Independence of ethacrynic acid-induced renal hydrogen ion excretion of sodium-volume depletion in man.
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The effect of diuretics on Na+-K+-ATPase and c-AMP levels in toad bladder epithelial cells.
Na+-K+-ATPase was inhibited by 1 times 10-4M ethacrynic acid and mercuderamide, and by 1 times 10-3M hydrochlorothiazide and furosemide. A modification of Gilman's (1970) protein displacement assay has been used to measure c-AMP levels in toad bladder epithelial cells. Vasopressin (50 mU/ml) caused c-AMP levels to rise from 4.27 to 9.27 pmol/mg protein. Ethacrynic acid had no effect on cellular c-AMP levels after 10 min exposure to the drug, but at 90 min caused a reduction of both basal and vasopressin stimulated levels. Furosemide caused an apparent rise in c-AMP levels, dilution ratio measurements indicated interference by this drug in the assay procedure, mecuderamide also caused substantial interference with the c-AMP assay. Hydrochlorothiazide had no effect on basal or hormone stimulated levels of c-AMP. It was concluded that the inhibition of sodium transport produced by ethacrynic acid in toad bladder is probably due to inhibition of adenylate cyclase, an effect not shared by other dieuretics.
Adenosine Triphosphatases↗
A K+-activated, ethacrynic acid-sensitive p-nitrophenylphosphatase from normal human white cells.
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4-Nitrophenylphosphatase↗
Glomerulotubular balance and prostaglandin synthesis.
We have tested a hypothesis proposed to explain glomerulotubular balance (GTB) as a consequence of variations in prostaglandin synthesis. Arachidonic acid (40 micrograms x kg-1 x min-1) infused into the renal artery of anesthetized dogs raised renal blood flow (RBF) by 41 +/- 5% in hydropenic and by 24 +/- 11% in volume-expanded dogs, but the absolute changes were similar. The infusion of arachidonic acid after the administration of indomethacin (10 mg x kg-1) had no effect on RBF. Arachidonic acid infusion increased the excretion of sodium and chloride in hydropenic dogs but not after the administration of ethacrynic acid in volume-expanded dogs. During continued infusion of ethacrynic acid, the glomerular filtration rate (GFR) was lowered by suprarenal aortic constriction and raised by carotid constriction. A linear relationship between electrolyte reabsorption and GFR (GTB) was observed when GFR was varied between 20 and 110% of control. GTB and tubular reabsorption at comparable GFR were not significantly altered during arachidonic acid infusion or after indomethacin administration. In all experimental settings, bicarbonate, chloride, and sodium reabsorption were altered in molar ratios of 1:2:3 during variations in GFR. We conclude that GTB is independent of variations in prostaglandin synthesis.
Animals↗
How bicarbonate loading inhibits tubular reabsorption of NaCl in dog kidneys.
During continuous infusion of ethacrynic acid in dogs, changes in glomerular filtration rate (GFR) and PCO2 at constant plasma bicarbonate concentration (PHCO3) alter bicarbonate and chloride reabsorption in a ratio of 1:2. This ratio did not apply when PHCO3 was raised by bicarbonate loading in 11 anaesthetized volume-expanded dogs. A rise in PHCO3 from 30 to 54 mM at constant PCO2 and GFR reduced sodium reabsorption during ethacrynic acid infusion from 3586 +/- 725 to 2449 +/- 403 mumol min-1. Bicarbonate and chloride reabsorption were reduced in a ratio of 1:10. When plasma pH was restored from 7.8 to 7.5 by raising PCO2, the inhibitory effect on chloride reabsorption was halved. At constant plasma pH 7.5 a rise in PHCO3 from 20 to 30 mM reduced chloride reabsorption by 20%. A further 30% inhibition was caused by raising PHCO3 from 30 to 54 mM. Bicarbonate reabsorption was highest at PHCO3 54 mM, suggesting a large capacity for bicarbonate reabsorption if PHCO3 is raised at constant plasma pH 7.5. Water and NaCl reabsorption remaining during ethacrynic acid infusion is almost equally inhibited by alkalosis and by an osmotic effect of unreabsorbed NaHCO3.
Animals↗
The effect of loop diuretics upon summating potentials in the guinea pig.
Ototoxic diuretics, ethacrynic acid (50 mg/kg) and furosemide (80 mg/kg) were injected intravenously in guinea pigs. Cochlear microphonics (CM), summating potentials (SPs) and endocochlear potential (EP) were recorded with a microelectrode in scala media of the second turn. CM changes after the injection were comparable with changes in the EP: an initial decrease was followed by an increase which was significantly slower in the case of the ethacrynic acid. SP changes following either diuretic were different from the CM and EP changes. In the first phase, roughly corresponding with the EP decrease to negative values, all SPs irrespective of the original polarity, attained high positive values. The high positive SPs then decreased and 12-18 min after injection reversed polarity. In the late phase all sounds evoked high negative SPs. Approximately 90 min after injection of furosemide normal SPs were again recorded. The return of SPs to control values was very slow after ethacrynic acid; even 140 min after injection the SPs were abnormal. The observed changes in the SPs were compared with those found during asphyxia and anoxia and are considered to result from diuretic effects on the inner and outer hair cells.
Animals↗
Cyclo-oxygenase and lipoxygenase pathways in mast cell dependent-neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve.
1. We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic inflammation in rat paw skin. We compared the effect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2. Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a five-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) significantly inhibited (40 to 60%) the development of neurogenic oedema, but did not affect cutaneous blood flow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating effect. 3. Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not affect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, significantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4. COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5. A mast cell stabilizer, cromolyn, and a H(1) receptor antagonist, mepyramine, significantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6. The co-injection of LOX inhibitors and compound 48/80 did not alter the effects of compound 48/80. Conversely, ethacrynic acid had a significant potentiating effect. The pharmacological profile of the effect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7. The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not affect neurogenic or SP-induced oedema. 8. Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a significant role in this process.
Animals↗
Diuretics and small intestinal lymph flow in the dog.
Simultaneous measurements of thoracic duct lymph flow and small intestinal lymph flow were carried out in mongrel dogs after the administration of mannitol, ethacrynic acid, furosemide and chlorothiazide. Thoracic duct lymph flow increased only after injection of mannitol. Intestinal lymph flow increased after injection of all diuretics except chlorothiazide. Furthermore, mannitol produced simultaneous increases in thoracic duct and intestinal lymph flows. The durations of response of the increased lymph flows from each lymph channel produced by mannitol were statistically identical. The durations of increased intestinal lymph flows observed with each drug were: 40+/-3 (S.E.), 43+/-2 and 38+/-2 minutes for mannitol, ethacrynic acid and furosemide, respectively. Mean arterial blood pressures and inferior vena cava pressures did not change from the control to the experimental state in any animal studied. Similarly measurements of serum and lymph sodium, potassium and protein concentrations were unchanged from the control to the experimental state. These studies demonstrate that mannitol simultaneously increases thoracic duct lymph flow as well as intestinal lymph flow. Secondly, the results suggest that the increases in thoracic duct lymph flow after ethacrynic acid and furosemide administration, observed in previous studies arose primarily from the small intestine.
Animals↗
Role of macula densa in diuretics-induced renin release.
Diuretic therapy may enhance renin release by various mechanisms, principally contraction of extracellular fluid volume and its effects, including a fall in arterial pressure. Awake hydropenic or volume-expanded rats received diuretics (amiloride and hydrochlorothiazide) that are known inhibitors of NaCl transport beyond the macula densa; also the well-known Na(+)-K(+)-2 Cl- transport system inhibitor furosemide was administered. We also evaluated the effect of a dose of ethacrynic acid (a drug that shares the same mechanism of action as furosemide but is not diuretic in the rat). The direct action of the diuretics on renin-producing cells was examined in isolated glomeruli; a rise in renin release was observed with the calmodulin inhibitor trifluoperazine (10(-5) M). Renin release in intact hydropenic rats was not altered by diuretic therapy, but furosemide increased plasma renin activity in hydropenic as well as in volume-expanded rats. This demonstrates the importance of furosemide inhibition of transport in the macula densa for its renin secretory action. None of the diuretics (amiloride, hydrochlorothiazide, ethacrynic acid, or furosemide) elicited changes in renin release from glomeruli (10(-6) to 10(-3) M); amiloride and hydrochlorothiazide (10(-4) to 10(-3) M) did not change renin release from slices, but 10(-3) M ethacrynic acid and furosemide increased renin secretion in this preparation. This suggests that an effect on the macula densa is essential in loop diuretic-mediated renin release.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Metabolic adaptation of renal carbohydrate metabolism. V. In vivo response of rat renal-tubule gluconeogenesis to different diuretics.
We have studied the effects of the diuretics mersalyl, furosemide and ethacrynic acid on renal gluconeogenesis is isolated rat-kidney tubules and on the activities of the most important gluconeogenic and glycolytic enzymes in both fed and fasted rats. Mersalyl (15 mg.kg-1 animal weight) significantly decreased the rate of gluconeogenesis in well-fed rats (68%) as well as in 24 and 48-h fasted ones (33 and 37% respectively). This inhibition occurred when lactate, pyruvate, glycerol or fructose were used as substrates. Ethacrynic acid at a dose of 50 mg.kg-1 animal weight provoked a transient inhibition of renal glucose production by almost 20% but only in fed rats with lactate as substrate, whereas the same dose of furosemide did not affect this metabolic pathway. Parallel to these changes, mersalyl caused a significant inhibition in the maximum activity of the most important gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase and glucose 6-phosphatase, in both fed and fasted rats. Neither ethacrynic acid nor furosemide produced any variations in the activities of these enzymes. The activity of the glycolytic enzymes phosphofructokinase and pyruvate kinase was not modified by these diuretics. Nevertheless, the activity of the thiol-enzyme glyceraldehyde 3-phosphate dehydrogenase was severely inhibited by mersalyl and to a lesser extent by the other diuretics. This inhibition was higher in fasted than fed rats. Hence, we conclude that the inhibitory effect of mersalyl on renal gluconeogenesis is due, at least partly, to a decrease in the flux through the gluconeogenic enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pathogenetic relationships between renal tubular acidosis and sodium metabolism alterations in liver cirrhosis.
5 cirrhotic patients with latent distal renal tubular acidosis (RTA) and 5 cirrhotic patients with normal distal acidification ability were studied. All the patients were maintained on a 80 mEq/day sodium diet for at least 5 days before the study. Only 2 of the 5 patients with RTA showed a reduced daily sodium excretion while the 3 other patients with RTA had a normal natriuresis. Acidification ability was retested in all the patients after increasing sodium distal delivery by intravenous administration of ethacrynic acid. Some hours after the maximal natriuretic effect induced by ethacrynic acid, a normalization of the acidification test was seen in all patients with RTA. These findings support the concept that although sodium metabolism alterations are not the only factor in the pathogenesis of RTA in liver cirrhosis, reduced availability of sodium at the distal tubule may impair tubular acidification, probably by influencing the distal transtubular potential difference.
Acidosis, Renal Tubular↗
Direct nitric oxide release from nipradilol in human coronary arterial smooth muscle cells observed with fluorescent NO probe and NO-electrode.
BACKGROUND:: Nipradilol (3,4-dihydro-8-[2-hydroxy-3-isopropyl-amino]propoxy-3-nitroxy-2-H-1-benzopyran), a potent non-selective beta-adrenoceptor antagonist, has been shown to increase NO production. The mechanisms are up-regulation of nitric oxide synthase (NOS) and direct release of NO from nipradilol. The process of direct NO release from nipradilol requires a reductase, such as glutathione S-transferase (GST) in some cells but non-enzymatic NO release was reported in pig coronary arteries. Direct NO release from nipradilol in human coronary arteries has not been examined yet, though this information is of importance. PURPOSE:: To demonstrate direct NO release from nipradilol in human coronary arterial smooth muscle cells (HCASMC) by using a fluorescent NO probe (DAF-2) and an NO-electrode. METHODS AND RESULTS:: HCASMC were loaded with DAF-2 and images of fluorescence (515nm) were obtained under excitation at 488nm through an intensified CCD with an inverted phase-contrast microscope. Concomitantly, NO was measured using an NO-electrode (0.2mm o.d.; 501, Inter Medical Co. Ltd., Nagoya, Japan) after addition of various concentrations of nipradilol (1, 5 or 10microM) with or without ethacrynic acid (GST inhibitor). The cells showed no fluorescence at baseline, but intense fluorescence appeared at 30min after addition of 10microM nipradilol. The intensities of fluorescence at 30min in the control, nipradilol and nipradilol with ethacrynic acid groups were 98 +/- 6, 163 +/- 10 and 128 +/- 6% of the baseline level, respectively. Ethacrynic acid itself did not affect the fluorescence. Continuous measurements of NO by the electrode showed the NO generation peaked at about 30min, remained at the same level till about 45min and then gradually declined. Nipradilol did not produce NO at all in the absence of cells. The dose-dependency study of NO release from nipradilol showed 45 +/- 12, 72 +/- 24 and 157 +/- 23nM, respectively, at 1, 5 and 10microM nipradilol. All experiments were performed under conditions where endogenous formation of NO was inhibited by an NOS inhibitor (10(-4)M N(G)-monomethyl-l-arginine (l-NMMA)). CONCLUSION:: Nipradilol can release NO in the presence of human coronary arterial smooth muscle cells and the denitration reaction catalyzed by a reductase such as glutathione S-transferase contributes substantially to NO release from nipradilol.
Journal Article↗
Characterization of Na-K-ATPase in dog tracheal epithelium: enzymatic and ion transport measurements.
The dog tracheal epithelium actively secretes Cl and absorbs Na. The possible dependency of this electrolyte transport on a Mg-dependent, Na-K-activated adenosine triphosphatase (Na-K-ATPase, EC 3.6.1.3) was examined. The characteristics of this enzyme system were investigated using homogenates of tracheal epithelium. The electrical properties and ion fluxes of this epithelium were determined in tissues mounted in Ussing chambers. Addition of Na and K produced an approximate 50% activation of basal Mg-ATPase activity. The apparent Km values for ATP, Na, K, and Mg were 0.4, 12.7, 1.9, and 1.6 mM, respectively. The total specific ATPase activity was 8.1 +/- 0.4 and that of the Mg-ATPase 4.3 +/- 0.1 mumol Pi. mg protein -1.h-1. Addition of ouabain (1 muM) or omission of K from the submucosal bathing solution reduced potential difference (PD) and short-circuit current (SCC) significantly. Relatively low concentrations (0.1 mM or less) of ethacrynic acid, furosemide, or 2,4-dinitrophenol (2,4-DNP) depressed SCC and PD significantly, i.e., at concentrations that were without effect on the Na-K-ATPase activity. Ethacrynic acid inhibited Cl secretion, whereas 2,4-DNP lowered both Na and Cl transport. These data demonstrate that 1) the tracheal mucosa of dogs contains a Na-K-ATPase at relatively high specific activity, 2) this enzyme is likely contained in the basal aspect of this membrane, 3) it appears to be essential for maintenance of Cl secretion, and 4) Cl secretion can be reduced (by ethacrynic acid, furosemide, and 2,4-DNP) without Na-K-ATPase inhibition.
Animals↗
Combined effect of 3', 4'-dideoxykanamycin B and potent diuretics on the cochlea. (A scanning and transmission electron microscopic evaluation).
In investigations on the action of DKB (3' 4'-dideoxykanamycin B), and aminoglycoside type drug, on the inner ears of mice and guinea pigs by means of scanning and transmission electron microscopy, it was evident that the action of DKB against the inner ear is similar to that of kanamycin. When the same type of investigation was performed using the diuretics furosemide and ethacrynic acid, changes were observed in the stria vascularis. When DKB and ethacrynic acid, which show no long lasting defects when given independently, were administered concurrently in the same doses, a very high level of degeneration was found in the organs of Corti of guinea pigs. From the above results, it is evident that when two or more types of ototoxic drugs are administered concurrently, they have a potentiating action on the ear and care should be taken clinically concerning this point.
Animals↗
Analysis of energy metabolism and mechanism of loop diuretics in the thick ascending limb of Henle's loop in dog kidneys.
AIM: The thick ascending limb of Henle's loop (TALH) absorbs up to 40% of filtered NaCl in volume-expanded dogs. To examine if a fraction of this absorption is passive, NaHCO3 absorption and associated NaCl absorption in proximal tubules were inhibited by acetazolamide, a carbonic anhydrase inhibitor. RESULTS: Ouabain, a specific inhibitor of Na,K-ATPase activity, reduced the remaining NaCl absorption and renal oxygen consumption in a ratio DeltaNa/DeltaO2 = 18, as expected for active transport. However, the responses to two loop diuretics were DeltaNa/DeltaO2 = 24 for ethacrynic acid and DeltaNa/DeltaO2 = 30 for bumetanide. Both loop diuretics induced potassium secretion. By superimposing ouabain potassium secretion was stopped and DeltaNa/DeltaO2 = 18 restored. Replacement of half of the circulating NaCl with Na2SO4 gave stop-flow pattern similar to those obtained after ethacrynic acid. CONCLUSIONS: Low entry of some sodium ions thorugh the apical membrane is permitted despite low chloride supply or blockade by loop diuretics of chloride entry by the Na-K-2Cl transporter. Continued Na-K-ATPase activity causes secretion of potassium ions through the apical ion channel, ethacrynic acid being more kaliuretic and less natriuretic than bumetanide. Greater paracellular recycling of sodium ions after bumetanide maintains ionic balance. In contrast, under normal conditions excess entry of chloride by the Na-K-2Cl-transporter leads to paracellular back-diffusion of chloride rather than paracellular absorption of sodium ions, consistent with DeltaNa/DeltaO2 = 18 after ouabain. Thus all NaCl transport along TALH is active in vivo, whereas absorption of other cations, such as lithium, probably is passive.
Absorption↗
A method for screening diuretic agents in the mouse: an investigation of sexual differences.
Acetazolamide, aminophyline, frusemide, ethacrynic acid and triamterene were tested for diuretic action at dosages of 3, 10 and 30 mg kg-1 (s.c.) in male and female mice. Each drug significantly raised sodium excretion and all but acetazolamide elevated urine volume and chloride excretion. Potassium excretion was significantly raised by acetazolamide and frusemide. Acetazolamide and triamterene evoked urinary alkalinization whereas frusemide and ethacrynic acid reduced urinary pH. Female mice were markedly more sensitive than males to the diuretic, natriuretic, chloruretic and urinary acidfying actions of ethacrynic acid.
Animals↗
Effect of alkali-treated lipopolysaccharide on the intracellular cations of human erythrocytes.
The adsorption to human erythrocytes of Escherichia coli lipopolysaccharide treated by mild alkaline hydrolysis (h-LPS) stimulated an increase in the intracellular Na+ concentration and a decrease in the intracellular K+ concentration of the erythrocytes. Erythrocytes treated by h-LPS remained responsive to the membrane adenosine triphosphatase inhibitors ouabain and ethacrynic acid, indicating that hLPS did not alter erythrocyte cations be depleting energy intermediates or uncoupling energy metabolism from active cation transport. The h-LPS-treated erythrocytes became non-agglutinable by the lectin concanavalin A prior to the development of changes in intracellular cations. In addition, h-LPS-treated erythrocytes demonstrated a three-fold greater cation response to ethacrynic acid than the untreated erythrocytes; this greater response was probably due to local membrane effects by h-LPS on the ethacrynic acid-sensitive adenosine triphosphatase. It is suggested that the h-LPS-induced alteration of erythrocyte cation content was secondary to an increase in ion permeability localized to the concanavalin A receptor regions of the erythrocyte membrane, possibly combined with indirect effects of membrane-bound h-LPS on ethacrynic acid-sensitive adenosine triphosphatase.
Agglutination↗
Partial isolation and characterization of the 15-hydroxyprostaglandin dehydrogenases and 9-ketoprostaglandin reductases in rabbit kidney.
Three types of 15-hydroxyprostaglandin dehydrogenase were identified in rabbit whole kidney homogenate when the centrifuged homogenate was sequentially fractionated by ammonium sulfate precipitation, DEAE-cellulose and Matrex Gel Blue A chromatographies, and Sephadex gel filtration. The first type is not adsorbed to DEAE-cellulose (peak 1). It catalyzes oxidoreduction of prostaglandins at both the C-15 and C-9 positions, is more active with NADP than NAD, is inhibited by indomethacin and ethacrynic acid, and migrates as three bands on disc gel electrophoresis. The second type is adsorbed to DEAE-cellulose (peak 2). It also migrates as multiple electrophoretic bands, has similar catalytic actions and co-factor requirements as the peak 1 enzyme and is inhibited by indomethacin and ethacrynic acid. A third type of 15-hydroxyprostaglandin dehydrogenase is also adsorbed to DEAE-cellulose but is partially separable from the other peak 2 enzymes on Matrex Gel Blue A and differs from those enzymes in preferentially oxidizing PGI2. It migrates as a single electrophoretic band and is also inhibited by indomethacin and ethacrynic acid.
Animals↗