VO 224
IS 3
A1 P A Steen
A1 J H Milde
A1 G A Gronert
YR 1983
UL http://jpet.aspetjournals.org/content/224/3/594.abstract
AB 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.