Renal Adaptations to Continuous Administration of Furosemide and Bendroflumethiazide in Rats

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

BG9719 (CVT-124), an A 1 Adenosine Receptor Antagonist, Protects Against the Decline in Renal Function Observed With Diuretic Therapy

“…Most studies evaluating the renal effects of furosemide have demonstrated decreased glomerular function. [15][16][17][18] These effects may be mediated by adenosine release in the kidney. The marked furosemide-induced decrease in creatinine clearance in the present study is consistent with the clinical observation that diuresis may be limited by worsening renal function.…”

The clinical pharmacology of loop diuretics in the pediatric patient

“…1 : Loop diuretics do not inhibit sodium reabsorption in the distal nephron segments [18]. Instead distal segments are most likely responsible for the diminishing potency of loop diuretics, a phenomenon known as diuretic tolerance [19,20]. Furosemide given continuously to rats without saline replacement resulted in "normalization" of sodium excretion after initial diuresis [19].…”

“…However, studies attempting to substantiate the effect of proximal inhibition have reported conflicting results [19,28,29]. By evaluating tubule fluid to plasma inulin ratios, micropuncture studies were able to measure the amount of net fluid and substrate reabsorption from the proximal tubules of dogs after furosemide administration [19]. The GFR was assumed to be stable since the dogs received replacement of all urinary losses.…”

“…Further evidence of a loop diuretic inhibitory effect on the proximal tubule comes from a rat study evaluating the renal adaptations to continuous furosemide infusion [19]. Fractional lithium clearance (FE Li ) was used as a measure of the fraction of delivered sodium ions passing unabsorbed through the proximal segment of the nephron.…”

“…The loop diuretics' main site of activity is at the loop of Henle, where reabsorption of approximately 20%-30% of the total filtered sodium is inhibited. In response to initial diuresis, enhanced reabsorption of sodium and water at distal sites occurs through cellular hypertrophy and activation of neurohormonal homeostatic mechanisms [19,20]. This distal compensation plays a critical role in the development of diuretic tolerance.…”