METABOLIC ADAPTATION OF RENAL CARBOHYDRATE-METABOLISM .5. IN-VIVO RESPONSE OF RAT RENAL-TUBULE GLUCONEOGENESIS TO DIFFERENT DIURETICS

We have studied the effects of the diuretics mersalyl, furosemide and ethacrynic acid on renal gluconeogenesis in isolated rat-kidney tubule s and on the activities of the most important gluconeogenic and glycol ytic enzymes in both fed and fasted rats. Mersalyl (15 mg.kg(-1) anima l weight) significantly decreased the rate of gluconeogenesis in well- fed rats (68%) as well as in 24 and 48-h fasted ones (33 and 37% respe ctively). This inhibition occurred when lactate, pyruvate, glycerol or fructose were used as substrates. Ethacrynic acid at a dose of 50 mg. kg(-1) animal weight provoked a transient inhibition of renal glucose production by almost 20% but only in fed rats with lactate as substrat e, whereas the same dose of furosemide did not affect this metabolic p athway. Parallel to these changes, mersalyl caused a significant inhib ition in the maximum activity of the most important gluconeogenic enzy mes, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase an d glucose B-phosphatase, in both fed and fasted rats. Neither ethacryn ic acid nor furosemide produced any variations in the activities of th ese enzymes. The activity of the glycolytic enzymes phosphofructokinas e and pyruvate kinase was not modified by these diuretics. Nevertheles s, the activity of the thiol-enzyme glyceraldehyde 3-phosphate dehydro genase was severely inhibited by mersalyl and to a lesser extent by th e other diuretics. This inhibition was higher in fasted than fed rats. Hence, we conclude that the inhibitory effect of mersalyl on renal gl uconeogenesis is due, at least partly, to a decrease in the flux throu gh the gluconeogenic enzymes. Blood glucose was not modified after diu retic treatment in fed animals whereas mersalyl decreased the levels o f blood glucose in 24-h fasted rats. The in vivo effects of diuretics on gluconeogenesis correlate well with the previously observed in vitr o effects, although ethacrynic acid was less potent as an inhibitor in vivo, probably because of its rapid clearance.