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PubMed1984

Acute effects of high ceiling diuretics on pancreatic blood flow and function.

The possibility that a decrease in extracellular volume, induced by diuretics, would cause a decrease in pancreatic blood flow which, in turn, might compromise pancreatic function was examined. Employing fasted anesthetized mongrel dogs, the acute effects of furosemide, a typical high ceiling diuretic, on pancreatic blood flow and plasma levels of insulin and glucose were examined. Furosemide was found to induce a decline in pancreatic blood flow which was similar in all regions of the pancreas and the decrease was antagonized when extracellular volume depletion was prevented by infusing saline at the same rate as urine flow. The decrease in blood flow was significantly correlated with cumulative volume loss. Plasma levels of insulin and glucose were, however, not significantly altered during the studies. To increase the likelihood of determining significant decreases in plasma levels of insulin, acute studies were repeated in dogs in which plasma levels of insulin were increased by a continuous infusion of glucose. Both furosemide and the structurally unrelated high ceiling diuretic, ethacrynic acid, caused a decrease in pancreatic blood flow which was similar in all regions of the pancreas. The cumulative volume loss observed with administration of either furosemide or ethacrynic acid was significantly correlated with the level of pancreatic blood flow observed. Plasma levels of insulin and glucose were not significantly altered. It can be concluded that high ceiling diuretic drugs such as furosemide and ethacrynic acid do produce a loss in volume which is correlated with a decrease in pancreatic blood flow, but decreases in pancreatic blood flow alone do not appear to be sufficient to produce overt changes in pancreatic function in acute studies.

Animals↗
PubMed1977

Effect of intraperitoneal diuretics on solute transport during hypertonic dialysis.

Hypertonic periotoneal dialysis in New Zealand white rabbits results in increased dialyzate volume, but the sodium content of net ultrafiltrate is 109.5 MEq/l, less than extracellular fluid sodium concentration. With intraperitoneal furosemide, mean net ultrafilrate sodium concentration increased significantly to 121.2 mE1/l while ethacrynic acid had no such effect and both drugs affected dialyzate volume very slightly. Hypertonic peritoneal dialysis increased urea clearance significantly above isotonic dialysis and the addition of ethacrynic acid increased clearances further (P LESS THAN.02). Added furosemide decreased urea clearances suggesting that the effect on sodium transport is not an overall permeability change. During isotonic peritoneal dialysis, furosemide increased peritoneal permeability, i.e. urea and creatinine clearances, but a significantly higher urea clearance resulted from intraperitoneal ethacrynic acid. Furosemide influx clearance average 0.31 ml/kg/min, a mean of 27 percent of the urea clearance. The data suggest that furosemide may be useful to prevent the hypernatremia that may complicate hypertonic peritoneal dialysis, but is not as efficacious as other vasoactive drugs in enhancing peritoneal permeability.

Animals↗
PubMed2000

Chemical modulation of chemotherapy resistance in cultured oesophageal carcinoma cells.

Oesophageal carcinoma is a common form of cancer in developing countries, especially in the Caspian littoral and northern China. In contrast, it has a much lower incidence in Japan, the U.S.A. and western Europe. Certainly in the case of squamous cell oesophageal carcinoma, dietary composition, smoking, alcohol and exposure to nitrosamines are major risk factors that may partly explain the disease's geographical distribution. The prognosis for oesophageal carcinoma is generally poor, due to the high incidence of distant metastasis and local recurrence. Combination treatment with both cisplatin and 5-fluorouracil is the most common chemotherapy regime used. We have carried out a detailed study of sensitivity of two oesophageal cell lines: OC1 cells from a squamous carcinoma of a male patient, and OC2, a squamous carcinoma obtained from a female patient. Both cell lines are sensitive to Vinca alkaloids and doxorubicin, while being quite resistant to alkylating agents such as cisplatin and 1,3-bis-(2-chloroethyl)-1-nitrosourea. This pattern of resistance suggests a possible role for glutathione S-transferase (GST) and/or glutathione (GSH) in resistance, and would seem to exclude the multidrug resistance phenotype. Both cell lines possess mainly Pi-class GSTs, and have distinct levels of GSH, with OC2 possessing some 25% of the level of OC1 cells. Effects of a variety of modulating agents on the pattern of resistance, such as the GSH depleter, buthionine sulphoximine, and the GST inhibitor, ethacrynic acid, were determined. An unexpected observation was that ethacrynic acid appears to increase the level of GSH in both cell lines.

Antineoplastic Agents↗
PubMed2002

A putative role for S-nitrosoglutathione as the source of nitric oxide in photorelaxation of the mouse gastric fundus.

Mouse gastric fundus strips were relaxed by ultraviolet light (UV) irradiation, exogenous nitric oxide (NO), isoproterenol, S-nitrosoglutathione, S-nitroso-L-cysteine and S-nitroso-N-acetyl-penicillamine. Glutathione did not affect relaxations in response to UV irradiation, exogenous NO and isoproterenol while inhibiting that with S-nitrosoglutathione. L-Cysteine inhibited responses to UV irradiation and exogenous NO, but not in the presence of exogenous Cu(2+)/Zn(2+) superoxide dismutase. However, L-cysteine alone or in combination with Cu(2+)/Zn(2+) superoxide dismutase did not affect the relaxations in response to S-nitroso-L-cysteine. Ethacrynic acid and diamide inhibited photorelaxations but not the relaxations with exogenous NO and isoproterenol. This inhibition was prevented by glutathione, but not by L-cysteine. S-nitrosoglutathione-induced relaxations were abolished by diamide and ethacrynic acid, whereas responses to S-nitroso-L-cysteine and S-nitroso-N-acetyl-penicillamine were only inhibited by ethacrynic acid. These results suggest that S-nitrosoglutathione may, at least in part, be the putative S-nitrosothiol, which is converted to NO in response to UV irradiation in mouse gastric fundus strips.

Acetylcysteine↗
PubMed1977

Microsomal ATPase of kidney papilla: sensitivity to diuretics and other inhibitors.

Microsomal ATPase isolated from rat kidney papilla was compared to that from kidney medulla. Microsomal Na, K-ATPase from papilla was more sensitive to inhibition by ouabain, Cad N-ethyl-maleimide, Hg++, Thiomerin, ethacrynic acid and Furosemide than the enzyme from the medulla. Mg-ATPase of the papilla was less sensitive than the medullary enzyme to inhibition by Ca++, Cd++, N-ethyl-maleimide, Hg++, ethacrynic acid and Furosemide. Papillary Mg-ATPase was less sensitive than papillary Na, K-ATPase to all the inhibitors mentioned. Medullary Mg-ATPase was more sensitive than medullary Na, K-ATPase to inhibition by ethacrynic acid and Furosemide but less sensitive than medullary Na, K-ATPase to all the other inhibitors. Papillary Na, K-ATPase is the most sensitive to inhibition and papillary Mg-ATPase is the most resistant to inhibition by various diuretic drugs. The possible significance of these characteristics is discussed.

Adenosine Triphosphatases↗
PubMed1978

Factors limiting renal proximal tubular reabsorption at high glomerular filtration rate.

To examine the factors limiting proximal reabsorption, distal reabsorption was inhibited by continuous infusion of ethacrynic acid in anaesthetized dogs. During combined infusion of ethacrynic acid and 0.9% saline, autoregulation of renal blood flow is impaired and glomerular filtration rate (GFR) can be varied by lowering or raising renal perfusion pressure. During lowering of GFR reabsorption of bicarbonate, chloride and sodium varied in proportion to reduction in GFR (glomerulotubular balance), but during elevation of GFR the increase in the filtered load of all three ions was excreted and a maximal rate of reabsorption was approached. Administration of acetazolamide reduced the reabsorption of bicarbonate, chloride and sodium in the ratio 1:2:3, whether GFR was at control, reduced (74% of control) or increased (124% of control). Renal blood flow was 80--90% greater at high than at low GFR. These observations indicate that bicarbonate concentration increases along the proximal tubules during elevation of GFR, until plasma bicarbonate concentration is approached at the distal end of the proximal tubules. From then on, bicarbonate reabsorption cannot be further raised by increasing GFR. Proximal tubular sodium reabsoption reaches a maximum at high GFR because NaCl reabsorption varies in proportion to bicarbonate reabsorption.

Acetazolamide↗
PubMed1992

Effects of phenol compounds, glutathione analogues and a diuretic drug on glutathione S-transferase, glutathione reductase and glutathione peroxidase from canine erythrocytes.

1. Phenol compounds (ellagic acid, quercetin and purpurogallin), glutathione analogues (S-hexylglutathione and S-octylglutathione) and a diuretic drug (ethacrynic acid) were compared for their inhibitory effects on glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in the canine erythrocytes. 2. All these compounds inhibited GST activity; quercetin was found to be the most potent inhibitor. 3. Ellagic acid, purpurogallin, quercetin and ethacrynic acid inhibited GR activity; S-hexylglutathione and S-octylglutathione had no effect on GR and GSH-Px activities. 4. Quercetin and purpurogallin inhibited GST non-competitively toward glutathione, whereas ellagic acid showed a competitive inhibition. Ellagic acid and purpurogallin inhibited GR non-competitively toward oxidized glutathione.

Animals↗
PubMed1996

A sensitive animal model to assess acute and chronic ototoxic effects.

BACKGROUND: Ototoxic side effects of aminoglycosides or cisplatin are strongly influenced by the nutritional state of the experimental animal. We previously demonstrated that guinea pigs fed a low-protein diet are a sensitive model to investigate chronic ototoxic effects of drugs. We now demonstrate that this model is equally sensitive to acute ototoxic insults. SUBJECTS AND DESIGN: Guinea pigs were fed either a full-protein (18.5% protein) or a low-protein (7% protein) diet. Gentamicin sulfate was given as a single injection (100 mg/kg of body weight subcutaneously), followed 90 minutes later by varying concentrations of ethacrynic acid intravenously. Auditory function was assessed by auditory brain-stem response and morphologic characteristics in surface preparations of the organ of Corti. RESULTS: In animals fed a full-protein diet, 35 mg of ethacrynic acid per kilogram of body weight was required for a significant threshold shift at all frequencies tested (3, 8, and 18 kHz). In animals fed a low-protein diet, 15 mg of ethacrynic acid per kilogram significantly elevated threshold at all frequencies, and 20 mg/kg caused a profound threshold shift (> 90 dB). Hair cell loss in the organ of Corti paralleled the pathophysiological findings. CONCLUSIONS: A metabolically challenged animal may better represent the situation of a severely ill patient undergoing drug therapy. Therefore, studies in diet-restricted animals may be more appropriated than studies in healthy animals for an assessment of potential adverse therapeutic side effects.

Acute Disease↗
PubMed2004

Inhibition of glutathione S-transferases by thonningianin A, isolated from the African medicinal herb, Thonningia sanguinea, in vitro.

There is evidence that increased expression of glutathione S-transferase (EC: 2.5.1.18, GST) is involved in resistance of tumor cells against chemotherapeutic agents. In this study we investigated the inhibitory effects of thonningianin A (Th A), a novel antioxidant isolated from the medicinal herb, Thonningia sanguinea on uncharacterized rat liver GST and human GST P1-1. Using 1-chloro-2,4-dinitrobenzene (CDNB) as substrate, rat liver cytosolic GST activity was inhibited by Th A in a concentration dependent manner with 50% inhibition concentration (IC50) of 1.1 microM. When Th A was compared with known potent GST inhibitors the order of inhibition was tannic acid>cibacron blue>hematin>Th A>ethacrynic acid with CDNB as substrate. Th A also exhibited non-competitive inhibition towards both CDNB and glutathione. Furthermore, using 1,2-dichloro-4-nitrobenzene, ethacrynic acid and 1,2-epoxy-3-(p-nitrophenoxy) propane as substrates Th A at 1.0 microM inhibited cytosolic GST by 2%, 12% and 36% respectively. Human GST P1-1 was also inhibited by Th A with an IC50 of 3.6 microM. While Th A showed competitive inhibition towards CDNB it exhibited non-competitive inhibition towards GSH of the human GST P1-1. These results suggest that Th A represents a new potent GST in vitro inhibitor.

Animals↗
PubMed1989

Vulnerability of the thick ascending limb to glutathione depletion in rat kidney: effects of diuretics and indomethacin.

Previous works supported the idea that the thick ascending limb of Henle was the target structure for glutathione (GSH) depletion effects. In order to obtain more evidence on this hypothesis, we compared GSH depletion effects with those of two loop diuretics: furosemide and ethacrynic acid. The submaximal tubular effects observed with furosemide were magnified when the kidneys were previously GSH depleted, but maximal tubular effects of furosemide were GSH independent. This last observation suggested that furosemide and GSH depletion have common sites or mechanisms of action. On the other hand, ethacrynic acid tubular effects were always magnified when the rats were GSH depleted. As it has been proposed that the renal actions of furosemide and ethacrynic acid are at least in part mediated by prostaglandins, another set of experiments was performed using indomethacin to examine the possible role of renal prostaglandins in GSH depletion effects. It was observed that indomethacin greatly improved tubular functions in GSH-depleted rats suggesting that an increase in prostaglandins levels should be involved in the renal defects observed during GSH depletion. All these data give additional support to the idea that the thick ascending limb cells may have a special sensitivity to the effects of GSH depletion probably mediated by prostaglandins.

Animals↗
PubMed1981

Inhibition of 5-methyltetrahydrofolic acid transport by amphipathic drugs.

Numerous chemically unrelated drugs after the membrane transport of folate compounds. To investigate drug structure-activity relationships, we measured the effect of amphipathic drugs (that is, compounds with polar-apolar character) on 5-methyltetrahydrofolic acid permeability of human erythrocytes. All drugs tested were inhibitory, but only compounds that exist at least partially in the anionic form were highly active. Ethacrynic acid, sulfinpyrazone, phenylbutazone, sulfasalazine, and furosemide were effective transport inhibitors in micromolar concentrations. In contrast, compounds that are capable of forming cations at physiologic pH, such as chlorpromazine, procaine, tetracaine, and papaverine, were inhibitory only in millimolar concentrations or caused hemolysis before major inhibition was seen. Inhibitory activity correlated with drug dissociation constant (r = 0.87). A double-reciprocal plot analysis of drug effect on 5-methyltetrahydrofolic acid transport showed changes in both Km and Vmax (indicating a mixture of competitive and noncompetitive inhibition) by ethacrynic acid, sulfasalazine, and phlorizin. Inhibitory activity of a series of eight phenoxyacetic derivatives, including ethacrynic acid, correlated highly with measurements of liposolubility (r = 0.87) but only weakly with the Hammet substituent constant (r = 0.56). These results suggest that the effect of amphipathic drugs on 5-methyltetrahydrofolic acid transport is influenced by drug pKa and by the presence of hydrophobic substituents, but is relatively independent of electron-attracting groups.

Adult↗
PubMed1995

Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells.

Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2.7- and 7.2-fold, respectively, relative to the MCF-7 parental line. No significant changes in glutathione peroxidase and NADPH cytochrome P450 reductase activity, and no increase in microsomal GST and GST pi mRNAs were found in the resistant cells. Treatment with the ALDH substrate octanal sensitized the cells to the cytotoxic effects of 4HC to a modest extent in both MCF-7 and MCF/HC cells [dose modification factor (DMF) of 1.4 and 1.6, respectively]. Depletion of GSH by treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) enhanced the cytotoxic effect of 4HC to a similar extent in both cell lines. By contrast, ethacrynic acid, which inhibited GST activity by > 85% in MCF-7 and MCF/HC cell extracts without depletion of GSH, sensitized the resistant but not the parental cells to 4HC cytotoxicity, indicating the importance of GST as a determinant of 4HC resistance in these cells. This conclusion is supported by the observation that in MCF/HC cells, ethacrynic acid in combination with BSO increased the DMF 3-fold higher than did BSO or EA alone, while in the parental MCF-7 cells ethacrynic acid with BSO had no significant chemosensitization effect over BSO alone. These studies establish that in addition to ALDH, GST overexpression can contribute to acquired resistance of tumor cells to 4HC and, furthermore, suggest that modulators that target the GSH/GST system could be useful in overcoming CPA resistance in the clinic.

Aldehyde Dehydrogenase↗
PubMed1975

Effects of certain diuretics on the electrophysiological characteristics of the nephron in the rat kidney.

Electrophysiological micropuncture techniques were used to study the effect of certain diuretics on transtubular transport of electrolytes in the rat kidney. The mercurial diuretic novurite caused a reduction of active sodium transport in the proximal tubule, measured by short-circuit current and increased permeability of the tubular wall to ions which led to a considerable drop in transtubular potential and transepithelial resistance. Ethacrynic acid decreased the short-circuit current in the proximal tubule, without changing the permeability characteristics of the nephron. Xanthine diuretic euphylline did not reduce the short-circuit current in the proximal segment of the nephron; however, it increased the transepithelial potential of the renal tubule. In the distal tubule, euphylline and ethacrynic acid increased the difference in transtubular potential, whereas novurite reduced the transtubular potential. An increase in the electrical gradient of the distal tubule as a result of euphylline and ethacrynic acid action may be responsible for increasing potassium excretion. A decrease of the transtubular potential in the potassium excretion under mercurial diuretic action. The reduction of tubular reabsorption as a result of diuretic action is due to drug effect on different levels of the transtubular-ion transport system.

Aminophylline↗
PubMed1975

Renal adenylate cyclase-effects of diuretics.

The in vitro effect of various diuretics on rat kidney adenylate cyclase was investigated in crude homogenates of the cortex, the outer and inner medulla. 10-3 M furosemide inhibited adenylate cyclase by 40% in the cortex, by 16% in the outer medulla and by 43% in the inner medulla. 10-3 M ethacrynic acid inhibited adenylate cyclase activity by 65% in the cortex, 59% in the outer medulla and by 57% in the inner medulla. Amiloride produced no significant inhibition of the adenylate cyclase reaction. In the cortex, furosemide partially inhibited adenylate cyclase under basal, fluoride-stimulated and parathyroid hormone-stimulated conditions. Ethacrynic acid produced a strong inhibition of adenylate cyclase activation by F- and parathyroid hormone. In the inner medulla 10-2 M F- and 1 mU antidiuretic hormone reversed the furosemide effect on adenylate cyclase. Ethacrynic acid produced a strong inhibition of adenylate cyclase in the presence of F- and antidiuretic hormone. It is suggested that inhibition of renal adenylate cyclase might be a possible mode of action of certain diuretics.

Adenylyl Cyclases↗
PubMed1983

Evidence for bicarbonate-dependent magnesium reabsorption.

During ethacrynic acid administration about 50% of the filtered load of magnesium is reabsorbed. To examine whether the remaining component of magnesium reabsorption is bicarbonate-dependent, i.e. varies with factors known to alter passive reabsorption, experiments were performed in anesthetized dogs. During ethacrynic acid administration MgCl2 infusion raised the plasma concentration of magnesium (PMg) from 0.64 +/- 0.05 to 3.06 +/- 0.27 mM and doubled magnesium reabsorption. The infusion of acetazolamide at high PMg reduced bicarbonate reabsorption by 41 +/- 3% and magnesium reabsorption by 31 +/- 16%. When plasma pH was reduced to 7.04 +/- 0.02 and increased to 7.83 +/- 0.02 by altering PCO2 at a constant plasma bicarbonate concentration of 31.2 +/- 0.8 mM, magnesium and bicarbonate reabsorption were correlated (r = 0.82). The infusion of mannitol, which acts by reducing passive solute transport without affecting bicarbonate reabsorption, halved magnesium reabsorption. By combining mannitol and acetazolamide infusions, only 6 +/- 4% of the filtered magnesium was still reabsorbed. These results indicate that the reabsorption of magnesium remaining after the infusion of ethacrynic acid and after raising PMg varies with changes in PCO2 and is inhibited by the infusion of acetazolamide and mannitol as expected for bicarbonate-dependent passive reabsorption.

Acetazolamide↗
PubMed2005

Selective modifiers of glutathione prevent restoration of photorelaxations in mouse gastric fundus.

S-nitrosoglutathione (GSNO) has previously been shown to have a role in ultraviolet (UV) light-elicited relaxations and proposed to account for the photosensitive store in the mouse gastric fundus. Furthermore, the depletion of this photosensitive store and its replenishment via long-term electrical field stimulation were demonstrated in the same tissue. In relation to these results, the aim of the present study was to investigate the putative role of S-nitrosothiols in the restorative effect of long-term electrical field stimulation on the reduced photosensitive store. Two series of UV light-elicited relaxations (photorelaxations) were obtained, and the magnitudes of the responses were 53 +/- 6 and 26 +/- 3%, respectively. The second series of photorelaxations attenuated statistically when compared with those in the first series. Ethacrynic acid (1 microm), diamide (1 microm) and glutathione (1 microm) had no effect on the photorelaxations occurred in the second series of responses. Electrical field stimulation (4 Hz, 25 V, 1 ms, 60 min), applied between two series of photorelaxations, revealed a complete recovery of the attenuated photorelaxations appeared in the second series. N(G)-monomethyl-L-arginine (100 microm), ethacrynic acid (1 microm) and diamide (1 microm) extensively prevented the restorative effect of electrical field stimulation on photorelaxations. In addition, glutathione (1 microm) reversed the prevention achieved by ethacrynic acid and diamide. The conclusion is that the restoration accomplished by electrical field stimulation is because of the activation of nitric oxide synthase, which in turn brings about the regeneration of GSNO proposed to be the photodegradable material store.

Animals↗
PubMed2002

[The role of thiol oxidants in inhibition of pancreatic exocrine secretory function and glutathione].

OBJECTIVE: Glutathione depletion has been described in all form of acute pancreatitis. This study evaluated the effect of glutathione depletion on pancreatic exocrine secretory function and explored the potential mechanisms. METHODS: Thiol oxidants ethacrynic acid and diamide were employed to deplete pancreatic acinar glutathione. The effect of glutathione depletion on caerulein-stimulated amylase release, cholecystokinin (CCK) receptor binding characteristics, and cytosolic free calcium was investigated. RESULTS: Both the thiol oxidants decreased the level of pancreatic acinar glutathione and caerulein (1 x 10(-10) mol/L)-stimulated amylase release in a dose-dependent manner without a marked increase in cell damage. Diamide also diminished the level of protein thiols. Ethacrynic acid and diamide both inhibited the caerulein (1 x 10(-9) mol/L)-induced Ca(2+) mobilization in pancreatic acinar cells. Neither ethacrynic acid nor diamide altered the CCK-receptor binding characteristics. CONCLUSIONS: The present findings strongly suggest that glutathione plays a potential role in the secretory process in pancreatic acinar cells and in the secretory blockade observed in acute pancreatitis. A decrease of caerulein-induced Ca(2+) mobilization might participate in the effect of glutathione depletion on pancreatic exocrine secretory function.

Amylases↗