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PubMed1991

Alpha-1 blockade inhibits compensatory sodium reabsorption in the proximal tubules during furosemide-induced volume contraction.

The renal effects of alpha-1 adrenoceptor blockade (i.v. infusion of doxazosin, 50 micrograms/kg prime; 30 micrograms/kg/h) on tubular sodium reabsorption during acute furosemide-induced volume contraction (i.v. infusion of furosemide, 7.5 mg/kg/h for 3 h) was investigated by clearance technique in conscious rats. By measuring inulin clearance, lithium clearance and urinary excretion rates of sodium and water, the changes in proximal and distal tubular sodium handling were dissociated. In furosemide-infused rats given doxazosin (n = 11) or volume replacement (n = 9), the fractional lithium excretion increased from 30% (control) to a steady-state value of 51% (last hour of furosemide infusion), whereas in rats infused with furosemide only (n = 9), the fractional lithium excretion increased transiently to a peak value of 52% and then declined to a steady-state value of 39%. Doxazosin attenuated the acute natriuretic response to furosemide by 54%, mainly due to increased sodium reabsorption in the distal nephron segment. This effect was associated with a significant lower mean arterial pressure compared with rats given furosemide only. The results are compatible with a contributory role of proximal tubular alpha-1 adrenoceptors in mediating compensatory Na reabsorption during furosemide-induced volume contraction.

Adrenergic alpha-Antagonists↗

PubMed1989

In vitro evidence that urine composition affects the fraction of active furosemide in the nephrotic syndrome.

Diuretic resistance to furosemide in the nephrotic syndrome (NS) may result from binding of drug to filtered albumin within the renal tubule. In buffer solutions intended to partially mimic the luminal environment of the distal nephron during the NS, we examined several chemical properties to determine their effect on furosemide-albumin binding equilibria. Dissociation constants were obtained by measuring furosemide's quenching of human serum albumin's intrinsic tryptophan fluorescence over ranges of pH, ionic strength (IS) and osmolarity. Neither pH nor osmolarity significantly affected binding; however, incremental increases in IS between 0.0 and 1.0 produced increases in Kd from 0.65 +/- 0.05 to 34.38 +/- 1.72 microM, resulting in a 5- and 28-fold increase in the unbound furosemide fraction when the furosemide-albumin concentrations were 3.0:5.0 and 10.0:45.0 microM, respectively. Our results indicate that human serum albumin contains one high affinity binding site for furosemide that is sensitive to IS. Because of changes in the concentrations of reactants as well as IS that can occur in nephron segments distal to furosemide's site of action, we conclude that the amount of unbound (i.e., pharmacologically active) drug in voided urine will not necessarily correspond to the amount at the active site. To clinically assess the pharmacodynamic consequence of protein binding in the NS, changes in the concentration of the reactants and IS in the distal nephron must be minimized so that the unbound furosemide measured in voided urine will accurately reflect the amount at the drug's active site.

Furosemide↗

PubMed1986

Furosemide pharmacodynamics: effect of respiratory and acid-base disturbances.

The aims of this study were to investigate the effect of changes in arterial blood gases and pH on furosemide pharmacodynamics and kinetics. Five groups of conscious rabbits were used: a control group breathing air with normoxia and normocarbia; a second group with hypercapnia and respiratory acidosis; a third with hypoxemia; a fourth with hypercapnia and respiratory acidosis combined with hypoxemia (HCHO); and the fifth group with metabolic acidosis. All experimental conditions, except hypoxemia, increased sodium tubular reabsorption and therefore, decreased urinary excretion of sodium. Renal blood flow was decreased by HCHO and metabolic acidosis. In response to 5 mg/kv i.v. of furosemide, natriuresis and diuresis were decreased by an average of 44% in animals with HCHO (P less than .05). The kinetics of furosemide were not affected by any of the experimental conditions except HCHO, in which the renal clearance of furosemide was reduced from 7.5 +/- 1.4 ml/min/kg (controls) to 2.7 +/- 0.7 ml/min/kg (P less than .05). The reduction in renal clearance of furosemide was associated with a decrease in urinary excretion of sodium (P less than .05). The reduction in renal clearance of furosemide was probably secondary to the decrease in renal blood flow and an increase in furosemide tubular reabsorption. Finally, HCHO did not decrease plasma volume, suggesting that the reduction in renal blood flow was secondary to blood flow distribution. In conclusion, only hypercapnia and respiratory acidosis combined with hypoxemia decreases the natriuretic and diuretic effect of furosemide.

Acidosis, Respiratory↗

PubMed1988

Immunoassay detection of drugs in racing horses. VI. Detection of furosemide (Lasix) in equine blood by a one step ELISA and PCFIA.

A one step enzyme-linked immunosorbent assay (ELISA) and a particle concentration fluorescent immunoassay (PCFIA) test for furosemide were evaluated as part of a panel of pre- and post-race tests for illegal medication of racing horses. These tests are very sensitive to furosemide with an I-50 for furosemide of about 20 ng/ml. The test is also rapid; an average pre-race complement of 10 samples can be analyzed in 90 minutes or less. The ELISA test results can be read with an inexpensive spectrophotometer, or even by eye. Both the PCFIA test and the ELISA test readily detect the presence of furosemide in equine blood for up to five hours after administration of the recommended therapeutic dose of this agent. The principal utility of these tests lies in rapid screening of samples for compliance with regulations governing the use of furosemide. Thus these tests can be used pre-race to determine whether horsemen have treated their horses with furosemide, and post-race to perform an initial evaluation of whether certain blood concentrations of furosemide have been exceeded. Pilot trials with these systems in Kentucky and Illinois suggest that these tests are economical and effective, and can form part of an analytical approach to substitute for the detention barn system of monitoring furosemide administration.

Animals↗

PubMed1988

Role of antidiuretic hormone in the attenuated furosemide response observed during indomethacin administration.

Recently we demonstrated that increased chloride reabsorption in Henle's loop is a major contributor to the blunted furosemide response observed during prostaglandin synthesis inhibition. Because antidiuretic hormone (ADH) modulates chloride reabsorption in the loop and because prostaglandin synthesis inhibition potentiates ADH-mediated water reabsorption, ADH may be necessary for the attenuated furosemide response observed during prostaglandin synthesis inhibition. If such were the case, then prostaglandin synthesis inhibition should have no effect on furosemide's chloruretic response in the absence of ADH. To test this hypothesis, the effect of indomethacin on furosemide chloruresis was determined in homozygous (ADH-deficient) Brattleboro rats and in homozygous Brattleboro rats receiving ADH (2.4 mU/hr) over a short period of time. Furosemide-induced chloruresis was not different (P was not significant) between indomethacin-treated homozygous Brattleboro rats and homozygous Brattleboro rats receiving the indomethacin vehicle (fractional excretion of chloride: 6.28% +/- 1.08% vs. 6.24% +/- 0.98%). However, in ADH-infused Brattleboro rats, furosemide chloruresis was lower in indomethacin-treated rat groups than in vehicle-treated rat groups (fractional excretion of chloride: 3.09% +/- 0.62% vs. 6.61% +/- 0.88%; P less than 0.02) and lower than in indomethacin-treated ADH-deficient Brattleboro rats as well (P less than 0.05). Mean arterial pressure, inulin clearance, and renal blood flow were not different between any groups. Urinary prostaglandin excretion rates were not different between ADH-deficient Brattleboro rats and ADH-treated Brattleboro rats during furosemide administration and were markedly reduced by indomethacin in both circumstances. Thus, ADH is necessary for the blunted furosemide response observed during prostaglandin synthesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Absorption and disposition of furosemide in healthy volunteers, measured with a metabolite-specific assay.

The objectives of this study were to qualitatively and quantitatively compare the metabolism, pharmacokinetics, and bioavailability of furosemide in healthy volunteers after intravenous and oral administration. We also determined the plasma protein binding of furosemide in vivo after iv administration. Nine males received furosemide (Hoechst, 40 mg iv and 80 mg po) in a random crossover fashion. Serial plasma samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced throughout the study. Furosemide as well as its potential metabolites were measured by a rapid, sensitive, and specific spectrofluorimetric HPLC assay. Total plasma clearance averaged 164 +/- 26 (SD) ml/min, of which 66.2 +/- 6.8% represented renal clearance of unchanged drug. Volume of distribution (steady-state) was 109 +/- 19 ml/kg. These clearance and volume measurements are in good agreement with data previously published by our group. The mean absolute bioavailability of furosemide was 42.8 and 44.0%, as calculated from plasma and urine data, respectively. Protein binding of furosemide in vivo was determined by a spectrofluorimetric HPLC assay and ranged from 98.5 to 99.1%. Approximately 5.5 mg of furosemide was excreted as a glucuronide conjugate after iv dosing and about 5.1 mg after po administration. We found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of our plasma or urine samples. In addition, we conclusively demonstrated CSA to be an analytical artifact.

Absorption↗

PubMed1983

Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites.

To investigate if lysine acetylsalicylate influences the hemodynamic and diuretic responses to furosemide in cirrhosis, 21 nonazotemic patients with ascites were studied. In 8 patients (group 1), the renal plasma flow and glomerular filtration rate were serially measured before and during three 30-min periods after the i.v. administration of lysine acetylsalicylate (450 mg). In 7 patients (group 2), renal plasma flow, glomerular filtration rate, urine volume, and sodium excretion were measured before and during three 20-min periods after the i.v. administration of furosemide (40 mg). After a 45-min period in which urinary losses were restored, a similar study was performed before and after a second injection of furosemide (40 mg). Six patients (group 3) were studied with an identical protocol as group 2, except that the second injection of furosemide was preceded by the administration of lysine acetylsalicylate (450 mg). In 6 patients of group 1, lysine acetylsalicylate caused a marked and reversible reduction of renal plasma flow and glomerular filtration rate. In groups 2 and 3, the i.v. injections of furosemide alone produced a significant increase in renal plasma flow and glomerular filtration rate, and a marked diuresis and natriuresis. In patients of group 3, pretreatment with lysine acetylsalicylate suppressed the renal hemodynamic effect and markedly reduced the diuretic effect of the second injection of furosemide. Lysine acetylsalicylate did not cause the appearance of renal insufficiency in any of these patients. These results suggest that prostaglandins are involved in the renal response to furosemide in cirrhosis with ascites and that furosemide protects these patients from developing renal insufficiency after acute administration of nonsteroidal antiinflammatory agents.

Aspirin↗

PubMed1978

Furosemide-induced adverse reactions during hospitalization.

The frequency and types of adverse reactions (ARs) occurring in hospitalized patients receiving furosemide were surveyed prospectively in a four-year study at the José Joaquin Aquirre Hospital in Santiago, Chile. A team of clinical pharmacists and clinical pharmacologists monitored 533 patients receiving furosemide and recorded patient characteristics, laboratory test results, drugs administered, and suspected ARs. Definite or probably furosemide-induced ARs were detected in 220 (39.8%) patients. No ARs were fatal but 7.6% of patients, all having cirrhosis of the liver, had severe ARs. Of the ARs recorded, 95.2% were dose-related. The most common ARs were electrolyte disturbances (23.5% of patients), extracellular volume depletion (9.0% of patients) and hepatic comma (3.6% of patients). Total and daily furosemide doses, lengthened hospitalization and hepatic disease were significantly associated with the frequency of ARs (p less than 0.001). The dosage of furosemide did not account for the increased frequency of ARs in patients with hepatic disease. The frequency of hypokalemia was not reduced significantly when furosemide was administered with potassium chloride or potassium-sparing diuretics (p less than 0.05). The frequency of severe furosemide-induced ARs is low, but ARs are more common in patients with cirrhosis of the liver. These patients should be closely monitored for furosemide-induced ARs.

Adolescent↗

PubMed1984

Effect of furosemide on urinary acidification in distal renal tubular acidosis.

Furosemide stimulates urinary acidification in normal humans probably by increasing distal Na delivery and transport, thus creating a favorable electric gradient for H+ and K secretion. Therefore, furosemide should stimulate urinary acidification in patients with distal renal tubular acidosis, provided the distal nephron is capable of transporting Na and the H+ pumps can respond to the favorable electric gradient. We examined the effect of short-term furosemide administration on urinary acidification in five normal participants and 12 patients with normokalemic, hypokalemic, or hyperkalemic distal renal tubular acidosis. In controls, furosemide decreased urine pH and increased net acid and K excretion. In six of eight patients with normokalemic or hypokalemic renal tubular acidosis, furosemide decreased urine pH and increased net acid and K excretion to levels not significantly different from control values. The patients that had normal responses were interpreted as having a rate-dependent or gradient distal renal tubular acidosis, and thus increased distal Na delivery created a favorable electric gradient for H+ and K secretion. The normokalemic patients who did not have a response were considered to have a defect in the pumps (secretory defect). Of the four hyperkalemic patients, two had a voltage-dependent defect and the other two had aldosterone deficiency. The patients with selective aldosterone deficiency had low baseline urine pH values that did not change with furosemide administration, but net acid and K excretion did increase significantly. The patients with voltage-dependent defect did not lower urine pH or increase net acid and K excretion. Our data demonstrate that administration of furosemide enhances urinary acidification in certain patients with distal renal tubular acidosis. We suggest that furosemide administration may be useful in the characterization of the mechanism responsible for distal renal tubular acidosis and in the treatment of distal renal tubular acidosis in selected patients.

Acidosis, Renal Tubular↗

PubMed1994

Pulmonary vascular pressures of strenuously exercising thoroughbreds after administration of flunixin meglumine and furosemide.

High-intensity exercise results in a dramatic increase in mean pulmonary capillary blood pressure of horses, and administration of furosemide 4 hours before exertion significantly attenuates this exercise-induced increment. To test whether this effect of furosemide is mediated via release of prostaglandins, right atrial and pulmonary vascular pressures were measured in 8 healthy, sound, exercise-trained Thoroughbreds at rest and during incremental-step exercise on a treadmill. Horses were studied on 3 separate occasions: after i.v. administration of saline (0.9% NaCl) solution, after administration of furosemide (250 mg, i.v., 4 hours before exercise) alone, and after administration of flunixin meglumine (1.1 mg/kg, i.v., q 8 h for 3 days) and furosemide (250 mg, i.v., 4 hours before exercise; last dose of flunixin meglumine was administered 90 seconds after furosemide injection). Experiments on each horse were separated by at least 7 days and were performed in random order. At rest and at the highest workload (14.5 m/s on a 5% uphill incline), mean pulmonary capillary blood pressure recorded after administration of furosemide alone was not significantly different from that recorded after administration of flunixin meglumine and furosemide. However, these values were significantly (P < 0.05) less than corresponding values of mean pulmonary capillary blood pressure recorded after administration of saline solution. Thus, it was concluded that furosemide-induced attenuation of the increment in pulmonary capillary blood pressure during strenuous exercise is probably not mediated via prostaglandin production.

Animals↗

PubMed1993

Effect of furosemide on the response of laryngeal receptors to low-chloride solutions.

Laryngeal irritant receptors are stimulated by water and solutions lacking chloride ions, such as isotonic dextrose. It has been reported that furosemide (frusemide) reduces cough evoked by inhalation of low-chloride solutions. We studied the effect of furosemide on the response of laryngeal receptors to isotonic dextrose. Experiments were performed on nine dogs anaesthetized, spontaneously breathing through a tracheostomy, and with the upper airway functionally isolated. We recorded the activity of 13 laryngeal irritant receptors. Isotonic dextrose (4 ml) was instilled into the laryngeal lumen, before and after administration of a furosemide solution (3.75 mg.ml-1) into the upper airway. Before furosemide, dextrose increased the activity of the 13 receptors from 1.0 +/- 0.5 to 25.0 +/- 3.5 impulses (imp).s-1 (average discharge in the first 10 s of activation) and, 1-2 min after furosemide, from 0.3 +/- 0.2 to 13.4 +/- 3.2 imp.s-1; the difference between the stimulation by dextrose before and after furosemide was statistically significant. In contrast, the response to distilled water of four respiratory-modulated mechano-receptors (known to be activated by low-osmolality solutions) was not modified by furosemide. These results suggest that the furosemide-mediated inhibition of cough induced by inhalation of low-chloride solutions is, at least in part, due to the inhibitory effect of this substance on irritant receptor stimulation.

Action Potentials↗

PubMed1993

Involvement of renal dopamine synthesis in the diuretic effect of furosemide in normohydrated rats.

The present study was designed to investigate whether the modification of dopamine synthesis affects furosemide responses. Experiments were performed on pentobarbital-anesthetized rats. Basal urine flow was approximately 3 microliters/min-1/g-1 of kidney weight (k.w.); furosemide (0.2 mg/kg-1 i.v.) induced a rapid diuretic effect (19.3 +/- 1.4 microliters/min-1/g-1 of k.w.). The dopadecarboxilase inhibitor, benserazide (25 mg/kg-1 i.v.), reduced furosemide-induced diuresis to 8.3 +/- 2.1 microliters/min-1/g-1 of k.w., whereas levo-dihydroxyphenylalanine (L-dopa; 1 micrograms/kg-1/min-1 infused for 60 min) increased it to 41.4 +/- 6.1 microliters/min-1/g-1 of k.w. Natriuretic response and fractional Na+ excretion induced by furosemide were significantly lower in benserazide-treated and higher in L-dopa-treated animals. Urine dopamine (DA) excretion was enhanced by furosemide from 0.44 +/- 0.05 to 0.98 +/- 0.22 ng/min-1/g-1 of k.w. and was markedly reduced in benserazide-pretreated animals, whereas both basal DA excretion and that induced by furosemide were increased significantly during L-dopa infusion. However, in benserazide- or L-dopa-treated animals, basal urine flow was not different from the control group. Urine furosemide excretion was reduced by 60% by benserazide treatment and increased by 62% during L-dopa infusion. The results are consistent with the suggestion that although endogenous DA is apparently unimportant in the maintenance of basal urine output, it is involved in furosemide-induced diuresis. The diuretic response can be altered by acute administration of substances that affect dopamine synthesis.

Animals↗

PubMedDate not supplied

Variable furosemide absorption and poor predictability of response in elderly patients.

STUDY OBJECTIVES: To determine the between- and within-patient variability of furosemide bioavailability and natriuretic response, and whether four marketed products differ in bioavailability and response. DESIGN: Open-label, crossover study. SETTING: General clinical research center at an academic medical center. PATIENTS: Convenience sample of 17 patients age 65 +/- 6 years receiving diuretics for the treatment of hypertension or congestive heart failure. INTERVENTION: Each patient received each of five furosemide products (one intravenous and four oral tablet formulations) twice in random order for a total of 10 treatments. MEASUREMENTS AND MAIN RESULTS: Measurements included absolute bioavailability using cumulative amounts of urinary furosemide collected over 8 hours after oral versus intravenous dosing, and cumulative amounts of urinary sodium. Extensive between- and within-patient variability in all measured values rendered any differences among the products neither clinically nor statistically significant. Mean (+/-SD) bioavailability was 49 +/- 17% (range 12-112%) and coefficients of variation with different products were from 25-43%. Coefficients of variation for urinary furosemide excretion and urinary sodium excretion were also large, 25-42% and 23-51%, respectively. Multivariate analyses that incorporated between- and within-patient effects failed to reveal differences among the products for bioavailability (F = 1.04, p = 0.403), urinary furosemide excretion (F = 1.09, p = 0.371), or urinary sodium excretion (F = 0.97, p = 0.448). Correlation coefficients were 0.81-0.85 for the rates of sodium and furosemide excretion, and half-maximum response using a sigmoid Emax model did not differ among products. CONCLUSION: Although furosemide concentration in urinary and natriuretic responses showed good correlation, variability in bioavailability considerably affects the drug's excretion into urine. Variability in absorption both among patients and within an individual patient is great and overwhelms any differences in bioavailability among approved furosemide products. Switching from one formulation to another will not likely result in any predictable change in patient response.

Administration, Oral↗

PubMedDate not supplied

Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.

STUDY OBJECTIVE: To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent. DESIGN: Retrospective population pharmacokinetic analysis. SETTING: Government biomedical research facility. PATIENTS: Twenty-six men with hormone-refractory prostate cancer and one with adrenocortical carcinoma. INTERVENTIONS: Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide. MEASUREMENTS AND MAIN RESULTS: Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high-performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three-compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two-stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0-63%, p < 0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model. CONCLUSION: Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half-life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.

Adrenal Cortex Neoplasms↗

PubMed1997

Effect of furosemide and subsequent intravenous fluid administration on right atrial pressure of splenectomized horses.

OBJECTIVE: To investigate the effect of i.v. administration of fluids on the furosemide-induced reduction in right atrial pressure (RAP) and relative change in blood volume (BV) of splenectomized mares. ANIMALS: 5 splenectomized mares. PROCEDURE: RAP was measured by use of a micromanometer placed in the right atrium. Jugular venous blood was collected for measurement of hematocrit, plasma total protein concentration, and hemoglobin concentration. Right atrial pressure was recorded and blood samples were collected immediately before furosemide (1 mg/kg of body weight, i.v.) administration, then every 15 minutes for 240 minutes. Beginning 120 minutes after furosemide administration, polyionic fluids (lactated Ringer's solution) were administered (2 L q 15 min) for 120 minutes. RESULTS: Furosemide induced a significant (P < 0.05) decrease in mean RAP (7.6 +/- 1.5 and 3.2 +/- 1.2 mm of Hg before and 15 minutes after furosemide administration, respectively), and BV (8.4 +/- 1.1 % by 15 minutes). Polyionic fluid administration restored RAP and BV. The volume of polyionic fluids administered (32 +/- 2 ml/kg) was not significantly different from the volume of urine produced (38 +/- 7.8 mg/kg). Difference was not apparent in the relation between change in BV and RAP before or after fluid administration. CONCLUSIONS: The effect of furosemide on RAP of horses is mediated in large part by furosemide-induced reduction in BV. However, an effect of furosemide on venous compliance cannot be excluded as contributing to the reduction in RAP.

Analysis of Variance↗

PubMed1976

A comparative diuretic and tissue distribution study of bumetanide and furosemide in the dog.

Intravenous dose-response data obtained from renal clearance studies in anesthetized dogs indicated that bumetanide was approximately 30-fold more potent than furosemide in enhancing sodium excretion. After the administration of 0.01 mg/kg of bumetanide or 1.0 mg/kg of furosemide, the relationship between i.v. diuretic activity and tissue distribution was evaluated. In dog renal clearance experiments, bumetanide and furosemide significantly enhanced urine flow, sodium and potassium excretion. Inulin clearance as an estimate of glomerular filtration rate was not altered by either drug, but sodium reabsorption was decreased with bumetanide (13%) and furosemide (12%). At these diuretic doses, both compounds were bound to dog plasma protein to about the same extent (86-91%), although total plasma levels were 100-fold higher for furosemide. Within 1/2 hour after the i.v. administration of 14C-bumetanide or 14C-furosemide, 86 to 99% of the 14C in urine, plasma, kidney, and liver appeared as unchanged drug. One minute after maximal diuresis bumetanide was found to have a higher affinity (3-fold) for kidney compared to furosemide. These data offer a possible explanation for the i.v. diuretic potency difference between these two compounds. Furthermore, the lack of significant difference in plasma protein binding and the absence of urinary metabolites of either drug suggest that other factors may also contribute to the marked differences in diuretic activity between bumetanide and furosemide.

Animals↗

PubMed1998

Aldosterone receptor blockade inhibits increased furosemide-sensitive sodium reabsorption in rats with liver cirrhosis.

We examined the role of chronic aldosterone receptor blockade on the altered furosemide-sensitive sodium reabsorption in rats with liver cirrhosis induced by common bile duct ligation. CBL and sham-operated control animals were treated with the aldosterone receptor antagonist canrenoate (20 mg/day i.v.) for 4 weeks. Untreated CBL and sham-CBL served as control groups. The plasma concentration of aldosterone was within the normal range in all groups. Sodium balance studies showed that aldosterone receptor blockade prevented sodium retention in cirrhotic rats. Clearance studies showed that the glomerular filtration rate was unchanged, whereas the renal plasma flow was increased in CBL rats. A test dose of furosemide (7.5 mg/kg b.wt. i.v.) produced significantly greater diuretic (+59%) and natriuretic (+56%) responses in CBL rats than in sham-operated controls. The urinary furosemide excretion rate (UFURV) reflects delivery of furosemide to the thick ascending limb. When the natriuresis was expressed relative to UFURV (i.e., the natriuretic efficiency), we found that natriuretic efficiency of furosemide was significantly increased in untreated CBL rats (+59%). However, the natriuretic efficiency of furosemide was normalized in CBL rats treated with canrenoate. The urinary excretion of furosemide was unchanged in untreated CBL rats, but it was significantly increased in cirrhotic rats treated with canrenoate (+43%). This suggests that in CBL rats, chronic canrenoate treatment increases the renal elimination of furosemide as a consequence of reduced metabolism. These data suggest that chronic aldosterone receptor blockade with canrenoate prevents sodium retention in cirrhotic rats partly by inhibition of increased sodium reabsorption in the thick ascending limb.

Animals↗

PubMed1976

Relationship of urinary furosemide excretion rate to natriuretic effect in experimental azotemia.

The relationship of natriuretic effect and furosemide excretion was studied in normal and azotemic dogs. Graded azotemia was produced in dogs by bilateral uretero-venous shunts of varying duration. The shunts were subsequently opened and urine and blood samples were taken to measure inulin, furosemide and sodium concentrations. Renal blood flow was measured by an electromagnetic flow probe. Two groups of dogs, control and experimental, were studied. The experimental group received a loading dose followed by a constant infusion of furosemide. This dose produced a natriuresis in nonazotemic normal dogs. The magnitude of this natriuresis correlated with furosemide excretion rate (P less than .005) and not with the plasma concentration of the drug. Furosemide clearance and extraction were inversely correlated with blood urea nitrogen. In the furosemide-treated group the augmentation of sodium excretion was not impaired except at blood urea nitrogen concentrations of greater than 200 mg/dl (two dogs). Thus the reduced clearance of furosemide may account in part for the high dose necessary. Further studies appear to be in order to clarify the relationship of the natriuretic response to furosemide to the rate of urinary excretion and plasma concentration of the drug.

Animals↗