RENAL ADAPTATIONS TO CONTINUOUS ADMINISTRATION OF FUROSEMIDE AND BENDROFLUMETHIAZIDE IN RATS

During continuous treatment with diuretics, the kidney adapts to the initial Na loss by activating antinatriuretic mechanisms which serve to prevent further Na and volume losses. To study the renal sites of adaptations to constant diuretic treatment, bendroflumethiazide (4 mg daily), furosemide (8 mg daily) or vehicle (0.24 ml daily) was infused intraperitoneally to female Wistar rats by implanted osmotic minipumps. Half of the animals (groups vol.) were randomized to receive a balanced saline solution to drink in addition to water in order to replace Na, K and volume losses. On the 6th day of treatment, clearances of inulin, Na, and Li were determined during four consecutive 6 hr periods. Circadian changes in renal excretions occurred in all groups with highest excretions of Na, Li and water in the dark period (6 p.m. to 6 a.m.). Renal changes induced by continuous infusion of diuretics were most pronounced in the dark period and would probably not have been disclosed if the clearance experiments had been restricted to the daytime. The average 24-hour clearance for inulin (glomerular filtration rate) was not different among groups, except for a 20% decrease in the furosemide group. The 24-hour fractional Na excretion, being approximately 0.5% in the vehicle group, increased to approximately 0.8% in group (bendroflumethiazide + vol) and to approximately 2.8% in group (furosemide + vol) but was not different from the vehicle group in the diuretic groups without volume replacement. Fractional Li excretion was approximately 28% in groups (vehicle +/- vol), approximately 19% in groups (bendroflumethiazide +/- vol), approximately 30% in the furosemide group and approximately 37% in group (furosemide + vol). Finally, C(Na)/C(Li) was approximately 1.7% in group (vehicle + vol), approximately 3.7% in group (bendroflumethiazide + vol) and approximately 7.0% in group (furosemide + vol). The results indicate that even though continuous furosemide administration caused a fall in glomerular filtration rate, there was no change in the flow rate of tubular fluid to the distal nephron (C(Li)) following treatment with loop diuretic. This contrasts the effects of continuous thiazide treatment, being a reduction of C(Li) in absence of changes in glomerular filtration rate. The reason for this difference may be that the adaptive increase in proximal tubular Na reabsorption is outbalanced by an inhibitory effect of furosemide itself on the proximal tubule. Both diuretics caused an adaptive increase in fractional distal Na reabsorption, probably at nephron sites beyond their respective sites of action. Furosemide but not bendroflumethiazide induced a persistent increase in urine flow.