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PubMed1985

Diuretics. Clinical pharmacology and therapeutic use (Part I).

25 years have elapsed since the introduction of the first effective oral diuretic, chlorothiazide. Diuretics are now amongst the most widely prescribed drugs in clinical practice worldwide. Availability of these drugs has not only brought therapeutic benefit to countless numbers of patients but it has at the same time provided valuable research tools with which to investigate the functional behaviour of the kidney and other electrolyte-transporting tissues. Despite many remaining gaps in our knowledge of the biochemical processes involved in diuretic drug action, available compounds can be divided into 5 groups on the basis of their preferential effects on different segments of the nephron involved in tubular reabsorption of sodium chloride and water. Firstly, there is heterogeneous group of chemicals that share the common property of powerful, short-lived diuretic effects that are complete within 4 to 6 hours. These agents act on the thick ascending limb of Henle's loop and are known as 'high ceiling' or 'loop' diuretics. The second group are the benzothiadiazines and their many related heterocyclic variants, all of which localise their effects to the early portion of the distal tubule. The third group comprises the potassium-sparing diuretics which act exclusively on the Na+-K+/H+ exchange mechanisms in the late distal tubule and cortical collecting duct. The action of drugs in groups 2 and 3 is prolonged to between 12 and 24 hours. The fourth group consists of diuretics that are chemically related to ethacrynic acid but have the unusual property of combining within the same molecule the property of saluresis and uricosuria. These compounds have actions, to different individual extents, in the proximal tubule, thick ascending limb, and early distal tubule and are known as 'polyvalent' diuretics. Finally, there is a mixed group of weak or adjunctive diuretics which includes the vasodilator xanthines such as aminophylline, and the osmotically active compounds such as mannitol. Available evidence on the molecular mechanisms of action of diuretics in each group is reviewed. The haemodynamic, humoral and physical factors involved in control of electrolyte and fluid handling by the kidney in normal conditions and pathological states are discussed in relation to rational choices of different diuretics in the treatment of various oedematous and non-oedematous conditions.

Animals↗
PubMed1985

Diuretics. Clinical pharmacology and therapeutic use (Part II).

25 years have elapsed since the introduction of the first effective oral diuretic, chlorothiazide. Diuretics are now amongst the most widely prescribed drugs in clinical practice worldwide. Availability of these drugs has not only brought therapeutic benefit to countless numbers of patients but it has at the same time provided valuable research tools with which to investigate the functional behaviour of the kidney and other electrolyte-transporting tissues. Despite many remaining gaps in our knowledge of the biochemical processes involved in diuretic drug action, available compounds can be divided into 5 groups on the basis of their preferential effects on different segments of the nephron involved in tubular reabsorption of sodium chloride and water. Firstly, there is a heterogeneous group of chemicals that share the common property of powerful, short-lived diuretic effects that are complete within 4 to 6 hours. These agents act on the thick ascending limb of Henle's loop and are known as 'high ceiling' or 'loop' diuretics. The second group are the benzothiadiazines and their many related heterocyclic variants, all of which localise their effects to the early portion of the distal tubule. The third group comprises the potassium-sparing diuretics which act exclusively on the Na+-K+/H+ exchange mechanisms in the late distal tubule and cortical collecting duct. The action of drugs in groups 2 and 3 is prolonged to between 12 and 24 hours. The fourth group consists of diuretics that are chemically related to ethacrynic acid but have the unusual property of combining within the same molecule the property of saluresis and uricosuria. These compounds have actions, to different individual extents, in the proximal tubule, thick ascending limb, and early distal tubule and are known as 'polyvalent' diuretics. Finally, there is a mixed group of weak or adjunctive diuretics which includes the vasodilator xanthines such as aminophylline, and the osmotically active compounds such as mannitol. The metabolic consequences of continued diuretic usage are considered along with non-metabolic sequelae such as ototoxicity or interactions with other concurrent treatments. The relationships between the clinical benefits conferred and the potential harms generated by long term diuretic therapy are also discussed.

Amiloride↗
PubMed1987

Characterization of xenobiotic biotransformation in hepatic, renal and gut tissues of cattle and sheep.

Microsomal and cytosolic preparations of hepatic, renal, ileal and ruminal tissues of cattle and sheep were used to measure oxidative, hydrolative and conjugative biotransformations of 11 xenobiotic substrates. Within species, enzyme activities were generally higher (P less than .05) in hepatic than non-hepatic tissue but, in both species, non-hepatic tissue exhibited considerable capacities for metabolizing certain substrates. Sheep rumen wall (with papillae) was notably high in cytochrome P-450 content (34% of hepatic value), in glutathione conjugation of ethacrynic acid (223% of hepatic activity; P less than .05), and UDP-glucuronidation of estrone (290% of hepatic activity; P less than .05). Sheep differed (P less than .05) from cattle, having lower cytochrome P-450 content in liver and ileum (but not kidney); lower N-demethylase activity in liver, but two- to threefold higher activity in kidney; lower sulfotransferase activity in liver and kidney; and higher glutathione S-transferase activity toward certain substrates. UDP-glucuronidation varied too widely among substrates to afford strong generalization in comparisons among tissues or between species. Non-hepatic tissues in ruminants exhibit considerable capacities for oxidative, hydrolative and conjugative metabolism of xenobiotics. Sheep and cattle differ widely in hepatic and non-hepatic capacities for biotransforming certain xenobiotics.

Animals↗
PubMed1997

Study of oxidative-stress in isoniazid-rifampicin induced hepatic injury in young rats.

The role of oxidative-stress as a mechanism of hepatotoxicity caused by combination of isoniazid (INH) and Rifampicin (RMP) was investigated in young growing rats. A successful model of hepatotoxicity was produced by giving 50 mg/kg/day each of INH and RMP in two weeks. Liver showed type II hepatocellular changes (microvesicular fat deposition) with mild portal triaditis. The glutathione and related thiols were significantly decreased in both blood and liver tissues with combination of INH and RMP treatment. Superoxide dismutase, glutathione peroxidase, catalase and glutathione-S-transferases with CDNB and DCNB as substrates were decreased in the combination treated group. Glutathione reductase, glutathione-S-transferase with ethacrynic acid as substrate and lipid peroxidation exhibited a significant increase with treatment. The altered profile of antioxidant enzymes with increased lipid peroxidation indicated the enhanced oxidative-stress in combination of INH and RMP treatment. All the findings are faithfully reflected in the blood tissue except superoxide dismutase which showed significant enhancement in this tissue. INH and RMP hepatotoxicity is thus appeared to be mediated through oxidative-stress.

Animals↗
PubMed1986

Acute pancreatitis in systemic lupus erythematosus.

Lethal acute pancreatitis developed in a 16-year-old Caucasian woman suffering from systemic lupus erythematosus. Until the time of onset of pancreatitis, the patient's medications included prednisone, furosemide, ethacrynic acid and chlorthalidone, all of which have been related to pancreatitis. At autopsy, no specific signs of autoimmune activity were found in the diseased pancreatic tissue. A review of the literature shows that information on the association of pancreatitis and SLE is scarce. This case illustrates the dilemma of pathogenesis and therapy of acute pancreatitis in SLE and the need for further investigation.

Acute Disease↗
PubMed1996

[Effects of chronic electrical stimulation on cochlear nuclear neuron size in deaf kittens].

It is now well recognized that normal afferent innervation is necessary for development of the auditory pathway. This study investigated the effect of chronic electrical stimulation of the auditory nerve on the size of cochlear nucleus somata of neonatally deafened kittens. Four kittens were deafened by using kanamycin and ethacrynic acid at 10 days of age and implanted at various ages with an active intracochlear implant in the left side and a dummy implant in the right side, and chronically electrically stimulated from ages 98-142 days for approximately 1000 hours at twice the EABR threshold. After chronic stimulation or after an equivalent period in the controls, the animals were injected with 2-deoxyglucose (2DG) and stimulated electrically for 45 minutes, then processed for autoradiography. Then the sections were stained for Nissle substance, and the cross-sectional areas (CSSA) of approximately 33,000 neuron somata in the cochlear nuclei were measured with an image-analysis system. Soma sizes in regions with 2DG uptake were compared with those without the uptake. The CSSA of 2DG-labeled regions was usually significantly larger than that of the unlabeled regions, but there were no significant right-left differences. Thus, chronic electrical stimulation of a restricted sector of the cochlea is correlated with a larger soma size in the corresponding region of the cochlear nucleus.

Animals↗
PubMed2000

Use of membrane vesicles to investigate drug interactions with transporter proteins, P-glycoprotein and multidrug resistance-associated protein.

BACKGROUND: The ATP-dependent drug transporter proteins, P-glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP) are known to be involved in drug efflux that reduces drug accumulation and so renders tumor cells resistant to the cytotoxic effects of a number of anticancer agents. The ways in which these transporters bring about drug expulsion are not fully explained and may involve intracellular factors as well. Thus detailed evidence may be difficult to obtain from studies on intact cells. MATERIAL AND METHODS: Inside-out plasma membrane vesicles prepared from multidrug-resistant cells expressing high amounts of Pgp or of MRP provide a simpler system for investigating the interactions of putative substrates and resistance modifiers with the transport process. We consider here some aspects of the accumulation of radiolabelled vincristine and of dinitrophenol glutathione conjugate by these vesicles and demonstrate the usefulness of this approach for determining whether potential inhibitors have their effects on transport at the cell membrane or by more indirect means. CONCLUSIONS: We show that information gained from analysis of the ATP-dependence, time course and osmotic sensitivity of accumulation is helpful in distinguishing between transport and changes in binding. We have also used the technique to demonstrate the effects of the resistance modifier, XR-9051 on Pgp-mediated transport and to explore interactions of MK571, indomethacin and ethacrynic acid with MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Purification and biochemical properties of glutathione S-transferase from Lactuca sativa.

A glutathione S-transferase (GST) from Lactuca sativa was purified to electrophoretic homogeneity approximately 403-fold with a 9.6% activity yield by DEAE-Sephacel and glutathione (GSH)-Sepharose column chromatography. The molecular weight of the enzyme was determined to be approximately 23,000 by SDS-polyacrylamide gel electrophoresis and 48,000 by gel chromatography, indicating a homodimeric structure. The activity of the enzyme was significantly inhibited by ShexylGSH and S-(2,4-dinitrophenyl) glutathione. The enzyme displayed activity towards 1-chloro-2,4-dinitrobenzene, a general GST substrate and high activities towards ethacrynic acid. It also exhibited glutathione peroxidase activity toward cumene hydroperoxide.

Enzyme Inhibitors↗
PubMedDate not supplied

[Prevention of phenylephrine-induced acute experimental pulmonary edema in the rat using furosemide].

The intravenous, intraperitoneal or oral administration of furosemide before intravenous infusion of phenylephrin protects rats, the highest doses and the longest the time between administration of the diuretic drug and the beginning of injection, inducing the best protection. The diuretic effects of furosemide do not seem to be the only ones involved because rehydrated animals by isotonic saline solution are still protected. Moreover other diuretic drugs as acetazolamide are useless and on the other hand ethacrynic acid, without any diuretic activity in the Rat, can protect that animal from the edematous effects of phenylephrin.

Acute Disease↗
PubMed1999

An approach to optimizing the active site in a glutathione transferase by evolution in vitro.

A glutathione transferase (GST) mutant with four active-site substitutions (Phe(10)-->Pro/Ala(12)-->Trp/Leu(107)-->Phe/Leu(108)-->Arg) (C36) was isolated from a library of active-site mutants of human GST A1-1 by the combination of phage display and mechanism-based affinity adsorption [Hansson, Widersten and Mannervik (1997) Biochemistry 36, 11252-11260]. C36 was selected on the basis of its affinity for the transition-state analogue 1-(S-glutathionyl)-2,4, 6-trinitrocyclohexadienate. C36 affords a 10(5)-fold rate enhancement over the uncatalysed reaction between reduced glutathione and 1-chloro-2,4-dinitrobenzene (CDNB), as evidenced by the ratio between k(cat)/K(m) and the second-order rate constant k(2). The present study shows that C36 can evolve to an even higher catalytic efficiency by an additional site-specific mutation. Random mutations of the fifth active-site residue 208 allowed the identification of 18 variants, of which the mutant C36 Met(208)-->Cys proved to be the most active form. The altered activity was substrate selective such that the catalytic efficiency with CDNB and with 1-chloro-6-trifluoromethyl-2,4-dinitrobenzene were increased 2-3-fold, whereas the activity with ethacrynic acid was decreased by a factor of 8. The results show that a single-point mutation in the active site of an enzyme may modulate the catalytic activity without being directly involved as a functional group in the enzymic mechanism. Such limited modifications are relevant both to the natural evolution and the in vitro redesign of proteins for novel functions.

Amino Acid Substitution↗
PubMed2000

Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.

The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system. p-[(14)C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, alpha-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [(14)C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics.

Acetazolamide↗
PubMed2001

Determination and multivariate statistical analysis of biochemical responses to environmental contaminants in feral freshwater fish Leuciscus cephalus, L.

Modulations of 11 prospective biochemical markers of impacts of aquatic pollutants in liver tissue of chub (Leuciscus cephalus), caught at several sampling sites of a river with various pollution types and rates, were matched against analytical data of concentrations of organochlorine compounds, polycyclic aromatic hydrocarbons (PAHs), and heavy metals. Multivariate principal component analysis (PCA) of the field data showed general patterns of biochemical responses to different types of pollutants and relationships among the biomarkers. Cytochrome P4501A-dependent 7-ethoxyresorufin O-deethylase (EROD) activity, inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin and structurally related planar compounds, was strongly enhanced in the more contaminated areas. Compared with polychlorinated aromatic hydrocarbons, PAHs did not contribute so significantly to EROD induction. Testosterone 6 beta- and 16 alpha-hydroxylase activities, as an expression of the cytochrome P4503A27, were slightly increased at several sites but were significantly decreased in samples from some heavily polluted areas. Recently, these activities have been suggested as potential biomarkers of exposure to contaminants that do not induce cytochrome P4501A. In this study, their inhibition or induction was not associated with a specific class of monitored contaminants, and selectivities of these modulations are still to be investigated. Similar modulations of the prospective biochemical indicators of oxidative stress, including microsomal glutathione S-transferase activity, cytosolic glutathione S-transferase with ethacrynic acid, and glutathione reductase, were demonstrated by PCA. The pattern of the modulations of the microsomal nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lipid peroxidation in vitro differed from the responses of the rest of oxidative stress parameters at some sampling sites. Further biochemical markers of oxidative stress under study, including in vivo lipid peroxidation, in vitro production of reactive oxygen species, and the concentration of metallothioneins did not correlate well with the concentrations of the contaminants. Principal component analysis demonstrated that the EROD activity, glutathione-dependent enzymes, and Fe(II)-enhanced lipid peroxidation formed a suitable battery of biomarkers of exposure.

Animals↗
PubMed2001

Efflux of glutathione conjugate of monochlorobimane from striatal and cortical neurons.

Evidence for the presence of a novel transporter in primary cultures of rat striatal neurons and mouse cortical neurons similar in function to the multidrug resistance-associated protein (MRP1) is presented. Functional activity was assessed by efflux studies with the glutathione conjugate of monochlorobimane (B-SG). The glutathione transferase-catalyzed formation of B-SG in rat striatal neurons and mouse cortical neurons was inhibited by ethacrynic acid. The efflux of B-SG from rat striatal neurons and mouse cortical neurons was lower at 20 degrees C than at 37 degrees C and was lower in cells with reduced ATP concentrations compared with cells with constitutive ATP concentrations. In addition, the efflux of B-SG was inhibited by MK-571 in both rat striatal and mouse cortical neurons and by probenecid in rat striatal neurons, but not in mouse cortical neurons. Verapamil did not inhibit B-SG efflux in either rat striatal or mouse cortical neurons. Although functionally similar to MRP1, Western blot analysis with commercially available antibodies directed against human and mouse MRP1 failed to show MRP1-like protein in either whole-cell homogenates of rat striatal neurons or mouse cortical neurons, indicating that the described neuronal transporter differs in structure from human or mouse MRP1 or lacks epitopes in common with MRP1.

ATP-Binding Cassette Transporters↗
PubMed1975

Effect of diuretics on oxidative phosphorylation of dog kidney mitochondria.

An effect of diuretics on cellular metabolism has been shown. In order to examine further the direct effect of diuretics on renal mitochondria, their effect on isolated cortical (C) and outer medullary (OM) mitochondrial respiration was examined. Oxygen consumption rate (QO2) was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. QO2, expressed in nanoatoms of O2 per milligram of protein per minute, was always higher in C than OM: 140.7 +/- 2.8 VS. 121.2 +/- 2.4 (P less than 0.001) with glutamate-malate and 181.1 +/- 6.3 vs. 129.7 +/- 5.2 (P less than 0.001) with succinate. A dose-response curve was constructed for each of the following: sodium ethacrynate, furosemide, chlorothiazide, acetazolamide and chlormerodrin. All diuretics inhibited C and OM equally. The 50% inhibitory molar concentration for EA was 6.2 times 10(-4); for furosemide 1.5 times 10(-3); for chlorothiazide 8.1 times 10(-3); for acetazolamide 10.8 times 10(-3); and for chlomerodrin 3.1 times 10(-5). Neither cysteine nor dithiothreitol inhibited the effect of EA. The effect of chlormerodrin was abolished by cysteine. These results demonstrate that while a difference exists between C and OM mitochondria during control studies, each of the diuretics examined exerted an equal inhibitory effect on mitochondrial respiration from both C and OM. Mercurials are the most potent inhibitors and presumably exert their effect by reacting with sulfhydryl groups. They are followed in potency by ethacrynic acid, furosemide, chlorothiazide and acetazolamide.

Animals↗
PubMed1975

Ouabain-sensitive adenosine triphosphatase from human kidneys.

Adenosine triphosphatase (ATPase) was studied in tissue homogenates and subcellular fractions derived from human cadaver kidneys maintained in an organ preservation unit for transplantation. The activity of ouabain-sensitive ATPase was highest in the medulla, intermediate in the cortex and lowest in the papilla, The cortical enzyme activity diminished with time during maintenance perfusion of the kidneys. Similar concentrations of K+, Na+, Mg++, ATP and MgATP were required for half-maximal rates of ouabain-sensitive ATPase activity from the cortex or the medulla. The sensitivity of the enzyme to ouabain from both parts of the kidney was similar. K+ antagonized inhibition of the enzyme by ouabain. Chlormerodrin, mersalyl, mercaptomerin and ethacrynic acid were inhibitors of the enzyme.

Adenosine Triphosphatases↗
PubMed1975

Oubain-sensitive adenosine triphosphatase from human kidneys.

Adenosine triphosphatase (ATPase) was studied in tissue homogenates and subcellular fractions derived from human cadaver kidneys maintained in an organ preservation unit for transplantation. The activity of ouabain-sensitive ATPase was highest in the medulla, intermediate in the cortex and lowest in the papilla. The cortical enzyme activity diminished with time during maintenance perfusion of the kidneys. Similar concentrations of K+, Na+, Mg++, ATP and MgATP were required for half-maximal rates of ouabain-sensitive ATPase activity from the cortex or the medulla. The sensitivity of the enzyme to ouabain from both parts of the kidney was similar. K+ antagonized inhibition of the enzyme by ouabain. Chlormerodrin, mersalyl, mercaptomerin and ethacrynic acid were inhibitors of the enzyme.

Adenosine Triphosphatases↗
PubMedDate not supplied

[A comparative study of the substrate and inhibitor specificity of the glutathione transferase from the spring grain aphid (Schizaphis gramina Rond.) and from rat liver].

Kinetic parameters of 9 substrates interaction with glutathione transferase (GST) from spring grain aphid and rat were studied. The most significant difference in Vmax values was noticed for 4-nitropyridine-N-oxide (6 times higher for aphid) and ethacrynic acid (7 times higher for rat). Km values were practically in all cases higher for aphid GST as compared to rat GST. New class of effectors of GST suggested by us, that is azimines (2 series), was used for the inhibitor analysis. GST interaction with these inhibitors was appreciated by three types of activity: nucleophilic replacement, thiolysis and N-deoxygenation. It has been shown that the degree of GST inhibition depended considerably both on the GST source and the substrate used. New high-effective inhibitors of GST were found among azimines and their higher specificity to rat GST as compared to aphid GST was demonstrated especially in thiolysis reaction.

Animals↗
PubMed1992

Biochemical characterization of resistance to mitoxantrone and adriamycin in Caco-2 human colon adenocarcinoma cells: a possible role for glutathione S-transferases.

Cytotoxicity of Adriamycin on human colon adenocarcinoma cell lines was investigated. Concentrations of Adriamycin producing 50% inhibition were very similar in HT29, Sw480, Sw620, and Sw1116 cells, whereas Caco-2 cells were relatively insensitive. As compared to the Sw1116 cell line, Caco-2 cells were also insensitive to mitoxantrone. Sensitivity to cisplatin, 5-fluorouracil, or ethacrynic acid was comparable in both cell lines. To find the mechanism for this mitoxantrone and Adriamycin resistance, several potential Adriamycin-detoxifying systems were characterized and quantified in both Sw1116 and Caco-2 cells. No dramatic differences in glutathione content and expression of both selenium dependent- and independent glutathione peroxidase, UDP-glucuronyltransferase, and cytochrome P-450 were found. However, highly significant differences in glutathione S-transferase activity were present, the expression of both class pi and class alpha glutathione S-transferases being much higher in the Caco-2 cell line. In addition, a slightly higher content of P-170 glycoprotein was present in the Caco-2 cells. These findings suggest that glutathione S-transferases, and to a lesser extent the P-170 glycoprotein, may be involved in mitoxantrone and Adriamycin resistance of Caco-2 colon carcinoma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗