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PubMed1996

Relationship between plasma membrane Ca(2+)-ATPase activity and acrosome reaction in guinea pig sperm.

The results obtained by biochemical measurement demonstrated for the first time that significant decrease of the plasma membrane Ca(2+)-ATPase activity occurred during capacitation and acrosome reaction of guinea pig sperm. Ethacrynic acid, one kind of Ca(2+)-ATPase antagonists, inhibited the plasma membrane Ca(2+)-ATPase activity, but calmodulin (50 micrograms/mL) and trifluoperazine (200-500 mumol/L) did not, suggesting that calmodulin is not involved in ATP-driven Ca2+ efflux from sperm. However, calmodulin is involved in the control of Ca2+ influx. TFP, one kind of calmodulin antagonists, accelerated the acrosome reaction and Ca2+ uptake into sperm cells significantly. Ca(2+)-ATPase antagonists, quercetin, sodium orthovandate, furosemide and ethacrynic acid promoted the acrosome reaction, but inhibited Ca2+ uptake, which cannot be explained by their inhibitory effects on the plasma membrane Ca(2+)-ATPase activity. It is speculated that this phenomenon might be caused by simultaneous inhibitions of the activities of Ca(2+)-ATPase present in the plasma membrane, the outer acrosome membrane and the outer mitochondrion membrane resulting in Ca2+ accumulation in the cytoplasm, which in turn blocks further Ca2+ entry through some negative feedback mechanism(s). The inhibitory effect of Ca(2+)-ATPase antagonist on glycolytic activity may also be the reason for Ca2+ accumulation in cytoplasm and inhibition of Ca2+ uptake.

Acrosome↗
PubMed2003

Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases: thiol ester hydrolysis and inhibitor maturation.

In addition to glutathione (GSH) conjugating activity, glutathione S-transferases (GSTs) catalyze "reverse" reactions, such as the hydrolysis of GSH thiol esters. Reverse reactions are of interest as potential tumor-directed pro-drug activation strategies and as mechanisms for tissue redistribution of carboxylate-containing drugs. However, the mechanism and specificity of GST-mediated GSH thiol ester hydrolysis are uncharacterized. Here, the GSH thiol esters of ethacrynic acid (E-SG) and several nonsteroidal antiinflammatory agents have been tested as substrates with human GSTs. The catalytic hydrolysis of these thiol esters appears to be a general property of GSTs. The hydrolysis of the thiol ester of E-SG was studied further with GSTA1-1 and GSTP1-1, as a model pro-drug with several possible fates for the hydrolysis products: competitive inhibition, covalent enzyme adduction, and sequential metabolism. In contrast to hydrolysis rates, significant isoform-dependent differences in the subsequent fate of the products ethacrynic acid and GSH were observed. At low [E-SG], only the GSTP1-1 efficiently catalyzed sequential metabolism, via a dissociative mechanism.

Antineoplastic Agents↗
PubMed1982

Partial characterization of the ouabain-insensitive, Na+-stimulated ATPase activity of kidney basal-lateral plasma membranes.

The present paper characterizes the Na+-stimulated ATPase activity present in basal-lateral plasma membranes from guinea-pig kidney proximal tubular cells. These characteristics are compared with those of the (Na+ + K+)-stimulated ATPase activity, and they are: (A) Na+-ATPase activity: (1) requires Mg2+; (2) may be activated by mu molar quantities of Ca2+; (3) optimal ratio Mg:ATP = 5:1-2 and Ka for Mg:ATP = 3:0.60 mM; (4) Ka for Na+:8 mM; (5) does not require K+; (6) is only stimulated by Na+ and Li+ (in a lower extent); (7) is similarly stimulated by the Na+ salt of different anions; (8) hydrolyzes only ATP; (9) optimal temperature: 47 degrees C; (10) optimal pH: 6.9; (11) is ouabain insensitive; (12) is totally inhibited by 1.5 mM ethacrynic acid, 2 mM furosemide and 0.75 mM triflocin. (B) (Na+ + K+)-ATPase activity: (1) also requires Mg2+; (2) is inhibited by Ca2+; (3) optimal ratio Mg:ATP = 1.25:1 and Ka for Mg:ATP = 0.50: 0.40 mM; (4) Ka for Na+: 14 mM (data not shown); (5) needs K+ together with Na+; (6) K+ may be substituted by: Rb+ greater than NH+4 greater than Cs+; (7) is anion insensitive; (8) hydrolyzes mostly ATP and to a lesser extent GTP, ITP, UTP, ADP, CTP; (9) optimal temperature: 52 degrees C; (10) optimal pH: 7.2; (11) 100% inhibited by 1 mM ouabain; (12) 63% inhibited by 1.5 mM ethacrynic acid, 10% inhibited by 2 mM furosemide and insensitive to 0.75 mM triflocin.

Adenosine Triphosphatases↗
PubMed1981

Filtered bicarbonate and plasma pH as determinants of renal bicarbonate reabsorption.

To examine if bicarbonate reabsorption varies with filtered bicarbonate and plasma pH, we infused anesthetized dogs i.v. with sodium chloride and sodium bicarbonate to alter plasma bicarbonate concentration (PHCO3) without changing hematocrit. Examinations in five dogs over a wide range of glomerular filtration rates (GFR) during ethacrynic acid infusion showed that bicarbonate reabsorption at equal filtered load and equal plasma pH of 7.5 was not significantly changed by increasing PHCO3 from 30.2 +/- 0.4 to 55.2 +/- 0.6 mM and PCO2 from 33.8 +/- 0.7 to 74.1 +/- 2.1 mm Hg. Examinations during respiratory and metabolic alkalosis in five dogs at plasma pH of 7.8 showed that bicarbonate reabsorption at equal filtered load was not significantly different at a PCO2 of 20.2 +/- 0.8 and 36.8 +/- 0.8 mm Hg. Finally, in five dogs that did not receive ethacrynic acid, plasma pH was lowered by inducing respiratory acidosis at a PHCO3 of 30 mM and raised during progressive respiratory and metabolic alkalosis, Bicarbonate reabsorption was linearly related to plasma pH within the range 7.1 to 7.85 (r = 0.92). By altering plasma pH by 0.1 unit, bicarbonate reabsorption was altered by 10 +/- 1%. Thus, filtered bicarbonate rather than GFR and plasma pH rather than PCO2 are important acute regulators of bicarbonate reabsorption. This regulation may be achieved by determining pH and bicarbonate concentration in the luminal fluid along the proximal tubules.

Alkalosis↗
PubMed2002

Glutathione might exert an important function in caerulein-stimulated amylase release in isolated rat pancreatic acini.

AIMS: The effect of different modes of thiol depletion on pancreatic exocrine secretory function and potential mechanisms of interference with the secretory process in pancreatic acinar cells were investigated. METHODOLOGY: After incubation with three thiol-modulating agents (L-buthionine sulfoximine, ethacrynic acid, and diamide) for 30 minutes, caerulein-stimulated amylase release and cholecystokinin (CCK) receptor binding characteristics were assessed in isolated rat pancreatic acini. The level of thiol groups (glutathione and protein thiols) and cytosolic-free calcium were measured in pancreatic acinar cells. RESULTS: All three thiol-modulating agents decreased caerulein (10(-10)M)-stimulated amylase release and the level of pancreatic acinar glutathione in a dose-dependent fashion without a marked increase in cell damage. Diamide also diminished the level of protein thiols. Ethacrynic acid and diamide, but not L-buthionine sulfoximine, inhibited the caerulein (10(-9)M)-induced Ca(2+) mobilization in pancreatic acinar cells. None of the three thiol-modulating agents altered the CCK receptor binding characteristics. CONCLUSION: The present findings strongly suggest an important role of glutathione in the secretory process in pancreatic acinar cells and in the secretory blockade observed in acute pancreatitis. A decrease in caerulein-induced Ca(2+) mobilization might participate in the inhibition of amylase release by some oxidative agents, but it is not the prominent cause in general.

Amylases↗
PubMed1984

The pentobarbital anesthetized dog: an animal model for assessing chemically induced changes in renal function and ultrastructure.

An experimental procedure was devised using the pentobarbital-anesthetized dog that could be used for the comprehensive evaluation of the renal effects of chemicals. After IV or renal arterial administration of 0.9% saline solution (vehicle), 12 renal function determinants were continuously monitored for periods of 2 and 6 hours. At the completion of the 2 or 6 hours of study, the kidneys of a number of dogs (usually between 1 and 7) in each vehicle-treated group were subjected to a modification of the intravascular perfusion-of-fixative technique to evaluate the ultrastructural status of the outer cortical, inner cortical, and outer medullary tissue. The remaining dogs (at least 3) in each vehicle-treated group were given a nonnephrotoxic, but maximally effective, diuretic dose of ethacrynic acid, which enabled an assessment of the functional integrity of the thick ascending limb of Henle's loop. Renal function and glomerular and tubular ultrastructure remained stable in the pentobarbital-anesthetized dog for up to 6 hours after administration of vehicle. Sustained infusion of inulin (included in the procedure to estimate glomerular filtration rate) throughout the duration of the experiments, and pentobarbital anesthesia of various durations did not alter the morphologic status of the canine nephron. The procedure used for the renal perfusion of fixative circumvented any manipulation of the kidneys before fixation and allowed for the acquisition of normal (unaltered) appearing tissue from all areas of the kidneys. The responses of pentobarbital-anesthetized dogs to ethacrynic acid administration were similar when given 2 and 6 hours after the vehicle administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1987

Mechanism of inhibition of glycolysis by vanadate.

Vanadate is known to inhibit several phosphatases including Na+, K+-ATPase, alkaline phosphatase, and glyceraldehyde-3-P dehydrogenase. Inhibition presumably results because vanadium adopts a stable structure which resembles the transition state of phosphate during the reactions involving these enzymes. We performed experiments to further examine the effects of vanadate (VO3-4) on erythrocyte (red blood cells (RBC] glycolytic intermediates. RBC obtained from human subjects were centrifuged and washed with lactated Ringer's 5% dextrose. 31P nuclear magnetic resonance analysis of the RBC revealed the characteristic peaks for the 3-phosphate and 2-phosphate of 2,3-diphosphoglycerate (DPG), inorganic phosphate (Pi), and ATP. Incubation of RBC with 10(-6) M VO3-4 led to a disappearance of ATP and 2,3-DPG while the peak for Pi increased. By the end of 4 h over 90% of the VO3-4 had been reduced to VO2+ (vanadyl) in the RBC. The effects of 10(-4) M iodoacetamide and 10(-5) M ethacrynic acid, known inhibitors of glyceraldehyde-3-P dehydrogenase that act by interactions with sulfhydryl groups (-SH) of the enzyme, were similar to those of VO3-4. Incubation with vanadyl did not affect the peaks for Pi, 2-DPG, or 3-DPG. Furthermore, using electron spin resonance we demonstrated that in the presence of glyceraldehyde-3-P dehydrogenase, VO3-4 is reduced to VO2+. The findings demonstrate that VO3-4 inhibits glycolysis at micromolar concentrations and that the ion is reduced to VO2+ in the cell. The similarity of the effect of VO3-4 to those of iodoacetamide and ethacrynic acid suggests that interactions with -SH groups is its mechanism of inhibition. Since under physiological conditions intracellular VO3-4 concentrations are in the micromolar range and may exist in oxidized and/or reduced forms, VO3-4 could regulate the activity of glyceraldehyde-3-P dehydrogenase through changes in the redox state of the enzyme rather than by substituting for the PO3-4 ion.

Dithiothreitol↗
PubMed1975

Some aspects of proximal tubular sodium chloride reabsorption in Necturus kidney.

Some aspects of proximal tubular sodium chloride reabsorption in Necturus kidney. Renal tubular reabsorption of fluid and sodium was measured by clearance methods in the doubly perfused Necturus kidney in which the bicarbonate concentration was varied between 0 and 60 mEq/liter. The effects of Damox (2.2 times 10-3M), ocubain (10-5M) and ethacrynic acid (10-4M) and of acidosis were also investigated. In addition to clearance experiments, stationary microperfusion experiments were carried out on promimal tubules to measure volume flow and steady-state sodium and chloride concentration differences across the tubular epithelium. In some experiments, the transepithelial electrical potential difference was also measured using an axial electrode system. The following results were obtained: 1) Bicarbonate is not essential to the operation of renal tubular fluid and sodium transport. 2) Total renal and proximal tubular fluid and sodium transport are partially inhibited by Diamox, ouabian and ethacrynic acid. 3) The proximal tubule maintains a significant transepithelial sodium and chloride concentration difference and a significant electrical potential difference (lumen-negative) in the presence of a poorly permeant nonelectrolyte. The direction and magnitude of the electrical polarization fully accounts for the observed chloride concentration difference. The data support the thesis that sodium chloride transport accross the proximal tubular epithelium takes place by active sodium transport and electically coupled passive chloride reabsorption. Important species differences with respect to mammalian transport mechanisms are discussed.

Action Potentials↗
PubMed1972

Excretion of urinary casts after the administration of diuretics.

The administration of ethacrynic acid and frusemide to healthy volunteers was regularly followed by the excretion of hyaline casts, without any concomitant proteinuria. Hydrochlorothiazide and chlorthalidone did not themselves induce cylindruria but augmented that provoked by acidifying agents. It was shown by the indirect immunofluorescence method that the casts were composed of uromucoid (Tamm-Horsfall mucoprotein), which is always present in the urine, usually in solution, and originates predominantly from the tubule cells of the ascending limb of Henle's loop. The urinary excretion of Tamm-Horsfall mucoprotein was not increased after the administration of ethacrynic acid. This mucoprotein is precipitated and forms aggregates when the concentration of electrolytes increases and when the pH of the urine declines. The casts that appear in the urine after strenuous physical exertion are of essentially the same composition. Casts produced by patients with kidney diseases, on the other hand, contain various protein fractions derived from the blood as well as mucoprotein. Cylindruria occurring during diuretic therapy and physical exertion is of no pathological significance, and the diagnostic value of byaline casts is very much limited if their exact composition cannot be determined.

Chemical Precipitation↗
PubMed1975

Ouabain-insensitive Na+ stimulation of an Mg-2+ -dependent ATPase in kidney tissue.

1. Freshly prepared microsomal fractions of the outermost cortex of guinea pig kidney show an Mg-2+-dependent ATPase activity which is partially inhibited by 100 mM NaCl, LiCl, KCl, RbCl, CsCl, NH4Cl or choline chloride. 2. If the microsomal preparation is aged by storage at 4 degrees C for 10-15 days, the Mg-2+-dependent activity shows stimulation by Na-+ and Li-+ but not by K-+, Rb-+, Cs-+, NH4-+ or choline. 3. Stimulation is similar with sodium salts of Cl-minus, HCO3-minus, CH3COO-minus, BR-minus, SO4-2-minus or methylsulphonate. 4. Stimulation is insensitive to 1 mM and 10 mM ouabain. 5. Stimulation is unaltered by the presence of 0.5 mM ethyleneglycol-bis-(beta-aminoethyl ether)N,N'-tetracetic acid. 6. Stimulation is 100% inhibited by 2 mM ethacrynic acid, a concentration which inhibits only 30% of the Mg-2+-dependent ATPase and 50% of the (Na-++K-+)-stimulated ATPase. 7. Some of these characteristics coincide with those of an ouabain-resistant, K-+-independent, ethacrynic acid-sensitive mode of Na-+ extrusion out of guinea pig kidney cortex cells.

Adenosine Triphosphatases↗
PubMed1979

Sodium outflux and influx within nerve terminals from chronic epileptogenic foci.

The Na+-pump (oMpNa) or maximal sodium outflux inhibited by ouabain was studied in nerve terminals isolated from the primary and mirror epileptogenic foci of freezing lesions. In addition, the Na+ for Na+ exchange diffusion that is sensitive to ethacrynic acid and furosemide was also analyzed. oMpNa in control and epileptogenic states had similar and indistinguishable activation curves for K0 (extracellular K) in a sodium medium except for a two-fold difference in magnitude. However, the apparent affinity of the Na+-pump for K0 as measured by K1/2 was shifted to the right or decreased in epileptogenic foci (2 mM K0 compared to 0.5 mM in controls) when measured in a magnesium medium. A decrease in the apparent affinity for internal sodium was also observed. Of the total sodium outflux (67.7 nmol/mg/min), Na+ movements which are insensitive to ouabain and external K+ but stimulated by external Na+ and inhibited by furosemide and ethacrynic acid (20 nmol/mg/min or 32% of sodium outflux) represented the Na+ for Na+ exchange diffusion in nerve terminals. Na+ influx rising with increasing internal sodium in the presence of ouabain and blocked by furosemide represent the corresponding inward Na+ movement. No differences were observed between controls and epileptogenic states.

Acetylcholinesterase↗
PubMed1994

Microdialysis analysis of effects of loop diuretics and acetazolamide on chloride transport from blood to CSF.

With the hypothesis that the NaCl cotransporter in mammalian choroid plexus (CP) has a role in CSF formation, we postulated that loop diuretic agents would curtail transport of Cl from blood to CSF. Microdialysis in the cisterna magna of Sprague-Dawley rats was used to assess the ability of furosemide and ethacrynic acid (i.e. loop agents that interfere directly with cotransport) to inhibit 36Cl transport from blood to CSF over a 3-h period. Cl uptake by CSF was quantified as % volume of distribution (Vd) of 36Cl, i.e. 100 x cpm/g CSF divided by cpm/ml plasma. Uptake curves of Vd vs. time were constructed for the various treatments; then, to compare drug effects, the curves were analyzed for: (i) the early slope of uptake (Kin), (ii) the steady-state value for Vd, and (iii) the area-under-curve (AUC). Assessment of the curve parameters collectively revealed that at 5 mg/kg, both furosemide (FUR) and ethacrynic acid (EA) reduced Cl penetration into CSF by one quarter; at 50 mg/kg, these loop agents decreased Cl uptake by about a third. On the other hand, 50 mg/kg of the carbonic anhydrase inhibitor, acetazolamide, reduced Cl uptake into CSF by 55-60%. Thus, NaCl cotransport inhibitors maximally reduced Cl transport in the rat by about 35%; this inhibition was less extensive than that brought about by acetazolamide, which interferes with CSF secretion by a different mechanism.

Acetazolamide↗
PubMed1991

A novel glutathione transferase (13-13) isolated from the matrix of rat liver mitochondria having structural similarity to class theta enzymes.

A rat liver mitochondrial-matrix fraction was prepared and shown to have 1-chloro-2,4-dinitrobenzene(CDNB)-metabolizing glutathione transferase (GST) activity. Further fractionation by sequential gel filtration, isoelectric focusing or chromatofocusing and hydroxyapatite chromatography yielded three GSTs of pI 9.3, 8.9 and 7.5, none of which bound to a GSH-agarose affinity matrix. Most of the activity was associated with the pI-9.3 form, which was selected for further study. Its activity was tested with the following potential substrates in addition to CDNB: 1,2-dichloro-4-nitrobenzene, p-nitrobenzyl chloride, trans-4-phenylbut-3-en-2-one, 1,2-epoxy-3-(p-nitrophenoxy)propane, ethacrynic acid, menaphthyl sulphate, cumene hydroperoxide, linoleic acid hydroperoxide and 4-hydroxynon-2-enal. Appreciable activity was obtained only with CDNB and ethacrynic acid (82 and 26 mumol/min per mg of protein respectively). The apparent Km for GSH, using 1 mM-CDNB, was 1.9 mM. The enzyme is a dimer of subunit Mr 26,500. It has a free N-terminus, which has enabled the first 33 amino acids to be sequenced. This portion of primary structure has a sequence in common with members of the Theta class of GSTs (eg. 36% identity with subunit 12) and also a sequence which might function as a mitochondrial import signal. It is novel and has been named 'GST 13-13'.

Amino Acid Sequence↗
PubMed1984

Site and magnitude of the tubular inhibitory effect of expanding the extracellular volume in dogs.

Ethacrynic acid inhibits energy-requiring transcellular NaCl reabsorption without affecting NaHCO3 reabsorption. Acetazolamide inhibits NaHCO3 and most of the remaining NaCl reabsorption in the proximal tubules (bicarbonate-dependent reabsorption) but raises distal transcellular NaCl reabsorption. After administration of both diuretics, the remaining bicarbonate-dependent and transcellular reabsorptions become constant until glomerular filtration rate (GFR) is almost halved. The inhibitory effect of expanding the extracellular volume (ECV) until plasma volume and GFR increased 30-40% was examined in anesthetized dogs. Examinations at comparable GFR obtained by altering arterial perfusion pressure showed that the inhibitory effect of ECV expansion was attenuated by administering acetazolamide. Ethacrynic acid amplified the inhibitory effect which for sodium and chloride reabsorption amounted to 6-7% of the filtered load at comparable GFR. An inhibitory effect of ECV expansion of bicarbonate reabsorption was disclosed only after raising plasma bicarbonate concentration. Thus, the small inhibitory effect of massive ECV expansion is confined to proximal tubular bicarbonate-dependent reabsorption and is of the same magnitude as previously demonstrated in experiments of similar design by raising plasma pH by only 0.07 unit. Since ouabain inhibits transcellular NaCl reabsorption, a natriuretic hormone is more likely to be an inhibitor of carbonic anhydrase than of Na,K-ATPase.

Absorption↗
PubMed1995

Cochlear effects of indacrinone are not altered by penicillin.

Indacrinone is a loop diuretic structurally related to ethacrynic acid. Indacrinone is a racemic mixture. Previous studies have shown that the (-) enantiomer caused reduction of endocochlear potential (EP) and elevation of compound action potential (CAP) threshold (Rybak and Whitworth, 1987a). It has been demonstrated that organic acids such as penicillin, probenecid and sodium salicylate prevent the reduction of EP normally observed after furosemide administration (Rybak et al., 1992a). The present study was designed to determine whether penicillin pretreatment could prevent changes in EP and CAP threshold in (-)-indacrinone treated chinchillas. Adult chinchillas were anesthetized with ketamine and pentobarbital. A microelectrode was advanced into the scala media using the round window approach, and CAP responses to clicks were measured. One group was treated with (-)-indacrinone 100 mg/kg via the jugular vein. A second group of animals received penicillin 50 mg/kg i.v. thirty minutes before (-)-indacrinone. The mean EP change in the indacrinone-treated animals was 38.38 +/- 19.32 millivolts (mv). The reduction of EP in the group receiving penicillin was 24.43 +/- 20.74 mv (P > 0.09). The mean CAP threshold changes in animals receiving indacrinone was 20 +/- 14.14 dB whereas those pretreated with penicillin showed a threshold shift of 21.43 +/- 20.35 dB (P > 0.05). These findings are consistent with previous studies which showed that the effect of ethacrynic acid on the EP and CAP was not changed by the pretreatment with penicillin (Rybak et al., 1990).

Action Potentials↗
PubMed1986

Glomerulotubular balance during renal sympathetic stimulation.

In volume-expanded dogs receiving ethacrynic acid, a linear relationship, glomerulotubular balance (GTB), applies between the remaining sodium reabsorption and the glomerular filtration rate (GFR) during mechanical aortic constriction. To examine whether GTB applies during sympathetic stimulation, the GFR was progressively reduced by 70-75% in anaesthetized dogs by renal nerve stimulation, intrarenal norepinephrine infusion or by selective stimulation of alpha-adrenoceptors by intrarenal methoxamine infusion. Linear relationships (GTB) were obtained (r greater than 0.9). Reabsorption was not different during the various kinds of sympathetic stimulation, but less than during aortic constriction; the largest difference in NaCl reabsorption at comparable GFR amounted to 10-15% and was obtained 30-40% below control GFR, whereas inhibition of NaHCO3 reabsorption was uncertain. To inhibit NaHCO3 reabsorption and associated NaCl reabsorption in the proximal tubules, acetazolamide (30 mg kg-1) was administered instead of ethacrynic acid. No difference in reabsorption was observed at comparable GFR during norepinephrine infusion and mechanical aortic constriction. Hence, GTB applies during sympathetic stimulation. Compared with data obtained during aortic constriction, alpha-adrenergic stimulation reduces proximal reabsorption of NaCl and, possibly, NaHCO3 and exerts no effect on distal transcellular NaCl reabsorption.

Acetazolamide↗
PubMed1987

Cation transport in the ampulla of the semicircular canal and in the endolymphatic sac.

We examined the effects of anoxia and ethacrynic acid on the endolymphatic potential and cation activity in the superior ampulla of the guinea pig, using double-barrelled ion-exchanger microelectrodes. In normal guinea pigs the ampullar endolymphatic potential was + 3.9 +/- 1.2 mV (n = 32), the Cl- activity 130 +/- 4.6 mM (n = 9), and the Na+ activity 18.4 +/- 4.4 mM (n = 20). After anoxia, the ampullar DC potential decreased rapidly and reversed its polarity within 5 min. It then decreased gradually for 60 min and increased afterwards to approximately zero. K+ activity decreased gradually after a latency of 10 min, whereas Na+ activity increased. During the gradual decrease of a negative ampullar endolymphatic potential, an increase in Na+ activity was observed. Thirty minutes after the intravenous injection of ethacrynic acid (100 mg/kg), the potential began to decrease, changed to a negative polarity, and approached a maximum negative level 100 min after the injection. The decrease in K+ activity corresponded to the reduction of potential whereas Na+ activity remained unchanged. The DC potential of the endolymphatic sac in normal guinea pigs was + 14.7 +/- 5.1 mV (n = 17). The Na+ concentration was 103.3 +/- 14.7 mM (n = 14) and the K+ concentration was 11.6 +/- 0.8 mM (n = 4). After anoxia, the DC potential decreased rapidly and approached 0 mV within 8 min. No negative potential could be observed. The Na+ concentration began to increase 2 min after anoxia and reached the extracellular Na+ concentration about 30 min later.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Cardiac effect of diuretic drugs.

Triamterene, amiloride, ethacrynic acid, and furosemide were studied to determine whether they modified the digitalis-induced egress of myocardial potassium which is thought to facilitate the development of digitalis arrhythmias. In a control group of 15 dogs, potassium was measured in samples obtained simultaneously from the femoral artery (FA) and the coronary sinus (CS) in a control period and at intervals after the administration of 1 mg. of acetylstrophanthidin. Acetylstrophanthidin caused a significant increase in cardiac A-V difference in the potassium concentration (CS-FA) averaging 0.47 mEq. per liter. In a group of 10 dogs, when 175 mg. of triamterene was infused prior to the acetylstrophanthidin, the rise in A-V differnece was abolished and the arrhythmias often aborted. In contrast, the infusion of potent diuretics (40 mg. of furosemide in five dogs and 100 mg. of ethacrynic acid in another five dogs) prior to acetylstrophanthidin, caused a doubling of the maximal A-V potassium difference. This study suggests that the clinical administration of antikaliuretic drugs may prevent the arrhythmias of digitalis toxicity not only by reducing kaliuresis and subsequent hypokalemia, but by a myocardial effect which antagonized the digitalis-induced loss of myocardial potassium. Contrariwise, potent diuretics may facilitate digitalis arrhythmias through a myocardial action causing a greater egress of myocardial potassium, thus explaining the development of arrhythmias despite normal serum potassium levels. These potent diuretics should be used cautiously, especially when given intravenously to patients receiving digitalis.

Amiloride↗