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PubMed1989

An ATP-driven Cl- pump in the brain.

EDTA-treated microsomes prepared from rat brain mainly consisted of sealed membrane vesicles 200-500 nm in diameter and were rich in both Cl- -ATPase and Na+,K+-ATPase activities. Such Cl- -ATPase-rich membrane vesicles accumulated Cl- in an ATP-dependent and osmotically reactive manner in the presence of 1 nM ouabain. The Cl- uptake was maximally stimulated by ATP with a Km value of 1.5 mM; GTP, ITP, and UTP partially stimulated Cl- uptake, but CTP, beta, gamma-methylene ATP, ADP, and AMP did not. The ATP-dependent Cl- uptake was accelerated by an increase in the medium Cl- concentration with a Km value of 7.4 mM. Such stimulation of Cl- uptake by ATP was dependent on the pH of the medium, with an optimal pH of 7.4, and also on the temperature of the medium, with an optimal range of 37-42 degrees C. Ethacrynic acid dose dependently inhibited the ATP-dependent Cl- uptake with a concentration for half-maximal inhibition at 57 microM. N-ethylmaleimide (0.1 mM) completely inhibited and sodium vanadate (1 mM) partially inhibited the ATP-dependent Cl- uptake. The membrane vesicles did not accumulate H+ in the Cl- uptake assay medium. The ATP-dependent Cl- uptake profile agreed with that of Cl- -ATPase activity reported previously (Inagaki, C., Tanaka, T., Hara, M., and Ishiko, J. (1985) Biochem. Pharmacol. 34, 1705-1712), and this strongly supports the idea that Cl- -ATPase in the brain actively transports Cl-.

Adenosine Triphosphatases↗
PubMedDate not supplied

Haloperidol reductase in human and guinea pig livers.

A GC assay method for haloperidol reductase was developed. Haloperidol reductase was present in guinea pig liver cytosol as well as in the microsomes, while in human liver only the cytosol exhibited the activity. The reductase activity was NADPH dependent for both species. Known substrates of ketone reductase such as menadione, daunorubicin, and ethacrynic acid strongly inhibited the human haloperidol reductase. The haloperidol reductase showed characteristics of ketone reductase.

Animals↗
PubMed1989

Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle's loop.

Studies were conducted to investigate direct effects of loop diuretics on prostaglandin E2 (PGE2) production using microdissected nephron segments. At first, the effect of indomethacin on the diuretic response to furosemide was re-evaluated in anesthetized rats. Indomethacin significantly attenuated the diuretic, natriuretic and chloruretic effects of furosemide without significantly affecting inulin and p-aminohippurate clearance or filtration fraction. But, in nondiuretic states, indomethacin had no significant effects on these parameters. Furosemide, ethacrynic acid and bumetanide significantly increased PGE2 production in cortical and medullary thick ascending limbs of Henle's loop (P less than .001), but not PGE2 production in the cortical and outer medullary collecting tubules. The effect of furosemide on PGE2 production in CTAL was dose-dependent, and higher concentrations of of furosemide than 10(-6) M significantly increased PGE2 production. On the other hand, chlorothiazide showed no PGE2 productive stimulation in these four nephron segments. This study demonstrates that the enhanced PGE2 production in the thick ascending limb of Henle's loop by furosemide and other loop diuretics is one possible mechanism of these drugs.

Animals↗
PubMedDate not supplied

Renal prostaglandins E2 and I2. Aspects of metabolism, and relationship to renal hemodynamics and renin release mechanisms.

Similar distributions of prostaglandins in urine and renal venous blood both during prostaglandin infusion and stimulated synthesis indicated a vascular origin for both urinary and renal venous PGE2 and PGI2. Various stimulation procedures demonstrated that the renal vasculature releases PGE2 and PGI2 in a fixed proportion. Renal degradation of circulating prostaglandins was not influenced by ureteral occlusion and seems to be mainly confined to the blood vessels. The vascular capacity for both synthesis and degradation was much greater for PGE2 than for PGI2. Urinary PGE2 was shown to be of renal origin, but constituted a small and variable fraction of renally produced PGE2, making it a poor estimate of renal PGE2 synthesis. Urinary 6-keto-PGF1 alpha may originate from renal PGI2 production or from circulating 6-keto-PGF1 alpha which readily appears in the urine. Equimolar infusions of PGE2 and PGI2 demonstrated that PGI2 was a more potent stimulator of renin release than PGE2, but the difference seemed to be mainly due to differences in degradation and not to differences in intrinsic potency. Prostaglandins stimulated renin release only when the intrarenal mechanisms for renin release were activated and not at control blood pressure and free urine flow. beta-adrenoceptor agonists stimulated renin release independently of activation of the macula densa, but required activation of the hemodynamic mechanism. Ethacrynic acid activated both the hemodynamic and the macula densa mechanism, but had no direct stimulatory effect on renin release. PGE2 and PGI2 were released during autoregulatory vasodilation, but neither PGE2 nor PGI2 participated in the autoregulatory mechanism. Autoregulatory and prostaglandin mediated vasodilation seems to be independent. Descending autoregulatory vasodilation was demonstrated during successive reductions in RAP, but a more simultaneous dilation of all preglomerular vessels was indicated during successive elevations of ureteral pressure. This difference may be due to participation of TGF together with the myogenic mechanism in autoregulation of RBF. Participation of TGF may also explain why prostaglandin and renin release dissociate during successive reductions in RAP, but increase in parallel during successive elevations of ureteral pressure. It also explains why maximal renin release induced both by the hemodynamic and the macula densa mechanism coincides with the breaking point of the RBF autoregulatory curve, and why loop diuretics induce complete autoregulatory vasodilation at control blood pressure.

Animals↗
PubMed1989

Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is known to be detoxified by a denitrosation reaction catalyzed by glutathione-dependent enzymes in rat liver cytosol (R. E. Talcott and V. A. Levin, Drug Metab. Dispos., 11:175-176, 1983). Using a modification of their procedure, we have measured the ability of different purified rat glutathione transferase isoenzymes to denitrosate BCNU. The catalytic efficiencies of the isoenzymes for the denitrosation reaction expressed as the ratio of Vmax to Km were as follows (isoenzyme, Vmax/Km): 1-2, 2.3; 3-3, 12.2; 3-4, 29.2; and 4-4, 26.1. Thus, the class mu isoenzymes containing subunit 4 are by far the best catalysts of the BCNU denitrosation reaction. The class pi transferase 7-7 and class alpha transferases 1-1 and 1-2 demonstrated very weak catalytic activity with BCNU. Determination of the glutathione transferase isoenzyme profiles of 9L rat brain tumor cells and the BCNU-resistant 9L-2 subline by immunoblotting revealed that although the resistant 9L-2 cells contain lower total glutathione transferase activity than 9L cells, they have elevated levels of the class mu transferases. Also, the class pi transferases were found to be down-regulated in 9L-2 as compared with 9L cells. Thus, the increased resistance of 9L-2 cells to BCNU may, in part, be explained by up-regulation of class mu transferase expression with consequent increased capacity for BCNU detoxication. Further support for this hypothesis comes from the fact that pretreatment of 9L-2 cells with the glutathione transferase inhibitors ethacrynic acid or triphenyltin chloride enhanced the cytotoxic effects of BCNU. These results suggest that the class mu transferases play a role in the resistance of brain tumor cells to BCNU.

Animals↗
PubMedDate not supplied

Use of antihypertensive agents in patients with glucose intolerance.

The selection, use, and potential adverse effects of antihypertensive agents in patients with glucose intolerance are reviewed. Thiazide diuretics frequently impair glucose tolerance, but this deterioration is usually modest and should not preclude use of these agents in most patients with glucose intolerance. The loop diuretics furosemide and ethacrynic acid have also been associated with decreased glucose tolerance. The beta-adrenergic blocking agents may inhibit insulin secretion, but few patients will experience clinically important elevations in blood glucose. Rather than producing glucose intolerance, these agents may delay recovery from hypoglycemic episodes and may mask catecholamine-induced symptoms of hypoglycemia. In certain cases, use of cardioselective beta blockers or avoidance of beta-blocker therapy may be indicated, especially in insulin-dependent diabetics. The calcium-channel blocking agents nifedipine and verapamil have been reported to produce diabetogenic effects in a few studies, but further investigations are needed to define the extent of these effects. Available evidence indicates that sympatholytic agents such as guanethidine and reserpine, alpha 2-adrenergic agonists such as methyldopa and clonidine, the alpha 1-blocking agent prazosin, and the vasodilators captopril and hydralazine produce few, if any, clinically important changes in glucose tolerance. While no antihypertensive agents are absolutely contraindicated in patients with glucose intolerance, patients with glucose intolerance who are receiving thiazide diuretics, beta blockers, and calcium-channel blocking agents should be monitored with extra care for hyperglycemia or deterioration in glucose tolerance.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Glutathione conjugates. Immobilized enzyme synthesis and characterization by fast atom bombardment mass spectrometry.

Glutathione transferase activity was shown to be present in an immobilized preparation of microsomal protein. Chlorodinitrobenzene, ethacrynic acid, captopril, styrene oxide, and iminocyclophosphamide were found to be substrates, each providing a different kind of electrophilic functional group for conjugation. The glutathione conjugates were characterized by thin layer chromatography (visualized by reaction with ninhydrin) and by high pressure liquid chromatography. A variety of conditions was evaluated for analysis of these glutathiones by fast atom bombardment mass spectrometry.

Animals↗
PubMed1987

Induction of anionic glutathione transferases in rat liver by propylthiouracil.

The treatment of rats with propylthiouracil (PTU) resulted in an induction of not only cationic but also anionic glutathione (GSH) transferases. DE-52 column chromatography of the anionic GSH transferases divided into five main peaks (I-V). Peaks I-IV had a high activity toward 1-chloro-2,4-dinitrobenzene (CDNB). Peak V, which is a new form of the enzyme, showed high activity to ethacrynic acid. PTU induced peaks I and V, whereas phenobarbital increased the activity of only peak I.

Animals↗
PubMed1988

The effects of cetrimide and potassium bromate on the potassium ion concentration in the inner ear fluid of the guinea-pig.

The mammalian inner ear is located deep within the temporal bone. The organ of Corti, the delicate sensory system for sound, is surrounded by two fluid systems; the potassium-rich endolymph and the sodium-rich perilymph. The pathogenesis of inner ear deafness is thought to be largely due to an imbalance of potassium and sodium ions in the inner ear fluids. Dynamic changes in K+ in the endolymph and perilymph were studied in the guinea-pig following cetrimide (cetrimonium bromide, a powerful cationic detergent which shows ototoxicity) applications on the round window membrane, intramuscular injection of potassium bromate (bread whitener, known to cause renal damage and permanent deafness in animals and man). Maximum fall in K+ concentration in the endolymoh (mM/min) and maximum K+ conductance (mM/min/mV) were 3.54 +/- 1.65 and 0.036 +/- 0.02 in cetrimide, and 1.85 +/- 0.35 and 0.021 +/- 0.009 in potassium bromate, respectively. In view of these findings, the influence of the active transport mechanism to K+ concentrations are discussed in comparison with dynamic changes in endolymph K+ induced by asphyxia and ethacrynic acid.

Animals↗
PubMed1985

Cross-resistance and biochemical studies with two classes of HeLa cell mutants resistant to cardiac glycosides. The unusual behavior of cardenolide SC4453.

In HeLa cells two different types of mutants resistant to the cardiac glycoside ouabain (OuaR mutants) or erythrophleum alkaloid cassaine (CasR mutants) have been obtained. One type of mutants resistant to these compounds (designated as group A) are highly resistant (between 50 and 2000-fold) to various cardiac glycosides and their genins such as ouabain, oleandrin, digitoxin, digitoxigenin, strophanthidin, convallatoxin, gitoxin, gitoxigenin, gitaloxin, bufalin, and digoxigenin, but exhibit no cross-resistance to SC4453, a digoxin analog which contains a pyridazine ring in place of the lactone ring in the C-17 position. The second type of mutants (group B) exhibit cross-resistance to all of the cardiac glycosides including SC4453, but their level of resistance is at least 5-10-fold less than that of group A mutants. Interestingly, both groups of mutants exhibited similar degree of cross-resistance towards digoxin and actodigin (AY22241), indicating some differences in their behavior from other cardiac glycosides. Both classes of mutants exhibit no cross-resistance to a wide variety of other structurally and functionally related compounds, e.g. sanguinarine nitrate, ethacrynic acid, penicillic acid, veratridine, harmaline hydrochloride, 5,5'-diphenylhydantoin, quindonium bromide, methyl quinolizinum bromide, estradiol 17 beta-acetate, 21-acetoxy-pregnenolone, vanadium pentoxide, digitonin, and adriamycin, indicating that the genetic lesions in both groups of mutants are specific for cardiac glycosides. This inference is supported by the observation that both group A and B mutants show reduced binding of [3H]ouabain. In group A mutants, a part of the Na+/K+-ATPase activity is highly resistant to inhibition by ouabain, indicating that the genetic lesion in these mutants directly affects Na+/K+-ATPase. In contrast, the Na+/K+-ATPase from the group B mutants showed similar resistance towards ouabain and SC4453 as observed for the parental HeLa cells, indicating that these mutants are affected in a cellular component, other than Na+/K+-ATPase, which is involved in the interaction of cardiac glycosides with the cells. The lack of cross-resistance of the group A mutants to SC4453 and normal sensitivity of their Na+/K+-ATPase to this compound provides strong evidence that the mechanism of interaction of SC4453 with Na+/K+-ATPase differs from that of other cardiac glycosides.

Abietanes↗
PubMed1986

Biochemical and cross-resistance studies with HeLa cell mutants resistant to cardiac glycoside SC4453. Regulation of the resistant form of Na+/K+-ATPase in the mutant cells.

In HeLa cells, stable mutants which are between 25-to about 200-fold resistant to the cardiac glycoside derivative SC4453 (a digoxin analog which contains a pyridazine ring in place of a lactone ring in the C-17 position) have been isolated after a single step selection in the presence of the drug. Based on their cross-resistance pattern towards various cardiac glycosides, the mutants resistant to SC4453 (SCR mutants) appear to be of two different kinds and they differ from the two classes of ouabain-resistant mutants described previously (Gupta, R. S., and Chopra, A. (1985) J. Biol. Chem. 260, 6843-6850). One type of SCR mutants (designated as group C) exhibit a high degree of cross-resistance to all cardiac glycosides and their genins (viz. ouabain, digitoxin, digoxin, digoxigenin, convallatoxin, gitoxin, strophanthidin, and bufalin). In contrast, the second type of SCR mutant (group D) exhibit considerable resistance to only SC4453, digoxin, and digoxigenin, but showed very little or no cross-resistance to the other cardiac glycosides examined. The cross-resistance of the mutants towards cardiac glycosides was highly specific as they exhibited no cross-resistance towards a large number of other structurally and functionally related compounds (viz. ethacrynic acid, sanguinarine nitrate, penicillic acid, methyl quinolizinum bromide, 5,5'-diphenylhydantoin, deoxycorticosterone, vanadium pentoxide, and adriamycin). The cellular uptake of 86Rb in the mutant cells was found to be resistant to specific cardiac glycosides. Studies on the sensitivity of plasma membrane Na+/K+-ATPase to cardiac glycosides show that about 10-15% of the enzymic activity in the mutant cells was highly resistant to inhibition by the specific drugs to which the mutants exhibit increased resistance. Very interestingly, when the mutant cells are grown in cardiac glycoside-containing medium, the resistant form of the enzyme accounts for about 50-60% of the total enzyme. These results show that both classes of SCR mutants are affected in Na+/K+-ATPase and that the amount of the resistant enzyme in the mutant cells is regulated in response to cardiac glycosides.

Cardiac Glycosides↗
PubMed1987

The glial blood-brain barrier of crustacea and cephalopods: a review.

1. The glial blood-brain barrier of invertebrates is an accessible, polarised glial layer that permits study of glial cells in their normal relations with neurons. Crayfish 2. The glial "perineurium" forms the blood-brain interface in crayfish, and acts as a barrier to horseradish peroxidase (HRP) and ionic lanthanum. By contrast, the perineurium of the peripheral nervous system is relatively permeable. 3. The ionic permeability of the blood-brain interface can be studied in a sucrose gap chamber, using an extra-cellular microelectrode to monitor the potential across the perineurium following changes in the bathing medium. Subtraction of the microelectrode trace from the sucrose gap records gives the change in the axonal membrane potential. 4. Raised [K+] in the bath causes a complex change in perineurial potential, with the initial transient indicating that the outer (basal) glial membrane is highly K+ selective. The axonal response shows that the time constant for K+ uptake (tau u) and efflux (tau E) across the perineurium of the order of 3-4 min, but the interstitial [K+] in the steady state, [K+] infinity is always less than in the bathing medium. The results are explained by a model incorporating a K+ sink, which may be glial. 5. Strophanthidin and ethacrynic acid have little effect on tau u or K infinity, but cause a rise of tau E. Cold temperature pulses causes changes in the perineurial potential compatible with depolarisation of the inner (apical) membrane. A model is proposed with a Na+-K+-2 Cl co-transporter on the perineurial basal membrane, and an electrogenic Na+-K+-ATPase on the apical.membrane, consistent with results from vertebrate glial/ependymal epithelia. Cephalopods 6. The brain of the cuttlefish Sepia has an extensive system of microvessels. In the vertical and optic lobes studied, a perivascular glial layer forms a barrier to HRP. The occluding structure appears not to be a classical tight junction but may involve condensation of extracellular material. There is no barrier between retinal axons and blood. 7. Studies with radiolabelled polyethylene glycol (PEG4000) and EDTA show that the Sepia blood-brain barrier is as tight as the endothelial barrier of mammals. 8. A modification of the Oldendorf arterial injection technique is used to show that glucose transport at the Sepia barrier is mediated by a Na+-independent hexose carrier resembling that of mammalian red cells and blood-brain barrier. 9. The blood-axon interface fo mantle nerves in the squid Alloteuthis is relatively impermeable to small ions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

[Effect of diuretics on the absorption of glucose in rat small intestine].

During acute experiments on rats with perfusion of the rat jejunum portion in situ it was shown that ethacrynic acid (10(-4) M) and novurit (10(-4) M) suppress glucose and water absorption. Furosemide (2.10(-3) M) and dichlothiazide (2.10(-3) M) failed to influence glucose absorption and to change sodium and water transport under the same experimental conditions.

Animals↗
PubMed1986

[Diuretics].

Microaspiration techniques and clearance studies have shown that reabsorption of filtered sodium approximates 65% in the proximal tubule, 25 to 30% in the ascending limb of the loop of Henle and 5 to 10% in the dilution segment. Reabsorption in the Henle loop is of special significance as it governs the process of dilution-concentration of urine. Moreover, inhibition of sodium reabsorption in the loop of Henle necessarily produces a substantial loss of sodium since only a fairly small fraction of urinary sodium is reabsorbed beyond the Henle loop (dilution segment, distal tubule). Excretion of water and electrolytes is regulated by humoral factors, such as the renin-angiotensin-aldosterone system, some prostaglandins and certain kinins. Factors that promote excretion of sodium, produced in particular by the myocardium, have recently been demonstrated. The correlation between blood pressure and salt has been substantiated by many findings. Diuretics are commonly used to treat high blood pressure as well as edema. Recent evidence indicates that sodium transport is altered in idiopathic hypertension, at least in red blood cells. Clinical trials of diuretics are designed to localize the drug's action and quantify its saluretic activity (evaluation of potency and effectiveness--single doses, sustained treatment). Furthermore, the minimal efficient antihypertensive dosage should be determined. Diuretics can be divided into two groups according to whether they produce an increase or decrease in serum potassium. Diuretics that are capable of producing hypokalemia belong to two main families. One consists of the Henle loop diuretics that interfere with the mechanisms of dilution-concentration of urine. Action of these drugs is potent and short-lived. For instance, following a single dose of furosemide, excretion of sodium can reach 25-30% of filtered sodium; renal blood flow increases; CH2O and TCH2O decrease. With furosemide, induction of diuresis is rapid (within a few minutes after IV injection and 20 mn after oral ingestion); elimination half-life is 50 mn; absolute bioavailability is 50-70%; 95% of the drug is bound to plasma proteins; elimination is mainly through the kidneys. Other Henle loop diuretics include ethacrynic acid, whose elimination half-life is less than one hour; bumetanide, which is 40 times more potent than furosemide; muzolimine, whose action is more lasting despite the fact that only 65% of the drug is bound to plasma proteins; and ozolinone, which has a saliuretic action comparable to that of furosemide and in addition exerts a direct vasodilating effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid-Base Equilibrium↗
PubMed1987

Induction and suppression of glutathione transferases by interferon in the mouse.

The administration of interferon-alpha/beta to female nude (nu/nu) mice caused significant changes in the levels of the cytosolic hepatic glutathione transferases. Antibodies raised against rat subunits, Ya, Yc, Yb1, Yb2, and Yk, and the subunits of the human transferases, mu (YbYb), lambda (YfYf), and epsilon (B1B1) all reacted with enzymes in the mouse and were used to demonstrate suppression and induction of transferase levels. Western blot analysis followed by semiquantitation by laser scanning showed the Ya, Yb1, Yb2, Yc, Yk, mu, and B1 subunits to be suppressed by 11, 11, 44, 30, 12, 14, and 47%, respectively, by interferon treatment. In contrast to these findings, the Yf subunit was induced 5-7-fold. A concomitant 220% increase was observed in the specific activity of the hepatic cytosol for ethacrynic acid, a substrate for the Yf subunit. Changes in the levels of transferase enzymes in normal and tumor cells may have significant implications when cytotoxic drugs are used in combination with interferons in cancer therapy. The Yf subunit, an enzyme found in human tumors and in placenta (Polidoro, G., Di Mio, C., Del Boccio, G., Zulli, P., and Fererici, G. (1980) Biochem. Pharmacol. 29, 1677-1680) has also been shown to be elevated in hepatic preneoplastic lesions (Kitahara, A., Satoh, K., Nishimura, K., Ishikawa, T., Ruike, K., Sato, K., Tsuda, H., and Ito, N. (1984) Cancer Res. 44, 2698-2703). These data indicate that the Yf subunit represents a potentially important interferon-inducible gene product.

Animals↗
PubMed1987

Reduced levels of drug-induced DNA cross-linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione S-transferase activity.

We have reported previously (C. N. Robson et al., Cancer Res., 46: 6290-6294, 1986) the isolation of a Chinese hamster ovary cell line, designated CHO-Chlr, that exhibits resistance to bifunctional nitrogen mustards while maintaining the normal parental level of sensitivity to several other alkylating agents. We have compared the rate of formation and repair of DNA cross-links induced by mechlorethamine in CHO-Chlr and parental CHO-K1 cells, both in intact cells and in isolated nuclei. Equimolar doses of mechlorethamine induce significantly fewer DNA interstrand cross-links in CHO-Chlr cells than in CHO-K1 cells, but levels of DNA-protein adducts are approximately equivalent in the two lines. There is a correlation between the relative resistance of CHO-Chlr cells to mechlorethamine (34-fold) and the amount of drug required to induce approximately equal numbers of DNA interstrand cross-links in the two cell lines. This strongly implicates DNA-DNA adducts in the cytotoxic action of mechlorethamine. DNA cross-linking studies on isolated nuclei reveal only minor differences between the two lines even with identical drug treatments. The rate of cross-link repair is comparable in the two cell lines. These results, taken together with our earlier observation that the rate of drug accumulation is identical in these two lines, suggest that enhanced cytoplasmic drug detoxification is the underlying resistance mechanism in CHO-Chlr cells. We have measured cellular glutathione S-transferase activity, using both the general substrate 1-chloro-2,4-dinitrobenzene, and substrates with some specificity for the different classes of transferase isoenzymes. Total enzyme activity (as measured with 1-chloro-2,4-dinitrobenzene) is elevated 3-fold in the resistant cells. A 2- and 5-fold increase, respectively, in activity against ethacrynic acid and cumene hydroperoxide is detectable in CHO-Chlr cells. This elevation in catalytic activity in the resistant cells is reflected in higher levels of both the Yf- and Ya-type transferase subunits.

Animals↗
PubMedDate not supplied

[Mechanism of the anti-ischemic protection of the kidneys by diuretics].

Experiments on rats showed that single doses of diuretics furosemide, ethacrynic acid, mannitol, hypertonic solution of sodium chloride administered subcutaneously 30 and 60 min and intravenously 10 and 20 min before complete arrest of the blood flow in the single kidney for 2.5 hours decrease creatinine content in the blood and increase survival rate of the animals. The anti-ischemic protection occurs provided that the natriuretic effect of the drugs coincides with the ischemic factor action. Morphometry revealed the ability of furosemide to prevent the development of hyperhydration of the epithelial cells, to increase lumina of the proximal and distal tubules. The role of hydrodynamic factors in the mechanism of anti-ischemic protection of the kidneys with diuretics is discussed.

Animals↗
PubMed1985

Inhibition of human red blood cell Na+, K+-cotransport by various "high ceiling" diuretics.

The rank order of diuretic efficacy of furosemide analogs, e.g. bumetanide and piretanide, in humans is reflected better by their ability to inhibit Na+, K+-cotransport in human red blood cells than by their natriuretic activity in rats. High ceiling diuretics which are structurally unrelated to sulfamoyl diuretics, e.g. muzolimine, tizolemide, MK 447, may be similarly effective in rat and man, but by acting via other mechanisms cannot be detected by use of the Na+, K+-cotransport system. On the other hand, a possible conversion of such compounds to metabolites active in the cotransport system cannot be ruled out. In contrast to ethacrynic acid, the weak inhibitory activity of muzolimine on the Na+, K+-cotransport was not potentiated by cysteine. These results suggest that the diuretic activity of muzolimine is not caused by inhibition of Na+, K+-cotransport.

Adult↗