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PubMed1982

Nature of the inhibition of Cl- transport by furosemide: evidence for competitive inhibition of active transport in toad cornea.

Furosemide inhibits short-circuit current (active Cl- transport) in isolated toad cornea, a model of the thick ascending limb of the loop of Henle. The relationship between furosemide and Cl- was assessed in corneas exposed to different concentrations of Cl-. Furosemide (2.2 x 10(-5) M) or drug vehicle was added to both sides of the corneas. Double-reciprocal plots of short-circuit current vs. Cl- concentration with or without furosemide revealed an interaction between furosemide and Cl- that appeared to be competitive in nature. That is, the 1/short-circuit current x 10(3) intercepts (short-circuit currentmax) of the lines were not significantly different (54 with furosemide and 40 for the control, P = .765), whereas the slopes of the lines were significantly different (7.9 with furosemide and 2.1 for the control, P = .037). Km values calculated from the slopes and intercepts with and without furosemide were 145 and 53 mM, respectively. The relationship between external Cl- and furosemide was unique in that a similar competitive relationship was not apparent for either external Na+ and furosemide or external Cl- and ouabain (another inhibitor of Cl- transport in amphibian cornea). These findings support the hypothesis that furosemide inhibits active Cl- transport by competitively blocking the access of Cl- to some component of the active transport mechanism, possibly the Na+-Cl- cotransport mechanism.

Animals↗

PubMed1980

Effects of furosemide on extravascular diffusion, protein binding and urinary excretion of cephalosporins and aminoglycosides in rabbits.

We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).

Aminoglycosides↗

PubMed1995

Furosemide renal excretion rate and the effects of the diuretic on different tubular sites are modified by endogenous dopamine in normohydrated rats.

The present study was designed to explore the involvement of endogenous dopamine in furosemide excretion and in the actions of the diuretic on tubular sodium reabsorption. The dose-response relationship for the diuretic effect of furosemide given as i.v. bolus injections (0.2-7.5 mg.kg-1) was studied by clearance technique in pentobarbital-anesthetized rats treated with vehicle, benserazide (BZ) (25 mg.kg-1 i.v.) or SCH 23390 (50 micrograms.kg-1 + 10 micrograms.kg-1.min-1 i.v.). Furosemide induced the maximal diuresis 15 to 30 min after i.v. administration. The diuretic response was dose-dependent and was reduced in the animals treated with BZ and SCH 23390. Fractional sodium excretion was also increased by furosemide from 1.8 to 7.5% during the same period. This effect was reduced by both BZ or SCH 23390 by 35 to 50%. The effects of furosemide on proximal and distal renal tubules were dissected by measuring the renal lithium clearance (CLi+). Furosemide effective on proximal tubular sites (measured by FENa+ prox = CLi+/Cln) were completely abolished by BZ and SCH 23390, whereas both drugs reduced furosemide effects on distal tubular sites (measured by FENa+ distal = CNa+/CLi+) by 20 to 40%. Furosemide excretion rate during the peak response to the diuretic was measured in the urine. BZ and SCH 23390 diminished furosemide excretion by 45 to 80% as compared with vehicle-treated animals. The furosemide tubular effects and the proximal and distal functions measured by CLi+ determined during the peak response were correlated to the maximal excretion rate of furosemide in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Desorption of furosemide from charcoal in vitro and in man.

The gastrointestinal absorption of furosemide preadsorbed onto activated charcoal was studied in 8 healthy volunteers using a randomized cross-over design with 3 phases. The 3 experimental furosemide formulations were capsules containing 40 mg furosemide only (reference) or 100 mg furosemide preadsorbed onto 160 mg or 200 mg charcoal. Timed plasma samples were taken and urine was collected for 24 hours for determination of drug concentrations and diuretic response. The release of furosemide from the formulations was also studied in vitro. Furosemide was found to dissolve rapidly from the reference formulation, whereas it was slowly desorbed from charcoal with the cumulative release reaching 50-60% in 24 hours (pH 5.3). The absorption rate of furosemide was smaller after intake of the charcoal formulations that after intake of the reference formulation. However, also the amounts of furosemide found in plasma and urine were clearly decreased due to preadsorption onto charcoal. The dose-adjusted relative bioavailabilities of the furosemide-charcoal formulations (compared to the reference formulation) remained less than 10%. The release mechanism of furosemide from charcoal is sensitive to physiological factors of the gastrointestinal tract. The large variability known to be typical for furosemide absorption was further increased when the drug was preadsorbed onto charcoal.

Administration, Oral↗

PubMed1993

Thromboxane synthase inhibition enhances furosemide-induced renal vasodilation.

The effects of furegrelate (a thromboxane synthase inhibitor), indomethacin, and the combination on urine volume (V), para-aminohippurate clearance (CPAH), and mean arterial pressure (MAP) before and after intravenous furosemide were examined in Sprague-Dawley rats. Prior to furosemide, none of the treatments changed MAP, V, or CPAH. Furosemide increased urine volume from 16 +/- 7 to 148 +/- 25 microL.min-1. Concomitant administration of furegrelate or indomethacin did not affect furosemide-induced diuresis, but the combination of indomethacin, furegrelate, and furosemide caused increased diuresis (to 254 +/- 40 microliters.min-1, p < 0.05, compared with furosemide alone). Furosemide alone or with the other drugs had no effect on mean arterial pressure. CPAH was increased from 3.0 +/- 0.4 to 4.6 +/- 0.8 ml.min-1.100g-1 (p < 0.05, n = 6) by furosemide, and to an even greater extent (6.7 +/- 0.8, n = 6) after pretreatment with furegrelate. Pretreatment with indomethacin alone or in combination with furegrelate abolished the furosemide-induced CPAH increment. Urine excretion of the prostacyclin hydrolysis product 6-ketoprostaglandin F1 alpha was increased by furosemide in the presence of furegrelate. Given that the transient renal vasodilation with furosemide is due to prostanoid precursor release, these results are consistent with redirection of arachidonate metabolism toward vasodilator prostaglandins by furegrelate.

6-Ketoprostaglandin F1 alpha↗

PubMed1997

Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia.

To elucidate the mechanism of impaired serum binding of furosemide observed in patients with renal dysfunction, we examined in vitro the serum protein binding of furosemide in the absence and presence of uremic toxins that are endogenously retained solutes in uremic serum and act as inhibitors of drug binding. Analysis of the binding data of furosemide at its therapeutic concentration (6.6 mg/L) indicated that, among the four uremic toxins studied, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) showed the greatest inhibitory potency for the binding of furosemide to serum; moreover, the inhibition was competitive. CMPF thus most likely represents the primary determinant for the serum binding defect of furosemide in uremia. However, CMPF and oleate appear to exert a synergistic effect on the inhibition of furosemide serum binding--perhaps through a cascade effect on furosemide-binding inhibition in the oleate-CMPF-furosemide system, in which the binding of oleate to its low-affinity sites indirectly displaces furosemide from albumin and thus increases the transiently liberated CMPF molecules. Similar cascade effects on furosemide binding in the presence of CMPF were also originated by other long-chain (C18) fatty acids, linoleate and stearate, although to a lesser extent. Because CMPF is not effectively removed by ordinary hemodialysis treatment, the combined direct and cascade effects of CMPF and fatty acids appear to contribute to the increase in the free fraction of furosemide during hemodialysis.

Adult↗

PubMed1983

Biotransformation of furosemide in kidney transplant patients.

The metabolic fate of furosemide was studied in kidney transplant patients after oral and intravenous administration of the diuretic at therapeutic doses. Serial urine samples were collected over a 24 h period and furosemide was analyzed by a specific high performance liquid chromatographic method using fluorescence detection. We found no evidence of the putative furosemide metabolite, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA), in any of the samples analyzed. The amount of furosemide excreted as the glucuronide metabolite accounted for 8% of the available dose, whether administered orally or by intravenous infusion. In addition, the significant positive correlation observed between the percent of the available dose excreted as furosemide glucuronide and the renal clearance of furosemide (r = 0.581, p less than 0.02) suggests that the glucuronidation process for furosemide may be occurring in the kidney. Furosemide and its glucuronide metabolite accounted for only 45% of the intravenous dose recovered in the urine. Biliary excretion of unchanged furosemide and/or furosemide glucuronide into the feces probably accounts for the remainder of the dose not recovered.

Biotransformation↗

PubMed1982

Rapid increase of mineralocorticoids after furosemide in low-renin essential hypertension: evidence for 18-hydroxycorticosterone to be a better marker than aldosterone.

The response of plasma renin activity (PRA), plasma aldosterone, 18-hydroxycorticosterone (18-OH-B), 18-hydroxydeoxycorticosterone (18-OH-DOC) and corticosterone to furosemide were compared in 20 normal control subjects, 16 patients with normal-renin essential hypertension (NREH) and 12 patients with low-renin essential hypertension (LREH). Analyses were performed before medication, and 15 min (supine) and 120 min (active orthostasis) after IV administration of 40 mg furosemide. In normotensive subjects PRA increased 15 min after administration of furosemide from 0.8 +/- 0.4 ng AI/ml . h (SD) to 3.4 +/- 1.4 (P less than 0.01), plasma aldosterone from 109 +/- 28 pg/ml to 139 +/- 40 (less than 0.01) and 18-OH-B from 199 +/- 90 to 279 +/- 85 (P less than 0.01). In patients with NREH, PRA increased significantly less (P less than 0.01) and no significant increase of plasma aldosterone or 18-OH-B was found. PRA of patients with LREH (0.2 +/- 0.1 ng AI/ml . h) remained practically unchanged 15 min after furosemide administration, but in contrast to NREH aldosterone increased from 111 +/- 37 to 160 +/- 66 (P less than 0.05) and 18-OH-B from 162 +/- 101 to 261 +/- 71 pg/ml (P less than 0.01). The relative increase in plasma 18-OH-B was significantly greater in patients with LREH than in patients with NREH. The plasma levels of aldosterone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide erone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide erone and 18-OH-B 120 min after furosemide administration were significantly higher in normotensive subjects than in either hypertensive group (P less than 0.01). Corticosterone and 18-OH-DOC levels were the same in all investigated groups and increased significantly (P less than 0.01) only at 120 min after furosemide administration combined with active orthostasis. In summary, our results support the concept that sensitivity of the mineralocorticoid-producing cells is enhanced in patients with LREH. Postfurosemide 18-OH-B seems to be a better marker of this phenomenon than aldosterone.

18-Hydroxycorticosterone↗

PubMed1984

Thiol-dependent passive K/Cl transport in sheep red cells: IV. Furosemide inhibition as a function of external Rb+, Na+, and Cl-.

The effect of the loop diuretic furosemide (4-chloro-N-furfuryl-5-sulfamoyl-anthranilic acid) on the thiol-dependent, ouabain-insensitive K(Rb)/Cl transport in low K+ sheep red cells was studied at various concentrations of extracellular Rb+, Na+ and Cl-. In Rb+-free NaCl media, 2 X 10(-3) M furosemide inhibited only one-half of thiol-dependent K+ efflux. In the presence of 23 mM RbCl, however, the concentration of furosemide to produce 50% K+ efflux inhibition (IC50) was 5 X 10(-5) M. In Rb+ containing NaCl media, the inhibitory effect of 10(-3) M furosemide was equal to that caused by NO-3 replacement of Cl- in the medium. The apparent synergistic action of furosemide and external Rb+ on K+ efflux was also seen in the ouabain-insensitive Rb+ influx. A preliminary kinetic analysis suggests that furosemide binding alters both maximal K+(Rb+) transport and apparent external Rb+ affinity. In the presence of external Rb+, Na+ (as compared to choline) exerted a small but significant augmentation of the furosemide inhibition of K+(Rb+) fluxes. There was no effect of Cl- on the IC50 value of furosemide. As there is no evidence for coupled Na+K+ cotransport in low K+ sheep red cells, furosemide may modify thiol-dependent K+(Rb+)/Cl flux or Rb+ (and to a slight degree Na+) modulate the effect of furosemide.

Animals↗

PubMed1997

Intratracheal furosemide in infants after cardiac surgery: its effects on lung mechanics and urinary output, and its levels in plasma and tracheal aspirate.

OBJECTIVE: Recent studies have suggested direct pulmonary effects of furosemide in asthmatics and infants with bronchopulmonary dysplasia. We tested the hypothesis that intratracheally administered furosemide also increases respiratory compliance in children after cardiac surgery, and investigated whether furosemide has a topical and/or systemic action. STUDY DESIGN: Prospective study with intra-individual control. In twelve infants and toddlers (age: 10 +/- 8 months, weight: 6.9 +/- 3 kg) mechanically ventilated for compromised lung mechanics after cardiac surgery, 0.5 mg/kg furosemide was intratracheally administered to the lungs. Lung mechanics were serially assessed using a computerised system (Sensormedics 2600) during a 2 h control and 2 h intervention period. Urine output was measured by an indwelling bladder catheter and levels of furosemide were determined in blood and tracheal aspirates. RESULTS: Static compliance improved within 30 min in all patients, reached a maximum of 44 (20-85)% above baseline and remained improved throughout the study (p < 0.05). An immediate, short and significant diuretic effect of intratracheally applied furosemide was observed. Furosemide levels 1 h after intervention were 795 ng/ml in the blood and 431 micrograms/ml (i.e. 1000-fold higher) in the tracheal aspirate. Changes in compliance were correlated only to urine output values over the 2 h (r = 0.82, p = 0.044, n = 9) after furosemide administration. CONCLUSION: We conclude that intratracheally applied furosemide improves static compliance in infants and toddlers with compromised lung mechanics after cardiac surgery. We demonstrated that furosemide is absorbed from the lung and has a systemic effect within 15 min after its intratracheal instillation.

Administration, Topical↗

PubMed1982

Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia.

The effect of combined hydrochlorothiazide and furosemide therapy was studied in eight hypertensive patients with renal insufficiency who had poor response to either furosemide or hydrochlorothiazide alone. The study was divided into two parts. In part A, five patients had an inadequate response to furosemide in doses of 160 to 240 mg/day followed a strict protocol in order to compare the effect of increased doses of furosemide with combined hydrochlorothiazide-furosemide administration. All had azotemia, presumable from nephrosclerosis, and had serum creatinine concentrations ranging from 2.3 to 4.9 mg/dl. Four of the five patients had inadequate arterial pressure control, and the remaining patients had fluid retention from the administration of minoxidil. In all five patients, plasma volume was either increased or normal, despite long-term treatment with furosemide. Increasing the dose of furosemide to between 320 and 480 mg/day had only a modest additional diuretic effect, and plasma volume and arterial pressure were not significantly changed. Adding hydrochlorothiazide, 25 to 50 mg twice a day, produced a marked diuresis, and a significant reduction in weight, plasma volume and mean arterial pressure (p less than 0.025 for all three patients). In part B, combined hydrochlorothiazide-furosemide therapy was used to treat three additional patients who had an inadequate response to either diuretic alone. The results indicate that combined hydrochlorothiazide-furosemide is a potent diuretic regimen and is effective in many patients wit chronic renal failure who have a poor response to furosemide alone.

Adult↗

PubMed1981

Occurrence of passive furosemide-sensitive transmembrane potassium transport in cultured cells.

Furosemide (1 x 10(-4) M) inhibits a proportion of the total passive (ouabain-insensitive) K+ influx into primary chick heart cell cultures (85%), BC3H1 cells (75%), MDCK cells (40%) and HeLa cells (57%). This action of furosemide upon K+ influx is independent of (Na+ + K+)-pump inhibition since the furosemide-sensitive component of the K+ influx is identical in the presence and absence of ouabain (1 x 10(-3) M). For HeLa cells the passive, furosemide-sensitive component of K+ influx is markedly dependent upon the external K+, Na+ and Cl- content. Acetate, iodide and nitrate are ineffective as substitutes for Cl-, whereas Br- is partially effective. Partial Cl- replacement by NO3- gave an apparent affinity of 100 mM [Cl]. Na+ replacement by choline+ abolishes the furosemide-sensitive component, whereas Li+ replacement reduces this component by 48%. Partial Na+ replacement by choline+ gives an apparent affinity of 25 mM [Na+]. Variation in the external K+ content gives an affinity for the furosemide-sensitive component of approx. 1.0 mM. Furosemide inhibition of the passive K+ influx is of high affinity, half-maximal inhibition being observed at 5 x 10(-6) M furosemide. Piretanide (1 x 10(-4) M) and phloretin (1 x 10(-4) M) inhibit the same component of passive K+ influx as furosemide; ethacrynic acid and amiloride (both 1 x 10(-4) M) partially so. The stilbene, SITS (1 x 10(-6) M), was ineffective as an inhibitor for the furosemide-sensitive component.

Animals↗

PubMed2004

Furosemide and the progression of left ventricular dysfunction in experimental heart failure.

OBJECTIVES: We tested the hypothesis that furosemide accelerates the progression of left ventricular systolic dysfunction in a tachycardia-induced porcine model of heart failure. BACKGROUND: Furosemide activates the renin-angiotensin-aldosterone system in patients with congestive heart failure (CHF). Such activation may contribute to CHF progression, but prospective data are lacking. METHODS: Thirty-two Yorkshire pigs were randomized to furosemide (1 mg/kg intramuscularly daily, mean 16.1 +/- 0.9 mg) or placebo. Thereafter, a pacing model of heart failure was utilized to produce systolic dysfunction in both sets of animals (fractional shortening <0.16 by echocardiogram). The goal was to determine if furosemide would accelerate the progression of left ventricular dysfunction in the "treated" group. After sacrifice, sodium-calcium exchanger currents and their responsiveness to isoproterenol were measured during voltage clamp. All investigators were blinded to treatment assignment. RESULTS: Furosemide shortened the time to left ventricular dysfunction (35.1 +/- 5.1 days in placebo versus 21.4 +/- 3.2 days for furosemide animals; p = 0.038, log-rank test). By day 14, aldosterone levels were significantly higher in furosemide animals (43.0 +/- 11.8 ng/dl vs. 17.6 +/- 4.5 ng/dl; p < 0.05). Serum sodium was reduced (133.0 +/- 0.9 mmol/l furosemide vs. 135.7 +/- 0.8 mmol/l placebo; p < 0.05), but no difference in norepinephrine, potassium, magnesium, creatinine, or urea nitrogen was present. Basal sodium-calcium exchanger currents were significantly increased and isoproterenol responsiveness depressed by furosemide. CONCLUSIONS: Tachycardic pigs given furosemide had significant acceleration of both contractile and metabolic features of CHF, including left ventricular systolic dysfunction, elevated serum aldosterone levels, and altered calcium handling in a controlled experimental model of heart failure.

Adrenergic beta-Agonists↗

PubMed2000

Activation of renal afferent pathways following furosemide treatment. I. Effects Of survival time and renal denervation.

Three experiments were performed to determine whether renal afferent pathways were activated by the diuretic drug, furosemide. It was hypothesized that activated neurons of the renal afferent pathway would express the protein product Fos of the c-fos immediate early gene and be identified by immunocytochemical staining for Fos in the cell nucleus. In the first two experiments, rats were injected with either furosemide (5 mg) or vehicle solution (sterile isotonic saline) and sacrificed either 1.75 h (short-survival experiment) or 3.5 h (long-survival experiment) after injection. In both experiments, the furosemide-treated rats had significantly more Fos-positive cell nuclei than vehicle-treated rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nuclei (SON), and magnocellular region of the paraventricular nuclei (PVN) - areas previously shown to be activated by hypovolemia or peripheral angiotensin. In the short-survival experiment, the furosemide-treated rats had more Fos-positive cell nuclei in the nucleus of the solitary tract (NTS) and in the dorsal horn of the spinal cord at spinal levels T(11), T(12), and T(13). In contrast, furosemide treatment did not produce more Fos-positive cell nuclei in the NTS and dorsal horn of the spinal cord in the long-survival experiment. These results suggest that the activation of the SFO, OVLT, SON and PVN may be via a different mechanism than that of NTS or spinal cord dorsal horn. Based upon our previous work, we hypothesized that the NTS and spinal cord dorsal horn labeling was due to activation of sympathetic afferents originating in the kidney and labeling in forebrain structures was due to stimulation by angiotensin generated by renal renin release. To test this hypothesis, a third experiment was devised that was identical to the short-survival experiment, except that all rats had bilateral renal denervation surgery 1 week previously. In this experiment, furosemide administration increased the number of Fos-positive cells in the SFO, OVLT, SON and PVN, but not in the caudal thoracic spinal cord or NTS. These results together with the results of first two experiments lend support to our hypothesis that furosemide-induced neuronal activation in the thoracic spinal cord and NTS is due to activation of second- and/or third-order neurons of a renal sympathetic afferent pathway. Furosemide-induced activation in the SFO, OVLT, SON and PVN does not depend on renal innervation. It is hypothesized that activation in these forebrain regions depends on the action of angiotensin II that is generated after furosemide treatment. Our results indicate that both a hormonal pathway and a renal sympathetic afferent pathway conduct information from the kidney to the central nervous system (CNS) after furosemide treatment.

Afferent Pathways↗

PubMed2003

In vivo and in vitro antioxidant properties of furosemide.

The aim of this study was to investigate in vivo and in vitro antioxidant properties of furosemide. In vitro, human red blood cells were submitted to oxidative stress (AAPH), in absence or in presence of different concentrations of furosemide. Potassium efflux was measured in order to quantify the oxidative stress after the action of AAPH on red blood cells. Allophycocyanin assay was also used to investigate antioxidant capacities of furosemide. For the in vivo experiment, male Wistar rats were used. A control group (n = 5) was treated by a daily intraperitoneal injection of saline solution (0.2 ml); 2 other groups (J0 and J+) were treated for 7 days by one daily intraperitoneal injection of furosemide (0.10 mg/kg/day). In the J+group, the injection of furosemide was done one hour before the experiment, while in the J0 group the last injection of furosemide was done on the 6th day and an injection of saline was performed one hour before the experiment. On the day of experiment, a laparotomy was performed under general anesthesia and blood was collected from abdominal aorta. Oxidative stress and antioxidant capacities were evaluated on Wistar rat red blood cells and plasma. In vitro results (oxidative challenge with AAPH) showed that oxidative stress was decreased in presence of furosemide. This was due to a potent free radical scavenging effect of furosemide. In vivo studies confirmed that furosemide had antioxidant properties. These data may be of great relevance in clinical practice, considering the use of large doses of furosemide in patients presenting pathology involving the production of free radicals.

Amidines↗

PubMed2002

Mechanisms of GABA(A) receptor blockade by millimolar concentrations of furosemide in isolated rat Purkinje cells.

The action of diuretic furosemide on the GABA(A) receptor was studied in acutely isolated Purkinje cells using the whole-cell recording and fast application system. Furosemide blocked stationary component of GABA-activated currents in a concentration-dependent manner with IC(50) value > 5 mM at -70 mV. The inhibition was rapid in the onset, fully reversible and did not require drug pre-perfusion. The termination of GABA and furosemide co-application was followed by transient increase in the inward current 'tail' current, which was not observed when furosemide was continuously present in the solution. The degree of furosemide block did not depend on GABA concentration. Furosemide block increased with membrane depolarization. Five millimolar furosemide depressed GABA currents by 32.4+/-1.3% at -70 mV and by 76.7+/-5.0% at +70 mV. Analysis of the voltage dependence of the block suggests that furosemide binds at the site located within GABA(A) channel pore with a dissociation constant of 5.3+/-0.5 mM at 0 mV and electric distance of 0.27. Our results provide evidence that furosemide interacts with Purkinje cell GABA(A) receptors (most probably composed of alpha1beta2/3gamma2 subunits) through a low affinity site located in channel pore and suggest that furosemide acts as a sequential open channel blocker, which prevents the dissociation of agonist while the channel is blocked.

Animals↗

PubMed1999

Immunosuppressive and cytotoxic effects of furosemide on human peripheral blood mononuclear cells.

BACKGROUND: We have previously shown that children with mild asthma have a modest improvement in their pulmonary function tests after aerosolized furosemide. The mechanism of action is not known. The observation that furosemide possesses a similar profile of protection as sodium cromoglycate and nedocromil sodium suggests that furosemide may inhibit mediator production and release. OBJECTIVE: We studied the in vitro effects of furosemide on cytokine release from normal human peripheral blood mononuclear cells (PBMC) induced by E. coli lipopolysaccharide (LPS). METHODS: Peripheral blood mononuclear cells were isolated by density gradient centrifugation, stimulated with LPS and incubated at 37 degrees C with varying concentrations of furosemide, hydrocortisone, sodium cromoglycate, and nedocromil sodium for 24 hours. Supernatants were extracted and study for levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8). Intracellular IL-6 and TNF-alpha concentrations were also measured by cell cytometry. Cell viability was examined using XTT cell proliferation test and-measuring the release of lactate dehydrogenase (LDH). RESULTS: There was a significant reduction in levels of TNF-alpha and IL-6 at a furosemide concentration of 0.5 x 10(-2) M and a reduction in IL-8 levels at 10(-2) M. This inhibition was comparable to that found with equivalent molar concentrations of hydrocortisone. These findings were also confirmed with measurements of intracellular IL-6 and TNF-alpha by cell cytometry. High concentration of furosemide at 10(-2) M caused significant cellular cytotoxicity. CONCLUSION: These data suggest that furosemide may exhibit an anti-inflammatory effect. Specifically, the addition of furosemide resulted in decreased production of cytokines. This effect may be due to an immunosuppressive activity on monocytes as well as a direct cytotoxic effect at high furosemide concentrations.

Anti-Asthmatic Agents↗

PubMedDate not supplied

Clinical pharmacology of furosemide in children: a supplement.

Furosemide is one of the most effective and least toxic diuretics used in pediatric practice. Experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in its diuretic effect. Also, the drug appears to have anti-inflammatory properties. In children with different diseases who received orally or intravenously 1 to 2 mg/kg doses of furosemide, a statistically significant positive linear relationship was found between the drug urinary excretion rate and the urine flow rate, but log dose-response curves to the drug were found to vary depending on the disease and the route of the drug administration. No sigmoid-shaped log dose-response curve (ie, one approaching a zero response at very low furosemide urinary excretion rates and a maximum response at very high excretion rates) was attained, which may suggest that the capacity of the kidney tubules to respond diuretically to the aforementioned doses of furosemide was not exceeded in these patients. However, in infants with different diseases and reasonably normal renal function who required administration of this diuretic, a very steep log dose-response curve to a 1 mg/kg intravenous dose of furosemide was found, which may suggest that higher doses may not result in a significant increase in diuretic response. The lowest mean furosemide urinary excretion rate and its concentration in urine associated with a significant diuresis were found to be 0.58 +/- 0.33 microg/kg/min and 24.2 +/- 10.5 microg/ml, respectively. Also, a significant correlation was found between the amount (in milligrams) of furosemide excreted in the urine during the first 6 hours after administration and the urine volume collected during that time. Patients with cystic fibrosis appeared to have a markedly more pronounced diuretic response to the average oral dose of 0.835 +/- 0.18 mg/kg than that reported in control children given 2 mg/kg. In children with acute renal failure caused by acute gastroenterocolitis or glomerulonephritis, a broad relationship was observed between a single intravenous dose and diuretic response after administration of furosemide (1.2 to 30.8 mg/kg). It was suggested that the total daily dose of the drug should not exceed 100 mg in these patients. Furosemide was found to be effective in management of bronchoconstriction accompanying chronic lung disease and narrowing of the upper respiratory airways; in hydrocephalus in infancy to avoid cerebrospinal fluid shunts; in some diagnostic procedures, such as an assessment of fetal and neonatal hydronephrosis; and in evaluation of different types of renal tubular acidosis. Among side effects accompanying clinical use of this drug were cholelithiasis in premature infants receiving total parenteral nutrition concomitantly with the diuretic; secondary hyperparathyroidism and bone disease in infants obtaining long-term furosemide treatment; and drug-induced fever.

Adolescent↗