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PubMed1978

Functional differences of ouabain and ethacrynic acid on renal potassium metabolism in dogs.

Current concepts provide inadequate explanations for the effects of ethacrynic acid (ECA) and ouabain (OUA) on renal potassium metabolism because neither the site of action, nor the tubular effects have been agrreed upon. In the present study on anaesthetized dogs, in vivo inhibitory effects of ECA on mitochondria or Na-K-ATPase were excluded. Firstly, ECA hardly reduced outer medullary metabolic rates in kidneys exposed to OUA and 2,4-dinitrophenol. Secondly, whereas OUA reduced renal Na-KATPase activity by 78% and induced parenchymal potassium release into the renal vein, none of these effects were observed during injection of ECA. During free flow, sodium reabsorption was equally reduced by the two drugs, but fractional potassium excretion was 0.54 +/-0.04 after OUA and 0.99 +/-0.02 after ECA. OUA alone or combined with ECA inhibited almost all ion transport in the distal 60% of the tubular volume as revealed by stop-flow. During ECA alone, chloride reabsorption was reduced more than sodium reabsorption because sodium was exchanged for potassium. ECA and SO4(2-) infusion produced similar stop-flow patterns. Thus, OUA is bound to Na-K-ATPases functionally located to the peritubular cell membrane. ECA promotes potassium secretion probably by inhibiting cellular anion entry at the luminal membrane.

Adenosine Triphosphatases↗

PubMed1999

Bimolecular glutathione conjugation kinetics of ethacrynic acid in rat liver: in vitro and perfusion studies.

The conjugation kinetics of glutathione (GSH) and ethacrynic acid (EA) were studied in rat liver perfusion studies, where efficient removal occurred (steady-state extraction ratio E(ss), approximately 0.8-0.4 at concentrations ranging from 10-200 microM) despite the appreciable plasma protein binding. The declining E(ss) paralleled the saturation in GSH conjugate (EA-SG) formation; EA-SG primarily appeared in bile as the unchanged glutathionyl adduct (90%) and minimally as cleavage products. The GSH conjugation of EA in perfused liver was described by the constants K(m)(overall) of 67 microM and V(max)(overall) of 0.23 micromol/min/g liver. These differed from those observed for the bimolecular nonenzymatic (constant of 126 microM(-1) min(-1)) and enzymatic (K(m) for GSH and EA were 1.2 mM and 94 microM, respectively; V(max) of 533 nmol/min/mg liver cytosolic protein or 32 micromol/min/g liver) GSH conjugation of EA in vitro. But they were similar to those estimated for EA uptake in isolated rat hepatocytes by saturable (K(m)(uptake) = 57 microM, and V(max)(uptake) = 0.55 micromol/min/g liver) and nonsaturable (0.015 ml/min/mg) processes. At increasing EA concentrations (>25 microM), time-dependent changes were observed for E(ss) and EA-SG formation, which rapidly decreased with time after the attainment of steady state due to the rapid loss of cellular GSH. The composite data were described adequately by a physiological model that accounted for transport and the GSH-dependent conjugation of EA. The results suggest that the rate-limiting process for hepatic EA GSH conjugation is cellular uptake, but cosubstrate availability controls the rate of metabolism when GSH becomes depleted.

Animals↗

PubMed1976

The acute hemodynamic effects of ethacrynic acid and furosemide in patients with chronic postcapillary pulmonary hypertension.

The acute hemodynamic effects of either ethacrynic acid or furosemide were studied in 27 patients who underwent diagnostic right and transseptal left heart catheterization. Twenth-three patients had postcapillary pulmonary hypertension secondary to isolated or predominant mitral stenosis. Of these, 21 patients were in New York Heart Association functional class III, and one each in class II and IV. In the remaining four patients pulmonary artery pressures were normal. Two patients had aortic stenosis and one each coronary artery disease and nonobstructive cardiomyopathy. All four patients were in class II. Cardiac index, pressures, and pulmonary blood volume (PBV) were measured in the control state and 20, 40, and 60 min after diuretic administration. Pulmonary extravascular fluid volume (PEV) was measured in the control state and at 60 min post drug infusion. A similar hemodynamic response was observed for each drug. Significant reductions in pulmonary artery and left atrial mean pressures, cardiac index, and plasma volume occurred over the one hour observation period and were accompanied by a significant duiresis. However, despite recutions in central pressures and blood flow, PBV, ev, and PEV/PBV remained unchanged, as did systemic arterial pressure. Since 23 of the subjects had postcapillary pulmonary hypertension it is postulated that the failure of PBV to decrease significantly despite significant decreases in pulmonary artery mean pressure is related to altered pressure volume characteristics in the pulmonary vascular bed in which the lung is operating on a steep portion of its pressure volume curve. The failure of the PEV to decrease supports the concept that the pulmonary extravascular space is relatively resistant to early decreases in pulmonary capillary pressure induced acutely. The failure of the pulmonary extravascular fluid volume to decrease despite a fall in plasma volume and pressures corresponds to the well recognized delay in resolution of radiologic evidence of pulmonary congestion.

Adult↗

PubMed1994

Effect of ethacrynic acid on aqueous outflow dynamics in monkeys.

PURPOSE: To determine the long-term effect of ethacrynic acid (ECA) on aqueous outflow dynamics in ocular normotensive monkeys. METHODS: (1) Twelve cynomolgus monkeys received 10 microliters of 2.5 mM (= 7.5 micrograms) ECA intracamerally in one eye, vehicle in the other; outflow facility (perfusion) was determined at 1 hour, 24 hours, or 1 week, and intraocular pressure (IOP; applanation) at 24 hours, 1 week, and 6 to 7 weeks later. Six other cynomolgi received 10 microliters of 0.13 or 1.3 mM phalloidin in one eye 45 minutes before receiving ECA OU; facility was measured 1 hour after ECA. (2) Groups of five rhesus monkeys underwent intracameral injection of 2.5, 5.0, or 10 micrograms ECA in one eye, vehicle in the other, with IOP measured hours to weeks thereafter. (3) Five rhesus monkeys received 540 micrograms of ECA unilaterally as a 30-microliter topical drop once daily for 4 days. On the first and fourth treatment days, baseline IOP, pupil diameter, and refraction were measured immediately before and again at 2, 4, and 7 hours after topical treatment. RESULTS: (1) ECA divided by vehicle facility averaged 1.83 +/- 0.23 (SEM) (P < 0.02, n = 6), 1.50 +/- 0.27 (P < 0.11, n = 7), and 1.05 +/- 0.10 (n = 7) at 1 hour, 24 hours, and 1 week, respectively. IOP was 1 to 2 mm Hg lower in ECA eyes 24 hours (P < 0.05, n = 5) and 6 to 7 weeks (P < 0.05, n = 7) after treatment. Phalloidin did not diminish the 1-hour ECA facility effect. (2) Five (but not 2.5 or 10) micrograms of ECA lowered IOP 1 to 3 mm Hg, starting at 2 hours and lasting up to 48 hours. The maximum ECA effect (-2.6 +/- 0.25 mm Hg; P < 0.001, n = 5) occurred at 4 hours. IOP, corneal thickness and endothelial cell count, and anterior chamber depth were not significantly different 8 weeks after 5 micrograms ECA or vehicle. (3) Once-daily unilateral topical application of 540 micrograms of ECA induced no change in IOP, refraction, or pupil diameter compared to contralateral vehicle-treated control eyes. There were no significant ECA-related ocular bio-microscopic abnormalities. CONCLUSIONS: ECA may lower IOP and increase outflow facility longer than previously thought, but not by affecting meshwork actin filaments.

Animals↗

PubMed1989

Design, synthesis, and testing of potential antisickling agents. 7. Ethacrynic acid analogues.

In search of a drug to treat sickle cell anemia, several analogues of the diuretic ethacrynic acid (ECA) have been synthesized and found equivalent in antigelling potency to ECA, but they have moderate or little diuretic activity. Structure-activity studies revealed that most of the highly active derivatives contain an acryloyl moiety. The latter functionality reacts covalently with protein sulfhydryl groups via a Michael addition reaction. Other derivatives, which lack the acryloyl moiety, showed notably lower antigelling activity. Since the antigelling assay is run under anaerobic conditions, activity implies a stereochemical inhibition of polymerization of deoxyhemoglobin S. The solubility ratios obtained from [HbS drug]/[HbS control] of several compounds (Table I) are near those expected for a drug with clinical potential (1.06-1.20 at tolerable doses in vivo).

Animals↗

PubMed1981

Renin release after furosemide and ethacrynic acid in man. Evidence for neural reflex control mechanisms.

The mechanisms of renin release after furosemide (F) and ethacrynic acid (EA) in man were examined. We evaluated whether acute volume shifts within the low pressure system after F induce renin release via neural pathways. Immersion in a water-bath or beta-blockade reduced the increase of plasma renin concentration after F but not after EA. It is concluded that acute renin release after F but not after EA in man is partially due to neurally mediated reflexes originating from volume receptors in the cardiopulmonary area.

Adult↗

PubMed2004

Effects of the new ethacrynic acid derivative SA9000 on intraocular pressure in cats and monkeys.

To evaluate the pharmacological characteristics of the new ethacrynic acid (ECA) derivative SA9000, we examined its ocular hypotensive effects in cats and cynomolgus monkeys, its corneal toxicity in rabbits, and its binding affinities for forty-three receptors, ion channels, and second messenger systems. A 20 microl injection into the anterior chamber of eye (intracameral injection) of 0.1 mM SA9000 significantly reduced intraocular pressure (IOP) 3.8 mmHg in cats. A 10 microl intracameral injection of 1 mM SA9000 significantly reduced IOP 7 mmHg in living monkeys without evidence of in vivo (or in vitro) toxicity. The ocular hypotensive effect of SA9000 in monkeys was greater than that of ECA. The morphology of corneal endothelial and epithelial cells in rabbit eyes after intracameral injection of SA9000 was observed using electron microphotography. SA9000 at 2 mM did not induce any abnormalities, indicating that it has no corneal toxicity at a concentration higher than the minimum needed for an ocular hypotensive effect (1 mM). SA9000 at 0.01 mM showed negligible binding affinity for, or inhibition of, forty-three different receptors, ion channel proteins, and second messenger systems. These findings indicate that SA9000 has the potential to be both effective and safe as an ocular hypotensive drug, although the mechanism of action remains unclear.

Animals↗

PubMed1995

Influence of ethacrynic acid on glutathione S-transferase pi transcript and protein half-lives in human colon cancer cells.

Ethacrynic acid (EA) is a plant phenolic acid that is both an inhibitor and an inducer of glutathione S-transferase (GST) activity. To determine contributory factors in the increased GST activity caused by EA treatment, human colon carcinoma HT29 cells were compared with a cloned EA-resistant population (HT6-8) maintained in medium containing 72 microM EA. Several factors are involved in the increased expression of GST pi in HT6-8. For example, nuclear run-on experiments showed an approximately 2-fold increase in the rate of transcription of GST pi. In addition, the half-life of GST pi transcript was increased from 4.1 (wild type, HT29, HT4-1) to 8.4 hr. The half-life of GST pi protein was 1-2 hr in HT4-1 cells versus 8-9 hr in HT6-8 cells. When either human ovarian carcinoma cells (SKOV3) or human prostatic carcinoma cells (DU145) were treated with EA, the half-life of the GST pi transcript was also increased. The transcript half-lives of another thiol-metabolism enzyme, gamma-glutamylcysteine synthetase (gamma-GCS), and a phase II detoxification enzyme, dihydrodiol dehydrogenase (DDH), were also increased in HT6-8, SKOV3 and DU145 cells treated with EA. However, the half-lives of transcripts from "housekeeping genes," such as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), beta-actin and beta-tubulin, were not changed in these cell lines following EA. Apparently, a number of coordinated factors are involved in EA-enhanced expression of GST pi and other detoxification enzymes.

Colonic Neoplasms↗

PubMed1981

Potentiating effects of cisplatin and ethacrynic acid in ototoxicity.

Seven milligrams per kilogram of body weight of cisplatin and 50 mg/kg of body weight of ethacrynic acid were given intravenously to guinea pigs. The threshold for Preyer's reflex, the cochlear microphonics (CM), and the endocochlear dc potential (EP) were measured during a four-day period after the injection. The changes in Preyer's reflex audiometry and the CM were more severe than that of the EP. These changes are greater than those that occur with the administration of each agent independently. The ototoxic interaction seemingly has a greater effect on the hair cells than on the stria vascularis. Baseline and periodic audiometry should be performed when both of these drugs are administered clinically.

Animals↗

PubMed1979

Ototoxic effects of the interaction between kanamycin and ethacrynic acid. Cochlear ultrastructure correlated with cochlear potentials and kanamycin levels.

The effects of the interaction between kanamycin (KAN) and ethacrynic acid (EA) on the ultrastructure of the guinea pig cochlea were studied 3, 4, 6, and 24 hours following administration of EA (40 mg/kg) to animals pretreated 2 h earlier with KAN (400 mg/kg). Appropriate saline (SAL) controls were included giving 4 treatments: KAN/EA, KAN/SAL, SAL/EA and SAL/SAL. The outer hair cells of the organ of Corti showed nuclear and plasma membrane changes at 3 h and were completely destroyed at 24 h. The inner hair cells were unaffected. Severe swelling was seen in the stria vascularis of both KAN/EA and SAL/EA animals at 3 h and was gone by 24 h. KAN/EA had a greater effect on the stria than had SAL/EA. These results were consistent with the time course of the effect of the drugs on the a.c. and d.c. endocochlear potentials. KAN concentrations in perilymph were unaffected by treatment with EA.

Animals↗

PubMed2003

Mitochondrial dysfunction and death in motor neurons exposed to the glutathione-depleting agent ethacrynic acid.

This study investigated the mechanisms of toxicity of glutathione (GSH) depletion in one cell type, the motor neuron. Ethacrynic acid (EA) (100 microM) was added to immortalized mouse motor neurons (NSC-34) to deplete both cytosolic and mitochondrial glutathione rapidly. This caused a drop in GSH to 25% of the initial level in 1 h and complete loss in 4 h. This effect was accompanied by enhanced generation of reactive oxygen species (ROS) with a peak after 2 h of exposure, and by signs of mitochondrial dysfunction such as a decrease in 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) (30% less after 4 h). The increase in ROS and the MTT reduction were both EA concentration-dependent. Expression of heme oxygenase-1 (HO-1), a marker of oxidative stress, also increased. The mitochondrial damage was monitored by measuring the mitochondrial membrane potential (MMP) from the uptake of rhodamine 123 into mitochondria. MMP dropped (20%) after only 1 h exposure to EA, and slowly continued to decline until 3 h, with a steep drop at 5 h (50% decrease), i.e. after the complete GSH loss. Quantification of DNA fragmentation by the TUNEL technique showed that the proportion of cells with fragmented nuclei rose from 10% after 5 h EA exposure to about 65% at 18 h. These results indicate that EA-induced GSH depletion rapidly impairs the mitochondrial function of motor neurons, and this precedes cell death. This experimental model of oxidative toxicity could be useful to study mechanisms of diseases like spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS), where motor neurons are the vulnerable population and oxidative stress has a pathogenic role.

Animals↗

PubMed2003

Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD-1 and suppression by N-acetyl-L-cysteine.

Since ethacrynic acid (EA), an SH modifier as well as glutathione S-transferase (GST) inhibitor, has been suggested to induce apoptosis in some cell lines, its effects on a human colon cancer cell line DLD-1 were examined. EA enhanced cell proliferation at 20-40 microM, while it caused cell death at 60-100 microM. Caspase inhibitors did not block cell death and DNA ladder formation was not detected. Poly(ADP-ribose) polymerase, however, was cleaved into an 82-kDa fragment, different from an 85-kDa fragment that is specific for apoptosisis. The 82-kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase 3. N-Acetyl-L-cysteine (NAC) completely inhibited EA-induced cell death, but 3(2)-t-butyl-4-hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were dose-dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen-activated protein kinase (MAPK) kinase (MEK) 1, extracellular signal-regulated kinase (ERK) 1 and GST P1-1 were increased in cells treated with 25-75 microM EA, while c-Jun N-terminal kinase (JNK) 1 and p38 MAPK were markedly decreased by 100 microM EA. NAC repressed EA-induced alterations in these MAPKs and GST P1-1. p38 MAPK inhibitors, SB203580 and FR167653, dose-dependently enhanced EA-induced cell death. An MEK inhibitor, U0126, did not affect EA-induced cell death. These studies revealed that EA induced cell death concomitantly with a novel PARP fragmentation, but without DNA fragmentation. p38 MAPK was suggested to play an inhibitory role in EA-induced cell death.

Acetylcysteine↗

PubMed1977

[Effect of ethacrynic acid on contractility and Ca flux of guinea pig taenia coli smooth muscle (author's transl)].

The effects of ethacrynic acid (ETCA) which has been known as an -SH groups inhibitor on the contractility and the Ca flux of guinea pig taenia coli were investigated. The results obtained were as follow: 1) Contractures induced by 10(-4) M ACh, or the tonic component of 150 mM K-contractures were markedly suppressed by previous treatment with a low concentration (2 X 10(-4) M) of ETCA for 40 min. Conversely with the same treatment, the phasic component of this K-contracture was only slightly suppressed. The inhibitory effects of ETCA in both cases were reversed by the repetitive washing out of ETCA from taenia coli with normal tris-buffered solution. 2) ETCA, at concentrations higher than 10(-3) M, more markedly inhibited the ACh-, and the K-contractures. In this case these inhibitions were irreversible. 3) Cysteine in an equimolar concentration of ETCA prevented the inhibitory effects of ETCA on both contractures. 4) ETCA (10(-4) M) inhibited the ACh-contracture in Ca2+-free isotonic KCl solution to approximately the same degree as that in normal solution. 5) Inhibition of ACh-contracture by ETCA in Na+-free isotonic LiCl solution was less than that in normal solution. 6) ETCA (2 X 10(-4), or 10(-3) M) markedly stimulated 45Ca efflux from taenia coli in 20 mM Ca-EGTA tris-buffered solution. 7) 45Ca efflux acceleration by ETCA in Na+-free (replaced by Li+) 20 mM Ca-EGTA tris-buffered solution was less than that in 20 mM Ca-EGTA tris-buffered solution. These results may be explained by assuming that the inhibitory effect of ETCA on ACh-contracture can be attributed to the depletion of stored intracellular Ca and the acceleration of Ca efflux as a result of ETCA treatment.

Acetylcholine↗

PubMed1994

Effects of topical ethacrynic acid ointment vs timolol on intraocular pressure in glaucomatous monkey eyes.

OBJECTIVE: To evaluate the long-term effects of ethacrynic acid (ECA) ointment, compared with timolol maleate on intraocular pressure (IOP) in cynomolgus monkey eyes with argon laser-induced glaucoma. METHODS: In a 5-day study, IOP was measured for 7 hours after once-daily topical applications of ECA ointment to four glaucomatous monkey eyes. For this study, ECA ointment was given in 0.5%, 1.0%, 1.5%, or 2.5% concentrations. In a separate 30-day study, IOP was measured after once-daily topical applications of ECA ointment in concentrations of 0.75% or 1.5%. The results were compared with IOP after the application of 0.5% timolol maleate administered twice daily on weekdays and once daily on weekends. RESULTS: In the 5-day study, 2.5% ECA ointment had the greatest effect on lowering IOP, with a maximum reduction of 8.5 +/- 2.9 mm Hg (mean +/- SEM). A more pronounced reduction in IOP was observed on the fifth day of treatment for each of the four concentrations. In the 30-day study, 1.5% ECA ointment or 0.5% timolol maleate reduced IOP as much as 11.5 +/- 3.7 mmHg and 14.0 +/- 4.5 mmHg, respectively. With repetitive dosing, the effect on IOP after using 1.5% ECA ointment increased with time. Mild eyelid edema, conjunctival hyperemia, and discharge were observed in some eyes treated with the highest concentrations. One eye of four treated with 1.5% ECA ointment for 30 days developed a superficial corneal erosion in the 30-day study. CONCLUSIONS: The ECA ointment reduced IOP in glaucomatous monkey eyes. This reduction was evident by the fifth day of treatment with all the concentrations tested. The reduction in IOP produced by once-daily treatment with 1.5% ECA ointment was comparable with that of 0.5% timolol maleate administered twice daily. Therefore, drugs in this class of compound may prove to be useful in glaucoma therapy.

Administration, Topical↗

PubMed1986

The effects of serum, lithium, ethacrynic acid, and a low external concentration of potassium on specific [3H]-ouabain binding to human lymphocytes after incubation for 3 days.

We have quantified specific [3H]-ouabain binding sites in normal human lymphocytes, and have measured the changes in the numbers of those sites which occur in response to various stimuli. We have confirmed previous findings that incubation for 72 h in the presence of fetal calf serum causes an increase in [3H]-ouabain binding, and that this does not occur if the cells are incubated in fetal calf serum which has first been dialysed. During incubation of the lymphocytes for 3 days in the presence of dialysed fetal calf serum each of the following stimuli caused an increase in specific [3H]-ouabain binding: addition of ethacrynic acid (1 mumol l-1), addition of lithium (1 mmol l-1), and reduction of the external potassium concentration (to 0.75 mmol l-1). By analogy with the similar results in HeLa cells reported by others, we suggest that the increase in [3H]-ouabain binding may, in the case of ethacrynic acid and the reduction of the external potassium concentration, be initiated by an increase in the intracellular sodium concentration. The mechanisms whereby fetal calf serum and lithium cause an increase in [3H]-ouabain binding are not clear.

Acridines↗

PubMed1999

Lipoxygenase-another pathway for glutathione conjugation of xenobiotics: A study with human term placental lipoxygenase and ethacrynic acid.

In this study, we examined the ability of human term placental lipoxygenase (HTPLO) to catalyze glutathione (GSH) conjugate formation from ethacrynic acid (EA) in the presence of linoleic acid (LA) and GSH. HTPLO purified by affinity chromatography was used in all the experiments. The results indicate that the process of EA-SG is enzymatic in nature. The reaction shows dependence on pH, the enzyme, and the concentration of GSH, LA, and EA. The optimal assay conditions to observe a maximal rate of EA-SG formation required the presence of 0.3 mM LA, 0.2 mM EA, 2.0 mM GSH, and approximately 300 microg HTPLO in the reaction medium buffered at pH 9.0. Under the experimental conditions employed, the reaction exhibited K(m) values of 1.1 mM, 200 microM, and 130 microM for GSH, LA, and EA, respectively. The estimated specific activity of HTPLO-catalyzed EA-GS formation was approximately 4.4 +/- 0.4 micromol/min/mg protein. This rate is more than twofold greater than the rate noted for the reaction mediated by the purified human term placental glutathione transferase. Under physiologically relevant conditions (20 microM LA, 2.0 mM GSH, at pH 7.4), HTPLO produced EA-SG at 56% of the maximal rate noted under optimal assay conditions. Nordihydroguaiaretic acid, the classical inhibitor of different lipoxygenases, significantly blocked the reaction. It is proposed that free radicals are involved in the process of EA-SG formation by HTPLO. The evidence gathered in this in vitro study suggests for the first time that lipoxygenase present in the human term placenta is capable of EA-SG formation.

Chromatography, Affinity↗

PubMed1992

Selective toxicity of ethacrynic acid towards lymphocytes of chronic lymphocytic leukemia in vitro.

We have used the MTT colorimetric assay to determine the sensitivity to ethacrynic acid of lymphocytes from normal donors and of peripheral blood cells from leukaemia patients. Whereas normal lymphocytes and cells from acute or chronic myeloid leukaemia showed similar sensitivities (median inhibitory dose, ID50 = 20-22 microM), lymphocytes from chronic lymphocytic leukaemia patients were much more sensitive (ID50 = 6 microM). This result was found irrespective of the assay duration.

Cell Survival↗

PubMed1978

The influence of ethacrynic acid, hydrochlorothiazide and clopamide on the renal excretion of chloramphenicol and its metabolites.

Simultaneous administration of chloramphenicol (1 g orally) and ethacrynic acid (150 mg orally), hydrochlorothiazide (25 mg orally) or clopamide (40 mg orally) increased the urinary excretion of chloramphenicol and its metabolites (aryl amines and total nitro compounds). The administration of diuretics did not change the time course of serum concentrations of substances under study. Since the urinary excretion of chloramphenicol and its metabolites is a urine flow-dependent process, the influence of the tested diuretics can be explained as a consequence of decreased tubular water reabsorption.

Adult↗