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[Study of the binding of diuretics by serum proteins according to changes in tryptophan fluorescence].

The effect of diuretics on tryptophan fluorescence of blood serum proteins divided by electrophoresis was studied. It was shown that ethacrynic acid produces the most significant extinction of tryptophan fluorescence in albumin fraction and novurit in globulin fraction. Furosemide possessing a high affinity for all three obtained fractions of protein does not exhibit a preferential binding to one or another of these fractions. It was also found that furosemide and ethacrynic acid by binding to human serum albumin molecule produce its conformational alterations. Mercury diuretic does not possess such effect.

Alkylmercury Compounds↗
PubMed1998

Microtubule disruption leads to cellular contraction in human trabecular meshwork cells.

PURPOSE: To determine whether microtubule- and actin-altering drugs, which have been shown to increase aqueous humor outflow, cause cellular contraction in human trabecular meshwork (HTM) cells. METHODS: HTM cells were plated in culture dishes containing a polymerized deformable silicone substrate. After 48 hours, the dishes were placed on an inverted microscope and treated with ethacrynic acid, colchicine, vinblastine, cytochalasin B, or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and then recorded on videotape for 15 minutes. An increase in silicone substrate wrinkle size and/or number indicated a contraction. Sham controls were used. RESULTS: Cellular contraction was observed with ethacrynic acid, colchicine, and vinblastine in the 10(-5) to 10(-4) M dosage range. Pretreatment with H-7 blocked these effects. Cytochalasin B did not produce cellular contraction. CONCLUSIONS: Microtubule disruption causes cellular contraction in HTM cells, and this effect depends on an intact actin cytoskeleton network. Contraction of trabecular meshwork cells in response to various stimuli is an attractive hypothesis for possible homeostatic mechanisms in the outflow pathway, and this may serve as a focus for novel glaucoma drug development.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1980

Further observations on the utilization of adenosine triphosphate in rat mast cells during histamine release induced by the ionophore A23187.

1 The relation between A23187-induced histamine release and the energy metabolism of the rat mast cells has been studied. 2 Ethacrynic acid was used as an inhibitor of calcium-induced histamine release from mast cells primed with the ionophore A23187, and to study calcium-induced changes in the adenosine triphosphate (ATP) content and the rate of lactate production of A23187-primed mast cells. 3 Ethacrynic acid by itself decreased the rate of glycolytic ATP production. 4 By measurement of the ATP content and the lactate production of mast cells with or without secretory activity, the increased demand of energy for exocytosis was estimated to be equivalent to 0.14 pmol of ATP pr 10(3) mast cells.

Adenosine Triphosphate↗
PubMed1974

Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cyanide.

Microperfusion experiments have shown that increases in flow rate of tubule fluid through the loop of Henle are followed by reductions in single nephron glomerular filtration rate (SNGFR) and stop-flow pressure (SFP) measured in the proximal tubule of the same nephron. Because changes in luminal sodium concentration are not consistently related to changes in SNGFR and SFP, we explored the possibility that a transport step at a flow-dependent distal-sensing site might be involved in feedback control of SNGFR. Because the macula densa cells of the distal tubule are adjacent to the glomerular vessels of the same nephrons, they could be the distal-sensing mechanism. We perfused superficial loops of Henle from late proximal to early distal segments in three groups of rats while measuring SFP in the proximal tubule of the same nephron, SNGFR in the proximal tubule of the same nephron, or flow rates of fluid, Na, K, and Cl emerging from the perfused loops. Perfusion solutions used were 0.15 NaCl, Ringer or Ringer with one of several inhibitors of electrolyte transport. Perfusion rates were 10 or 40 nl/min (also, zero during measurements of SFP and SNGFR). With Ringer alone the loop-flow rate increased from 10 to 40 nl/min, caused a decrease in SFP from 37.6 to 32.1 mm Hg, and a decrease in SNGFR from 29.9 to 18.7 nl/min. Concentrations of Na, K, and Cl in early distal fluid and absorption of Na and Cl along the loop segment were also increased when loop perfusion rate was increased. Decreasing the perfusion rate to zero had little effect on SFP or SNGFR. The SFP response to increased flow rate did not occur when the perfusion solution contained furosemide (10(-4) M). No reduction of the SFP response was seen with other diuretics tested (amiloride, acetazolamide, ethacrynic acid, mercaptomerin) or with 0.15 M NaCl alone. The SNGFR response to increased perfusion rate was reduced by furosemide, triflocin, and cyanide but not by amiloride. Na and Cl absorption by the perfused segment were inhibited by furosemide, triflocin, cyanide, and amiloride. Amiloride and acetazolamide, probably do not act in the ascending limb. Ethacrynic acid and mercaptomerin are known to be ineffective in rat nephrons. Thus, agents that could have inhibited NaCl absorption by macula densa cells interfered with the feedback mechanism.

Acetazolamide↗
PubMed1989

The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary bladder.

1. The effects of some possible inhibitors of ectonucleotidases on the breakdown of extracellular ATP by strips of guinea-pig urinary bladder were investigated. 2. Suramin and ethacrynic acid (10 mM) both inhibited ATP breakdown significantly, and difluorodinitrobenzene (10 mM) inhibited it slightly whereas N-ethylmaleimide, adenosine 5'-(gamma-thiotriphosphate) (ATP-gamma-S) and reactive blue-2 (10 mM) were without effect. 3. The inhibitory effects of suramin on ATP breakdown were non-competitive. 4. Ethacrynic acid (1 mM) irreversibly inhibited contractions of the guinea-pig bladder induced by ATP, substance P, histamine, non-adrenergic, non-cholinergic nerve stimulation or KCl, whereas suramin (100 microM) had no inhibitory effect. 5. The results suggest that suramin might provide a starting point for the design of selective inhibitors of ectonucleotidases.

Adenosine Triphosphate↗
PubMed1985

Urinary sodium excretion and the renin-aldosterone system in new-born calves.

Urinary Na+ and K+ excretion, plasma aldosterone levels (PAL) and plasma renin activity (PRA) were measured in three groups of four 3-day-old calves infused with aldosterone, ethacrynic acid and hydrochlorothiazide or with vehicle. Aldosterone infusion (16.7 micrograms/kg body wt. given by rapid injection, followed by the infusion of 33.3 micrograms/kg body wt. during 6 h) decreased urinary Na+ concentration and excretion during the 6 h period of infusion. This effect disappeared during the following 18 h. Ethacrynic acid (2 mg/kg body wt. by rapid injection, followed by the infusion of 1.5 mg/kg body wt..h during 6 h) and hydrochlorothiazide (8 mg/kg body wt. by rapid injection, followed by the infusion of 6 mg/kg body wt..h during 6 h) increased urinary volume and urinary excretion of Na+, but decreased urinary K+ concentration without affecting urinary K+ excretion during the 6 h period of infusion. During the same time, the plasma Na+ concentration decreased, PRA increased rapidly and was followed by a significant rise in PAL. These results demonstrate that in very young healthy calves, the renal tubules are able to respond to aldosterone. The renin-aldosterone system is also operative in these animals since it responds to Na+ depletion induced by the combination of diuretics and inhibitors of tubular Na+ reabsorption.

Aldosterone↗
PubMed1984

Role of ouabain and diuretics on sodium, potassium and chloride retention in perfused rat kidney.

A novel in situ kidney perfusion technique is described in Sprague-Dawley rats. The procedure involves retrograde perfusion from the renal veins via the kidneys, and then through the renal arteries and dorsal aorta. Ouabain (15 mM) in perfusate increased Na retention by 92%, decreased K retention by 53% and produced no effect on Cl retention. Ethacrynic acid (1 mM) in perfusate decreased Na retention by 52%, increased K retention by 105% and decreased Cl retention by 27%. Furosemide (1.5 mM) in perfusate decreased Na retention by 52%, increased K retention by 47% and decreased Cl retention by 56%. The Na-K-ATPase pump localized at the peritubular side of the proximal tubule cell is ouabain sensitive and Mg dependent. An Na-K pump responsible for Na influx and K effux exists at the luminal side of the proximal tubule cell and is ethacrynic acid and furosemide sensitive.

Animals↗
PubMed1986

Hypernatremia inhibits NaHCO3 reabsorption and associated NaCl reabsorption in dogs.

To examine the effect of selective rise of plasma NaCl concentration (hypernatremia) on NaHCO3 reabsorption and associated NaCl reabsorption remaining during continuous ethacrynic acid infusion, hypertonic NaCl solution was infused in three groups of anesthetized volume-expanded dogs. In six dogs examined at constant hematocrit and plasma pH, bicarbonate and water reabsorptions were inversely related to PNa and reduced by 37% and 39% respectively by raising PNa from 140 to 200 mM. Chloride reabsorption remained essentially constant until PNa exceeded 170 to 180 mM. At PNa 200 mM, sodium reabsorption was reduced by 22 +/- 6%. In six other dogs, mechanical variations of GFR showed that the inhibitory effects of hypernatremia (PNa 199 +/- 3 mM) were less pronounced at low GFR. After subsequent administration of acetazolamide (30 mg/kg body wt), only 20% of control bicarbonate reabsorption remained and glomerulo-tubular balance was completely abolished. Both hypernatremia and acetazolamide inhibited NaHCO3 and NaCl reabsorption in a molar ratio of about 1:2, as in normonatremic dogs. Finally, experiments in six dogs showed that the inhibitory effects of hypernatremia (PNa 213 +/- 4 mM) were not altered by varying PCO2 and plasma pH. We conclude that hypernatremia inhibits paracellular water and NaCl reabsorption in the proximal tubules by reducing the osmotic force caused by transcellular NaHCO3 reabsorption. A rise in PNa does not stimulate transcellular NaCl reabsorption during distal inhibition by ethacrynic acid.

Acetazolamide↗
PubMed1992

Hormonal and pharmacologic regulation of sodium absorption in rabbit cecum in vitro.

The rabbit cecum is a moderately tight epithelium with amiloride-resistant but phenamil-sensitive electrogenic Na absorption. We performed flux and electrical studies under short-circuit conditions in vitro to further characterize the mechanisms of ion transport in cecum in normal and animals pretreated with methylprednisolone (MP) and deoxycorticosterone acetate (DOCA). MP treatment increased Na absorption and decreased tissue conductance. In contrast, DOCA increased Isc but did not significantly alter Na or Cl fluxes. Amiloride analogs with primary specificity for Na channel and Na/H exchanger both inhibited Isc and Na absorption. Ethacrynic acid, but not bumetanide, inhibited Isc. Nystatin and amphotericin B increased Isc. We conclude that: (1) Steroids have a differential effect on cecal ion transport; methylprednisolone increases Na absorption, but DOCA does not. (2) The response to amiloride analogs is different from other electrogenic transport systems, suggesting a distinct mechanism of Na transport in cecum. (3) The effect of ethacrynic acid was unexpected, suggesting an inhibitory response on an alternate transport system. (4) The effects of polyene antibiotics are similar to those found in other tight epithelia. Electrogenic Na absorption in rabbit cecum represents a distinct transport system, significantly different from Na absorptive mechanisms in other segments of the gut.

Amiloride↗
PubMed1977

Increased dexamethasone resistance of cystic fibrosis fibroblasts.

We demonstrate previously that fibroblasts from cystic fibrosis (CF) patients are significantly more resistant to the toxic effects of ouabain than normal human fibroblasts are. Ouabain is generally assumed to act primarily at the level of the cell membrane and to cause killing of cells by inhibiting ion transport. We have therefore examined the ability of normal and CF cells to survive exposure to ethacrynic acid, another inhibitor of ion transport, and to survive colchicine and aminopterin, resistance to which has been associated with membrane alterations in other cells. The effect of dexamethasone, which has a sterol nucleus similar to that of ouabain but is thought to have a different site of cellular action, was also tested. Exposure of the cells to ethacrynic acid, colchicine, or aminopterin did not reveal any differences in survival between normal and CF fibroblasts. However, CF cells survived exposure to dexamethasone significantly better than normal cells did. These results suggest that normal and CF cells do not differ in terms of a generalized resistance to ion transport inhibitors or to drugs that must pass through the membrane to be active. Instead, the results raise the possibility that CF cells have an enhanced resistance to drugs that have the sterol nucleus found in ouabain and dexamethasone.

Aminopterin↗
PubMed1973

Relationship between tubular net sodium reabsorption and peritubular potassium uptake in the perfused Necturus kidney.

1. K influx from peritubular space into renal tubular cells, varphi(i) (K), was measured in doubly perfused Necturus kidneys by studying tissue uptake of (42)K added exclusively to the portal circulation. Concomitantly, net tubular Na reabsorption, varphi(n) (Na), was measured by clearance techniques. varphi(n) (Na) and varphi(i) (K) were varied widely by replacing solutions of physiological composition (controls) with solutions containing high K, low K, low Na, cyclamate instead of Cl, ouabain (10(-7)-10(-4)M) or ethacrynic acid (10(-5)-10(-4)M).2. The ratio of varphi(n) (Na) to varphi(i) (K) was found to vary with the experimental conditions, the control value of about 2 was maintained over a threefold variation in absolute Na reabsorption. This ratio increased with low K or ouabain to values near 4. With high K, ethacrynic acid, low Na or cyclamate the relationship was one or lower. Thus, net Na reabsorption can be uncoupled from peritubular K influx.3. These results can be best explained if there are two Na pumps working in parallel: pump A transporting Na (with Cl) and pump B, a Na-for-K-exchange pump. The ratio of Na efflux to K influx could approach infinity if only pump A works (if B is inhibited) and could approach one if only B works. It should vary between these limits in controls when both pumps are active, or when neither of the two pumps is completely inhibited.4. Alternatively, the experimental findings could be explained by a Na pump with a coupling ratio that varies within two extreme values, from high Na-K ratios (with Na reabsorption at, or near, control values but with very low K influx values) to low ratios (with normal K influx values but with low Na reabsorption values).

Absorption↗
PubMed1972

Intestinal calcium transport: the role of sodium.

The role of sodium in intestinal calcium transport was investigated in everted rat intestine. Ethacrynic acid, but not ouabain, inhibited calcium transport. However, ouabain did inhibit net water transport and, therefore, sodium transport, establishing the dissociation of the two transport processes. In addition to a magnesium-dependent adenosine triphosphatase (activated by sodium and potassium), a phosphatase dependent on sodium and calcium was localized to the lateral and basal membrane fractions of the mucosal cell. Activity of the latter phosphatase, similar to calcium transport in intact tissue, was inhibited by ethacrynic acid and not by ouabain. Sodium, therefore, may participate in the calcium transport process by activating an enzyme complex, dependent on adenosine triphosphate, that mediates calcium transport.

Adenosine Triphosphatases↗
PubMed1997

Improved chromatographic performance of a modified human albumin based stationary phase.

Derivatization of the free cys34 in human serum albumin (HSA) anchored to a silica matrix has been performed by in situ reaction with ethacrynic acid. This modification, which is reported to occur under physiological conditions, gives rise in practice to a new column with different binding properties with respect to the column based on the native protein. Significant differences were observed in the binding of drugs known to bind to site I, (R)-(S)-warfarin and phenylbutazone, and to site II, 1,4-benzodiazepin-2-ones and nonsteroidal anti-inflammatory agents. In particular, the chromatographic retentions markedly decreased for most of the drugs, and, in the case of chiral compounds, significant differences were often observed in the behavior of the two enantiomers, with higher values of enantioselectivity obtained for some of the examined compounds. Furthermore, the noncovalent binding of ethacrynic acid to the protein modifies the binding properties of the albumin.

Binding Sites↗
PubMed1987

Loop-acting diuretics do not bind to Tamm-Horsfall urinary glycoprotein.

1. Binding between the radiolabelled loop-acting diuretics ([14C]frusemide, [14C]ethacrynic acid and [3H]bumetanide) and human Tamm-Horsfall glycoprotein or human serum albumin in vitro was evaluated by equilibrium dialysis. 2. The diuretic action and binding to urinary Tamm-Horsfall glycoprotein of the radiolabelled diuretics in vivo, after intravenous administration, were examined in rabbits. 3. In vitro, all three radiolabelled diuretics bound strongly to human serum albumin, but not to Tamm-Horsfall glycoprotein. 4. Radiolabelled frusemide and bumetanide, but not ethacrynic acid, caused a diuresis in rabbits, but no binding between the drugs and Tamm-Horsfall glycoprotein was seen in vivo. 5. Binding to Tamm-Horsfall glycoprotein does not appear to be an important mechanism in the action of loop diuretics.

Animals↗
PubMed1977

Renal responses to diuretic drugs in freshwater catfish Ictalurus punctatus.

Renal tubules of freshwater teleosts consist of proximal, intermediate, distal, and collecting segments. Diuretic drugs were injected into freshwater channel catfish to define the mode of natriuresis and diuresis. Although the catfish lack a loop of Henle, ethacrynic acid (1 mg/kg), furosemide (1 mg/kg) and, to a smaller extent, hydrochlorothiazide (2 mg/kg) produced marked chloruresis and natriuresis. The amount of sodium and chloride reabsorbed decreased, and the decrease in fractional reabsorption of chloride was greater than that of sodium. All three drugs, however, elicited only mild diuresis. This finding suggests that these drugs inhibit sodium and chloride reabsorption in tubules which are highly impermeable to water, most likely along distal segments of the nephron. Ethacrynic acid and furosemide appear to inhibit both reabsorption and secretion of potassium. Acetazolamide (50 mg/kg) induced moderate diuresis which seemed to reflect increased glomerular filtration rate. Smaller doses of acetazolamide increased urinary bicarbonate excretion without the increase in filtration rate, suggesting a possible inhibition of carbonic anhydrase in the renal tubules.

Acetazolamide↗
PubMed1980

The isolated duct of the rat cauda epididymidis as a model for isosmotic transport studies.

Electrolytes and water transport have been studied in the perfused isolated duct of the rat cauda epididymis in vitro. The rates of reabsorption of sodium, chloride and water and of secretion of potassium were found to be comparable to those in the perfused rat cauda epididymidis in vivo. Sodium reabsorption was isotonic and inhibited by the metabolic uncoupler 2,4-dinitrophenol and cooling. Removal of sodium ions from the intraluminal fluid abolished water reabsorption in the isolated duct. When potassium ions were removed from the peritubular medium the secretion of potassium was abolished, but the reabsorption of sodium and water was unaffected. Under this condition, the reabsorption of chloride was enhanced. Removal of calcium ions from the lumen increased the rates of sodium and water reabsorption and potassium secretion by twofold. Amiloride (10(-4) M) added to the intraluminal fluid had no effect on the electrolyte and water transport in the isolated duct, whereas triaminopyrimidine produced a dose-dependent inhibition of sodium and water reabsorption when added to both sides. Sodium and water reabsorption were found to be inhibited by the application of ouabain (10(-3) M) to the peritubular side and of ethacrynic acid (10(-4) to 10(-5) M) to the luminal peritubular side and of ethacrynic acid (10(-4) to 10(-5) M) to the luminal side. These results are discussed in the light of the recent concepts of isosmotic transepithelial transport.

Amiloride↗
PubMed1975

The effect of diuretics on sodium transport across the mouse intestine.

The effects of three natriuretic agents on Na transport across the mouse intestine were determined. It was found that ethacrynic acid at a concentration of 1mM, markedly reduced the net transmural transport of Na ion by decreasing themucosa-to-serosa flux with little or no effect on serosa-to-mucosa flux. Furosemide or amiloride at a concentration of 1 mM produced similar but less profound effects. A reduction of net Na22 flux was observed in the presence of either diuretic, but with furosemide and amiloride this inhibitory effect observed only if glucose was present in the bathing solution. It is, therefore, concluded that the intestinal transport of Na ion involves two processes, one is glucose or substrate-dependent, and the other glucose or substrate-independent. Ethacrynic acid inhibits the substrate-independent process while furosemide and amiloride affect only the substrate-dependent process of Na transport.

Amiloride↗
PubMed1985

Renal responses to diuretics in the turtle.

We administered the diuretics furosemide and ethacrynic acid to conscious freshwater turtles to assess changes in renal function and plasma renin activity (PRA) in an animal which lacks a loop of Henle. Furosemide (2 and 5 mg/kg) produced no changes in blood pressure, hematocrit, plasma electrolytes, glomerular filtration rate (GFR), or PRA. Furosemide doubled urine volume while sodium excretion increased 20-fold and chloride and potassium excretion increased 12-fold (P less than 0.05 in each case). Net potassium secretion was observed. Ethacrynic acid (2 and 5 mg/kg) also produced no changes in blood pressure, hematocrit, plasma electrolytes, or PRA. At the lower dose GFR increased by 40% and urine volume nearly doubled (P Less than 0.05 in each case). Sodium, chloride, and potassium excretion increased roughly 10-fold (P less than 0.05 in each case). At the higher dose, GFR increased by 80% and urine volume more than doubled (P Less than 0.05 in each case). Sodium excretion rose 40-fold, chloride excretion rose 25-fold, and potassium excretion rose 10-fold (P less than 0.05 in each case). At both doses net potassium secretion occurred. The results demonstrate that both drugs inhibit tubular reabsorption in the turtle, acting primarily on distal segments of the nephron. The failure of either drug to alter PRA suggests that the turtle lacks a tubular mechanism for altering renin release.

Animals↗