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1. Patients with sickle-cell anaemia were unable to increase free water reabsorption (TcH2O) in response to intravenous hypertonic sodium chloride solution. 2. Ethacrynic acid caused a brisk natriuresis in patients with sickle-cell anaemia but fractional sodium excretion was lower in these patients. 3. These findings could be explained by abnormal function of the loop of Henle.
The use of micellar liquid chromatography for the determination of diuretics in urine by direct injection of the sample into the chromatographic system is discussed. The retention of the urine matrix at the beginning of the chromatograms was observed for different sodium dodecyl sulphate (SDS) mobile phases. The eluent strengths of a hybrid SDS-methanol micellar mobile phase for several diuretics were compared and related to the stationary phase/water partition coefficient with a purely micellar mobile phase. The urine band was appreciably narrower with a mobile phase of 0.05 M SDS-5% methanol (v/v) at 50 degrees C (pH 6.9). With this mobile phase the determination of bendroflumethiazide and chlorthalidone was adequate. Acetazolamide, ethacrynic acid, furosemide, hydrochlorothiazide and probenecid were overlapped by the urine matrix, and the retention of amiloride and triamterene was too long.
Determination of auditory threshold was carried out under a response duration schedule of tone and/or light-dipper presentation. This schedule enabled an exact assessment of auditory sensitivity, since the direction and distance from rat to sound source were constant and the rat could thus acquire the conditioned behavior in a short time. The rat has to press the lever and hold it until a CS(tone and/or light) was presented. The animal could get water-reinforcement with release of the lever during the period of CS. The intensity of 3 KHz pure tone was reduced, from 110 dB (starting point), by 2 dB steps in each trial, until the subject made 3 non-response trials (i.e., no dipper approach within 0.7 sec after the tone onset) among 5 trials. The highest tone intensity among non-response trials was taken as the threshold. The auditory sensitivity of the rats with cotton-stuffed ears and the pierced eardrums decreased about 10 and 20 dB, respectively. The auditory sensitivity in rats was decreased by administration of streptomycin sulfate(SM), 300 mg/kg/day, i.m., in combination with ethacrynic acid(EA), 50 mg/kg/day, p.o., for forty days and in combination with EA, 100 mg/kg/day, p.o. for ten days. The auditory sensitivity was not influenced by administration of SM, 300 mg/kg/day, i.m., for forty days.
We examined the effects of atrial natriuretic polypeptide (hANP) on exocrine function in the isolated and blood-perfused dog pancreas in situ. Intra-arterial injection of hANP (1-10 micrograms) resulted in the dose-dependent increases of the pancreatic juice secretion. The secretory activity of 3 micrograms of hANP was approximately equal to one third of the secretory activity of 0.1 units of secretin. The use of hANP increased the concentration of bicarbonate but not that of sodium and protein in the pancreatic juice as compared with the basal values. These secretory responses to hANP were not inhibited by treatment with haloperidol, sulpiride, phentolamine, propranolol, atropine, cimetidine or ethacrynic acid. These results suggest that hANP acts directly on the pancreatic exocrine gland to stimulate pancreatic secretion; without, however, increasing sodium excretion. The mechanism of this effect remains to be elucidated.
The effects of bumetanide, a new potent diuretic, on net sodium transport of the isolated frog skin and on rat renal Na-K-ATPase were studied. A dose-related decrease in short-circuit current and potential difference with increased electrical resistance was observed when bumetanide was added to the corial side of the skin. Addition to the epithelial side resulted in enhanced net sodium transport with decreased electrical resistance. When applied to the corial side it abolished vasopressin- and aldosterone-stimulated transport. Present in the epithelial bath ouabain-inhibited transport was unaffected by this drug, while triamterene-induced inhibition of sodium transport was completely abolished. In vitro, no significant effects on Na-K-ATPase were noted. It is concluded that bumetanide shares properties of both furosemide and ethacrynic acid and excerts its effects on epithelial sodium transport by altering membrane permeability and possibly by inhibition of some step in the active transport mechanism for sodium.
1. Activities of several biotransformation enzymes were determined in male and female Sigmodon hispidus. Benzphetamine N-demethylase and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene and sulfobromophthalein were higher in male Sigmodon hispidus than the female animals. 2. The study also determined the effect of microsomal enzyme inducing agents on hepatic biotransformation in male Sigmodon hispidus. 3. Cytochrome P-450 concentration was similar in cotton and Sprague-Dawley rats, and was increased after phenobarbital, pregnenolone-16 alpha-carbonitrile, or 3-methylcholanthrene treatment. 4. Benzphetamine N-demethylase was 4-fold higher in Sigmodon hispidus and was induced by 75-100% after phenobarbital. 5. UDP-Glucuronosyltransferase toward estrone, 1-naphthol, diethylstilbestrol and testosterone was 2- to 4-fold higher in cotton rats and was not altered by treatment with the inducing agents. 6. Conjugation of 1-chloro-2,4-dinitrobenzene, ethacrynic acid and sulfobromophthalein with glutathione was similar in both rodent species and was not inducible. 7. Sulfation of 2-naphthol was 15-30% of that in Sprague-Dawley rats and was not increased by inducer administration.
The adverse reactions of antihypertensive agents are reviewed, including their clinical implications and suggested methods of preventing, detecting and managing them. The drugs discussed are: (1) diuretics--thiazides, furosemide, ethacrynic acid and spironolactone; (2) sympatholytics--reserpine, methyldopa, guanethidine, propranolol and clonidine; (3) vasodilators--hydralazine, prazosin and minoxidil. It is suggested that cooperative multi-disciplinary efforts should be undertaken to counteract the factors which contribute to improper use of antihypertensive agents.
We critically reviewed the English language literature pertaining to drug-induced pancreatitis and attempted to determine whether the reported association between each drug and pancreatitis was valid. The following drugs seem to cause pancreatitis: azathioprine, thiazides, sulfonamides, furosemide, estrogens, and tetracycline. Less convincing, but suggestive evidence exists for: 1-asparaginase, iatrogenic hypercalcemia, chlorthalidine, corticosteroids, ethacrynic acid, phenformin, and procainamide. Evidence implicating other drugs is either inadequate or contradictory. Little is known about the pathogenesis of drug-induced pancreatitis. Ethanol was not considered in this review.
Rates of drug-induced gastrointestinal bleeding were estimated from data on 16 646 consecutively monitored medical inpatients who had no known predisposing illness. Heparin, warfarin, ethacrynic acid, steroids, and aspirin-containing drugs were associated with gastrointestinal bleeding and were estimated to account for about two-thirds of such bleeds. Major gastrointestinal bleeding, defined as bleeding severe enough to require transfusion, occurred in only 57 patients (0.3%).
The interaction of three diuretics with bilirubin-albumin complexes was studied using the peroxidase assay, erythrocyte uptake, and sephadex gel filtration. On a molar basis, each diuretic was as potent or more potent than sulfisoxazole in displacing bilirubin from albumin. Furosemide and ethacrynic acid, when used at the recommended dosage (1 mg/kg), would probably not produce a significant increase in free bilirubin in most infants. Chlorothiazide could introduce a significant risk to jaundiced infants because of the higher dosage required.
beta-tubulin (beta-TUB), Bcl-XL, and additionally glutathione S-transferase pi (GSTpi) were found to participate in sensitivity to docetaxel (TXT) in 7 human gastrointestinal cancer cell lines. The gene expression level of beta-TUB, Bcl-XL, and GSTpi was closely correlated with the IC50 for TXT. beta-TUB amount related to TXT resistance, and GST activity was correlated with IC50 for TXT in the 30-min treatment setting. Bcl-XL transfection increased TXT resistance of COLO201 cells, whereas GST inhibition by ethacrynic acid enhanced TXT cytotoxicity. Continuous TXT treatment increased beta-TUB and GSTpi expression, but the increased GSTpi mRNA was observed in TXT-resistant HCC-48 cells alone.
It has been demonstrated that histamine induces in rabbit small intestine an ATPase activity which is stimulated by NaCl or NaHCO3. The Na+/HCO3- (C1-)-stimulated ATPase activity, unlike the Mg2+,HCO3(-)-ATPase activity, has a pH optimum at pH 6.2, is inhibited by ethacrynic acid (10(-4) M) and bivalent metal ions (but not 10(-2) M thiocyanate). The substrate specificity of Na+/HCO3- (C1-)-ATPase and its regulation by Ca2+ ions has been studied. The feasible role of the enzyme in secretion is discussed.
Cerebral ischemia in vivo or oxygen-glucose deprivation (OGD) in vitro are characterized by major disturbances in neuronal ionic homeostasis, including significant rises in intracellular Na(+), Ca(2+), and Cl(-) and extracellular K(+). Recently, considerable attention has been focused on the cation-chloride cotransporters Na-K-Cl cotransporter isoform I (NKCC-1) and K-Cl cotransporter isoform II (KCC2), as they may play an important role in the disruption of ion gradients and subsequent ischemic damage. In this study, we examined the ability of cation-chloride transport inhibitors to influence the biochemical (i.e. ATP) and histological recovery of neurons in adult hippocampal slices exposed to OGD. In the hippocampus, 7 min of OGD caused a loss of ATP that recovered partially (approximately 50%) during 3 h of reoxygenation. Furosemide, which inhibits the NKCC-1 and KCC2 cotransporters, and bumetanide, a more specific NKCC-1 inhibitor, enhanced ATP recovery when measured 3 h after OGD. Furosemide and bumetanide also attenuated area CA1 neuronal injury after OGD. However, higher concentrations of these compounds appear to have additional non-specific toxic effects, limiting ATP recovery following OGD and promoting neuronal injury. The KCC2 cotransporter inhibitor DIOA and the Cl(-) ATPase inhibitor ethacrynic acid caused neuronal death even in the absence of OGD and promoted cytochrome c release from isolated mitochondria, indicating non-specific toxicities of these compounds.
It is known that bisulfite ions can selectively deplete red blood cells of 2,3-diphosphoglycerate (2,3-DPG). Studies of the effects of bisulfite on sodium-potassium permeability and metabolism were undertaken to clarify the physiologic role of the abundant quantities of 2,3-DPG in human erythrocytes. Treatment of cells with bisulfite results in a reversible increase in the passive permeability to Na and K ions. Metabolism of glucose to lactate is increased, with a rise in the intracellular ratio of fructose diphosphate to hexose monophosphate. Cell 2,3-DPG is quantitatively converted to pyruvate and inorganic phosphate. The permeability effects of bisulfite are countered by ethacrynic acid and by such oxidizing agents as pyruvate and methylene blue. Taken together, the results suggest that the effects on Na-K flux of bisulfite are related more to the reducing potential of this anion than to its capacity to deplete cells of 2,3-DPG.
Gamma-aminobutyric acid (GABA) has been proposed as a neurotransmitter of a subset of efferent nerve fibers in the mammalian cochlea. We tested this hypothesis by examining if GABA was released by high concentrations of K+ from the guinea pig cochlea. Artificial perilymph solutions containing either normal K+ (5 mM) or high K+ (50 mM) were perfused through the perilymphatic compartment of the guinea pig cochlea while collecting the effluent. Nineteen primary amines including GABA were quantified in the effluent by HPLC. This was carried out in normal animals and in animals pretreated with ethacrynic acid and kanamycin to destroy the organ of Corti. Significantly greater levels of GABA, taurine, glutamate, aspartate, glycine and three unidentified substances appeared in effluent collected during exposure of the cochlea to solutions containing higher K+ than normal K+. Compared to normal animals, destruction of the organ of Corti significantly decreased the K(+)-induced release of GABA, taurine, glutamate, aspartate, glycine and one of the unidentified substances; although significant release of glutamate and taurine still occurred in the destroyed ears. The release of GABA is consistent with it being a neurotransmitter in the cochlea. In addition the results: confirm the release of glutamate and taurine from the organ of Corti; suggest that additional substances may be released; and demonstrate the release of glutamate and taurine from tissue other than the organ of Corti.
Rat brain Cl(-)-ATPase was solubilized and reconstituted in asolectin liposomes. Phosphatidylinositol-4-monophosphate increased Cl(-)-ATPase and ATP-dependent Cl- uptake activities in proteoliposomes. The ATP-dependent Cl- uptake was inhibited by a Cl(-)-ATPase inhibitor, ethacrynic acid, and increased at an inside-positive membrane potential or in the presence of a protonophore. These findings suggest that Cl(-)-ATPase is an electrogenic Cl- transporter, or a primary Cl- pump, probably regulated by phosphoinositide turnover in vivo.
1. Gilthead gill 10(-3) M ouabain-inhibited (Na+ + K+)-ATPase and 10(-2) M ouabain-insensitive Na+-ATPase require the optimal conditions of pH 7.0, 160 mM Na+, 20 mM K+, 5 mM MgATP and pH 4.8-5.2, 75 mM Na+, 2.5 mM Mg2+, 1.0 mM ATP, respectively. 2. The main distinctive features between the two activities are confirmed to be optimal pH, the ouabain-sensitivity and the monovalent cation requirement, Na+ plus another cationic species (K+, Rb+, Cs+, NH4+) in the (Na+ + K+)-ATPase and only one species (Na+, K+, Li+, Rb+, Cs+, NH4+ or choline+) in the Na+-ATPase. 3. The aspecific Na+-ATPase activation by monovalent cations, as well as by nucleotide triphosphates, opposed to the (Na+ + K+)-ATPase specificity for ATP and Na+, relates gilthead gill ATPases to lower organism ATPases and differentiates them from mammalian ones. 4. The discrimination between the two activities by the sensitivity to ethacrynic acid, vanadate, furosemide and Ca2+ only partially agrees with the literature. 5. Present findings are viewed on the basis of the ATPase's presumptive physiological role(s) and mutual relationship.
The intracellular Cl concentration ([Cl]i) in rat cardiac ventricular muscle, measured with double-barreled microelectrodes in vitro, was 21.3 +/- 1.5 (SD) mM [number of observations (n) = 46]. With the Na-K-Cl cotransport inhibitor bumetanide (10 microM), it fell to 13.4 +/- 1.4 mM (n = 27), and with 1 mM acetazolamide, it fell further, to 7.2 +/- 1.5 mM (n = 5), close to equilibrium with the membrane potential. In the absence of Na, [Cl]i was 15.9 +/- 1.4 mM (n = 8), and with 1 mM acetazolamide, it fell to 6.5 +/- 0.6 mM (n = 4), again close to equilibrium. The bumetanide- and Na-insensitive components of inward Cl pumping were inhibited by chlorothiazide and ethacrynic acid but were unaffected by the Na-Cl cotransport inhibitor metolazone. There was inhibition of Na-K-Cl cotransport by chlorothiazide = acetazolamide > metolazone. The anion exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and HCO3 had no effect on [Cl]i in any condition. Thus Cl accumulation in the rat ventricle is fully accounted for by two systems, namely, Na-K-Cl cotransport and an Na-independent, possibly primary active, process.