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PubMed1976

Effect of diuretics on intestinal transport of electrolytes, glucose, and amino acid.

The jejunal mucosal membrane of albino mice was used to study the electrical properties and ion transport. The membrane was bathed in Krebs-Ringer solution with or without glucose. When ethacrynic acid (EA), furosemide, or amiloride was added to the bathing fluid of both sides, a transient increase followed by a decrease of both potential difference (PD) and short circuit current (Isc) were observed. In glucose-containing bathing medium, EA inhibited both net Na and Cl flux and residual flux; however, EA had little effect on both Na and Cl flux in glucose-free bathing medium. Studies using everted intestinal sac technique showed that EA inhibited both glucose and L-tyrosine across the mucosal membrane against concentration gradients. Furosemide and amiloride were less potent than EA in inhibiting the Na and Cl flux when the bathing solution contained glucose. But these two compounds had no effect on glucose and L-tyrosine transport across the intestinal mucosa. Furthermore, they did inhibit Cl flux even in the condition of glucose-free bathing medium. It is postulated that all three diuretics act on the brush-border membrane of the intestine. EA probably inhibits the Na-glucose cotransporting system; furosemide and amiloride inhibit the simple diffusion process of Na entry of Cl exit by decreasing the conductance of the membrane.

Amiloride↗
PubMed2005

Characterization of cytosolic glutathione S-transferases in juvenile Chinook salmon (Oncorhynchus tshawytscha).

Four cytosolic glutathione S-transferase (GST) classes were isolated and characterized from juvenile winter run Chinook salmon (Oncorhynchus tshawytscha) liver. Two techniques were used: (1) gel electrophoresis/immunoblotting against a polyclonal striped bass GST antibody and (2) high-pressure liquid chromatography (HPLC). Nanospray liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to elucidate peptide sequences and the proteins were identified as pi, theta, mu and alpha, by searching against the NCBI non-redundant database (nrDB). Catalytic activity of the cytosolic GSTs towards 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid (ETHA) were determined to be 0.3+/-0.05 U/mg cytosolic protein and 0.06+/-0.02 U/mg cytosolic protein, respectively.

Amino Acid Sequence↗
PubMed1991

Screening for diuretics in human urine by gas chromatography-mass spectrometry with derivatisation by direct extractive alkylation.

A rapid, sensitive and reliable gas chromatographic-mass spectrometric (GC-MS) screening procedure for diuretics in human urine has been developed. The procedure uses derivatisation by extractive methylation directly from the urine. The suitability of a number of phase transfer reagents and solvents were studied for the detection of sixteen diuretics. The results obtained indicate that the screening procedure employing tetrahexylammonium hydrogensulphate at pH 12 with methyl iodide in toluene at room temperature was the most effective. This method gives selectivity and sensitivities down to 0.03-0.1 microgram/ml and provides a substrate suitable for GC-MS confirmation without further manipulation. The application of the method is demonstrated by the screening of urine for bumetanide, ethacrynic acid, acetazolamide, chlorothiazide and hydrochlorothiazide.

Acetazolamide↗
PubMed1984

Effect of extracellular fluid volume depletion on renal regulation of acid-base and potassium equilibrium during prolonged mineral acid administration.

Previous studies of the renal and systemic acid-base response to prolonged administration of mineral acids in dogs have suggested that during the steady state of acidosis, the level at which plasma bicarbonate concentration is regulated by the kidney is dependent on the degree of augmentation of "distal delivery" of sodium imposed by the increased filtered load of administered mineral acid anion with filtered sodium, and on the degree of augmentation of "distal avidity" for sodium reabsorption imposed by ECF volume ( ECFV ) contraction secondary to renal sodium losses accompanying the administered mineral acid anion. This formulation, however, fails to predict the level at which plasma bicarbonate concentration would be regulated under conditions of preexisting ECFV depletion, which would simultaneously limit distal delivery of sodium salts and yet increase distal avidity for sodium reabsorption. Our studies assessed the renal and systemic acid-base responses to prolonged daily administration of 5.0 mEq/kg of H+ as HCl (groups 1 and 2) or H2SO4 (groups 3 and 4) in dogs with normal ECFV (groups 1 and 3) vs. preexisting ECFV depletion (groups 2 and 4) induced by administration of ethacrynic acid. In response to HCl administration, dogs with depleted ECFV developed more severe acidosis than ECFV -replete dogs (delta[HCO-3,]p, -5.0 +/- 0.6 mEq/L, group 2 vs. -2.7 +/- 0.5 mEq/L, group 1, p less than 0.02). The exacerbated metabolic acidosis in group 2 persisted in the steady state, even though the steady-state net systemic acid load was not greater than in group 1. No exacerbation of acidosis was observed in H2SO4-fed dogs with depleted ECFV . In response to either HCl or H2SO4, persistent hypokalemia caused by increased renal potassium clearance occurred in ECFV -replete dogs but not in ECFV -depleted dogs. Our results indicate that preexisting ECFV depletion results in impaired renal hydrogen ion secretion during prolonged HCl feeding, but not during H2SO4 feeding. These results suggest that during prolonged HCl loading under conditions of preexisting ECFV depletion, hypovolemia-mediated restriction of the normal augmentation of distal delivery of sodium salts overrides the effects of enhanced distal cation secretory capacity that attends hypovolemia-mediated augmentation of distal avidity for sodium reabsorption.

Acid-Base Equilibrium↗
PubMed1976

[Ototoxicity of the aminoglycoside antibiotics (author's transl)].

A report is given on advances in our knowledge of the ototoxicity of aminoglycoside antibiotics. The pharmacokinetics of gentamicin, tobramycin, sisomicin and amikacin in the inner ear, cerebrospinal fluid, compartments of the eye and serum were determined by means of pharmacokinetical investigations. The influence of long-term treatment, and the effects of otitis media and uremia were also studied. Furthermore, the influence of therapeutic methods on ototoxic damage was investigated, and the ototoxicity of these antibiotics was compared. The experiments were performed in guinea pigs, concentrations of the antibiotics being measured by a microbiological method and confirmed by investigations with C14 labeled gentamicin. The hair cell degeneration pattern after administration of the new aminoglycosides was determined using surface preparations. The prophylactic effect upon ototoxicity of the administration of dimercaptopropanol or of dividing up the daily dosage was examined. Studies were made of ototoxicity in children, and in patients with otitis media or renal impairment, and the effect of simultaneous ethacrynic acid or noise was assessed. The problem of delayed and progressive ototoxicity, and the reversibility of ototoxic damage caused by these antibiotics was examined histologically, and the ototoxicity of gentamacin, tobramycin, sisomicin and amikacin was compared. The influence of the new aminoglycoside antibiotics upon the amount of acidic and alkaline phosphatase and unspecific esterases in the inner ear was studied. The clinical importance of the latest experimental findings is emphasised. The clinical picture of ototoxic damage after administration of the new aminoglycoside antibiotics shows no special characteristics. The ototoxicity of these antibiotics after topical use is mentioned. Attention is drawn to guidelines for the prevention of ototoxic damage by aminoglycosides.

Acid Phosphatase↗
PubMed1998

The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines.

BACKGROUND: The chemotherapy of melanoma patients must be improved because of the naturally poor response and acquired resistance of this disease. METHODS: The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA). RESULTS: Melphalan was the most effective individual drug, followed by lomustine, fotemustine, and 4-HA. The simultaneous administration of two agents was disappointing, although some combinations slightly improved the response compared with the individual treatments. Pretreatment with BSO enhanced the cytotoxicity of melphalan and lomustine 10-fold in B16F10 and 7.5-fold in SK-MEL-28, increasing the toxicity of fotemustine in all 3 lines. EA potentiated lomustine and fotemustine 9-fold and melphalan 5-fold in B16F10 and SK-MEL-28. AZA increased the effectiveness of lomustine and fotemustine in B16F10 and to a lower degree in the two human lines. 4-HA was the poorest drug for sensitization; only B16F10 BSO followed by 4-HA treatment demonstrated increased toxicity, and all other combinations with 4-HA were negative or antagonistic. There was a strong relationship between dopa oxidase activity and the toxicity of 4-HA. CONCLUSIONS: B16F10 was the most sensitive to all treatments and SK-MEL-1 the most resistant. Melphalan was the most active individual drug and 4-HA the least. Combinations of two drugs did not result in improved activity compared with drugs administered alone. Pretreatment with modulator seems to be a potential method for enhancing some treatments.

Animals↗
PubMed1996

Glutathione S-transferases in the Japanese quail: tissue distribution and purification of the liver isozymes.

Cytosolic glutathione S-transferase (GST) activities toward 1-chloro-2,4-dinitro-benzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EA), 1,2-epoxy-3-(p-nitrophenoxyl)propane (EPNP), trans-4-phenyl-3-buten-2-one(t-PBO), delta 5-androstene-3,17-dione (ASD) and trans-stilbene oxide (t-SO); cytosolic glutathione peroxidase activity toward cumene hydroperoxide (CuOOH); and microsomal GST activity toward CDNB were examined in liver, kidney, brain, and lung of adult male and female Japanese quail. In all cases, the renal specific activity per milligram protein was higher than the hepatic activity and was the highest among the four tissues examined. No consistent sex differences in GST activity were observed. The GSTs were purified from quail liver cytosol by S-hexylglutathione and glutathione affinity chromatography. Total GSTs eluted from the S-hexylglutathione affinity column were further separated by chromatofocusing, and the microheterogeneity of the GST isozymes was shown by high-resolution native isoelectrofocusing (IEF) in polyacrylamide slab gels and by SDS-PAGE. Five subunits were identified: QL1 (30.5 kDa), QL2 (27.2 kDa), QL3a (26.8 kDa), QL3b (26.5 kDa), and QL4 (25.5 kDa). Western blot analysis revealed that QL1 and QL2 reacted with antibodies raised against the rat Mu class GSTs (Yb1 and Yb2), and QL3a and QL3b reacted with those raised against the Alpha class (rat Ya and mouse a). Substrate specific activity of each isoform was determined with CDNB, DCNB, CuOOH, EA, t-PBO, ASD, and t-SO. QL3a and QL3b have high reactivity toward CuOOH, while QL1 and QL2 showed high activity toward t-SO. The N-terminal amino acid sequence of QL2 was identical to that of the chicken Mu class GST subunit CL2. However, no sequence was obtained with QL1 due to possible N-terminal blockage.

Amino Acid Sequence↗
PubMed1976

The effects of temperature and inhibitors on HCO3-stimulated swelling and ion uptake of monkey cerebral cortex.

In the presence of high concentrations of K+, additions of HCO3- as low as 0.35 mM caused a 23% increase in swelling, and concomitant increases in the chloride content of incubating monkey cerebrocortical slices. The uptake of chloride was accompanied by increased uptake of sodium and was highly temperature dependent, showing a marked activation at approximately 30 degrees C. A similar temperature activation was also found for a Mg2+-dependent, HCO3-stimulated ATPase activity in monkey cerebral cortex, consistent with a possible role for this enzyme in the K+ and HCO3-dependent swelling process and its associated ion movements. K+-dependent, HCO3-stimulated cerebrocortical tissue swelling with uptake of Na+ and Cl- was inhibited by acetazolamide indicating that carbonic anhydrase was also involved. The addition of ouabain also inhibited swelling and K+ and Cl- uptake at low concentrations, but led to increased swelling at higher concentrations ( greater than 10 mum). A similar biphasic effect on swelling was also seen following addition of ethacrynic acid.

Acetazolamide↗
PubMed2004

Characterization and molecular cloning of a glutathione S-transferase from the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae).

Glutathione S-transferases (GST) catalyzing the conjugation of reduced glutathione to a vast range of xenobiotics including insecticides were characterized in the whitefly Bemisia tabaci. GST activities were determined in susceptible and resistant strains of B. tabaci towards artificial substrates, i.e. 1-chloro-2,4-dinitrobenzene (CDNB) in a photometric microplate assay and monochlorobimane (MCB) in a fluoroemtric microplate assay and characterized by their Michaelis-Menten kinetics. The inhibitory potential of ethacrynic acid was very effective with IC50-values between 0.9 and 5.8 microM depending on substrate and strain. The inhibitory effect of dicumarol was 10 times lower. Glutathione-affinity chromatography purified GST enzymes of two different B. tabaci strains appeared as a single band on SDS-PAGE and had a molecular mass of 23.5 kDa determined by MALDI mass spectrometry. The N-terminus of the purified enzyme was sequenced by Edman degradation. The nearly full-length cDNA of the enzyme was isolated by RT-PCR using a degenerate primer derived from the N-terminal amino acid sequence and contained an open reading frame encoding a 194-amino-acid protein. Comparison of the deduced amino acid sequence with GSTs from other species revealed that the enzyme is closely related to insect class sigma GSTs.

Amino Acid Sequence↗
PubMed1989

Cisplatin: nephrotoxic action in vertebrates and its prevention.

1. The kidney of frog and black sculpin appeared to be much less sensitive to the toxic action of CP in comparison with rat and pigeon. 2. The impairment of renal function after CP administration resulted in increased serum urea in rat, uric acid in pigeon and magnesium in black sculpin. 3. Kidney swelling is important feature of CP nephrotoxicity in rat and pigeon but not in frog and fish. 4. Pretreatment with choline chloride, PAH, furosemide and ethacrynic acid reduced the nephrotoxic action of CP in rat but did not prevent the accumulation of platinum in renal tissue which appeared to be a function of the dose injected to investigated animals.

Animals↗
PubMed2002

Antimicrobial peptides initiate IL-1 beta posttranslational processing: a novel role beyond innate immunity.

Human monocytes stimulated with LPS produce large quantities of prointerleukin-1beta, but little of this cytokine product is released extracellularly as the mature biologically active species. To demonstrate efficient proteolytic cleavage and export, cytokine-producing cells require a secondary effector stimulus. In an attempt to identify agents that may serve as initiators of IL-1beta posttranslational processing in vivo, LPS-activated human monocytes were treated with several individual antimicrobial peptides. Two peptides derived from porcine neutrophils, protegrin (PTG)-1 and PTG-3, promoted rapid and efficient release of mature IL-1beta. The PTG-mediated response engaged a mechanism similar to that initiated by extracellular ATP acting via the P2X(7) receptor. Thus, both processes were disrupted by a caspase inhibitor, both were sensitive to ethacrynic acid and CP-424,174, two pharmacological agents that suppress posttranslational processing, and both were negated by elevation of extracellular potassium. Moreover, the PTGs, like ATP, promoted a dramatic change in monocyte morphology and a loss of membrane latency. The PTG response was concentration dependent and was influenced profoundly by components within the culture medium. In contrast, porcine neutrophil antimicrobial peptides PR-26 and PR-39 did not initiate IL-1beta posttranslational processing. The human defensin HNP-1 and the frog peptide magainin 1 elicited export of 17-kDa IL-1beta, but these agents were less efficient than PTGs. As a result of this ability to promote release of potent proinflammatory cytokines such as IL-1beta, select antimicrobial peptides may possess important immunomodulatory functions that extend beyond innate immunity.

Adenosine Triphosphate↗
PubMed1994

cDNA and deduced amino acid sequences of a human colon dihydrodiol dehydrogenase.

A 1.24 kbp cDNA encoding a human colon HT29 cell dihydrodiol dehydrogenase of 323 amino acid residues (M(r) 36,735) has been isolated and sequenced. The deduced amino acid sequence was 97%, 81%, and 76% identical to human liver dihydrodiol dehydrogenase (also called bile acid binder), human liver chlordecone reductase, and bovine lung prostaglandin f synthase, respectively. It was 98% identical in 990 bp overlap with the nucleotide sequence of human liver pseudochlordecone reductase. Northern blots revealed that dihydrodiol dehydrogenase(s) were markedly induced in HT29 colon cells by treatment with the Michael acceptor agent ethacrynic acid.

Alcohol Oxidoreductases↗
PubMedDate not supplied

[Effect of diuretics on the course of experimental arrhythmias].

The protective effect of triamterene was demonstrated on aconitine (rats) and strophanthin (cats) models of arrhythmias. Furosemide potentiates the antiarrhythmic effects of calcium chloride (rats) and strophanthin, ethacrynic acid potentiates the arrhythmogenic action of all agents used.

Aconitine↗
PubMed1999

Enthacrynic and acid effects on inner wall pores in living monkeys.

PURPOSE: The influence of the inner wall of Schlemm's canal on aqueous outflow facility remains poorly understood. We examined the relationship between inner wall pore characteristics and outflow facility in living primate eyes in which facility had been pharmacologically increased by ethacrynic acid (ECA) infusion and in contralateral control eyes. METHODS: Outflow facility (two-level constant pressure perfusion) was measured in eight pairs of living monkey eyes before and after administration of a bolus dose of either 0.125 mM ECA or vehicle. After exsanguination, eyes were fixed in situ under constant-pressure conditions (mean fixation pressure approximately 19 mm Hg). The density and diameter of inner wall pores and the number and area of platelet aggregates on the inner wall of Schlemm's canal were measured by scanning electron microscopy. RESULTS: In ECA-treated eyes, outflow facility increased 63% (P < 0.0001), intracellular pore density decreased 46% (P = 0.0094), intracellular pore size increased 27% (P = 0.049), platelet aggregate density increased 158% (P < 0.0001), and area covered by platelets increased 210% (P = 0.012) relative to contralateral controls. Although the average density and size of intercellular pores were essentially unaffected by ECA, an increased density of large (> or = 1.90 microm) intercellular pores was seen in ECA-treated eyes. The density of intracellular pores increased with the duration of fixative perfusion. Other than a weak negative correlation between outflow facility and intracellular pore density in ECA-treated eyes (P = 0.052), facility was not correlated with inner wall pore features. CONCLUSIONS: Our data are most consistent with a scenario in which ECA promotes formation of large intercellular pores in the inner wall of Schlemm's canal, which are then masked by platelet aggregates. Masking of intercellular pores, combined with fixation-induced alteration of inner wall pore density, greatly complicates attempts to relate facility to inner wall structure and suggests that in vivo pore density is smaller than in fixed tissue. Additionally, facility-influencing effects of ECA on the juxtacanalicular tissue cannot be excluded.

Animals↗
PubMed2004

Molecular cloning, expression and characterization of glutathione S-transferase from Mytilus edulis.

The gene coding for glutathione S-transferase (GST) has been isolated from the Mytilus edulis hepatopancreas. Open reading frame analysis indicated that the M. edulis GST (meGST) gene encodes a protein of 206 amino acid residues with a calculated molecular mass of 23.68 kDa. The deduced amino acid sequence showed high sequence similarity with the sequence of the pi class GST. The meGST was expressed in Escherichia coli, and the recombinant meGST was purified by affinity chromatography and characterized. The recombinant meGST exhibited high activity towards the substrates ethacrynic acid (ECA) and 1-chloro-2,4-dinitrobenzene (CDNB). Kinetic analysis with respect to CDNB as substrate gave a K(m) of 0.68 mM and a V(max) of 0.10 mmol/min per mg protein. The recombinant meGST had a maximum activity at approximately pH 8.5, and its optimum temperature was 39 degrees C. The predicted three-dimensional structure of the meGST revealed the N-terminal domain possesses a thioredoxin fold and the six helices of the C-terminal domain make a alpha-helical bundle. These features indicate that the meGST belongs to pi class GST.

Animals↗
PubMed1991

cAMP activates Cl-/HCO-3 exchange for regulation of intracellular pH in renal epithelial cells.

The role of cAMP in regulation of intracellular pH in the confluent LLC-PK1 cells was investigated. DibutyrylcAMP and forskolin induce intracellular acidification. This acidification is inhibited by DIDS and ethacrynic acid, inhibitors of Na(+)-independent Cl-/HCO3- exchange, and by removal of extracellular Cl-. In addition, Bt2 cAMP causes Cl- entry into LLC-PK1 cells. These results suggest that cAMP activates Cl- transport, namely Na(+)-independent Cl-/HCO3- exchange, which participates in pHi regulation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMedDate not supplied

Connective tissue activation. IX. Modification by pharmacologic agents.

Alpha- and beta-adrenergic blocking agents and imipramine inhibit the increased hyaluronate synthesis that may be induced in human synovial cultures by connective tissue activating peptide (CTAP). Considerations of drug concentration requirements, actions of analogues, and time studies all indicate that the adrenergic blockers do not act in this circumstance as conventional blockers of alpha or beta receptor sites. It is suggested that the membrane-stabilizing properties of these agents may be the important determinant for their limited "antiactivation" effect. Ethacrynic acid, a potent and more complete inhibitor of connective tissue activation, appears to act via a different mechanism.

Alprenolol↗