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PubMed1980

Inhibition of alkaline phosphatase by several diuretics.

Acetazolamide, furosemide, ethacrynic acid and chlorothiazide, diuretics of considerable structural diversity, inhibit alkaline phosphatase. The inhibition is reversible and the mechanism is of the mixed type, having both competitive and non-competitive characteristics. Ki is calculated to be 8.4, 7.0, 2.8 and 0.1 mmol/l for acetazolamide, furosemide, ethacrynic acid and chlorothiazide, respectively. Chlorothiazide is a much more potent inhibitor of alkaline phosphatase than the other three diuretics. The combination of ethacrynic acid and cysteine, itself an alkaline phosphatase inhibitor, is less inhibitory than ethacrynic acid alone. Rat and human kidney alkaline phosphatase are equally sensitive to chlorothiazide, ethacrynic acid and furosemide.

Acetazolamide↗
PubMed2000

Induction of apoptosis and cell cycle arrest in mouse colon 26 cells by benastatin A.

Benastatin A, isolated from Streptomyces bacteria, is reported to inhibit mammalian glutathione transferases (GSTs). Since GST inhibitors such as ethacrynic acid are suggested to induce apoptosis in some cell lines, the effect of benastatin A on the survival of mouse colon 26 adenocarcinoma cells was compared with that of ethacrynic acid. When cells in stationary phase were treated with benastatin A, viable cells were found to be dose-dependently decreased after 3 days. In the case of ethacrynic acid, this became apparent within 24 h. Electrophoretic analysis revealed DNA fragmentation, indicating that cell loss was due to apoptosis in both cases. The dominant GST in colon 26 cells was identified as the class Pi-form (GST-II), and the activities in crude extracts as well as purified GST-II were almost completely inhibited by 50 microM ethacrynic acid. Immunoblot and northern blot analyses revealed increased GST-II protein and mRNA levels in cells treated with ethacrynic acid. Benastatin A did not significantly affect the activity in the crude extract even at 20 microM, a 10-fold higher concentration than that which almost completely inhibited the activity of purified GST-II. However, GST activity and GST-II protein were decreased in colon 26 cells treated with benastatin A for 5 days, no significant activity being detected in the range of 16 - 20 microM. In addition, beta-actin and bax mRNAs were also decreased in a dose-dependent manner. Furthermore, flow cytometric analysis of colon 26 cells revealed that benastatin A blocked the cell cycle at the G1/G0 phase. Thus, benastatin A also induces apoptosis of colon 26 cells, but this is unlikely to be due to inhibition of GST activity.

Adenocarcinoma↗
PubMed1989

Is a Ca2+ -ATPase involved in Ca2+ regulation during capacitation and the acrosome reaction of guinea-pig spermatozoa?

The Ca2+-ATPase antagonists quercetin and ethacrynic acid accelerated the onset of the acrosome reaction in guinea-pig spermatozoa incubated in the continuous presence of Ca2+, whereas furosemide had no effect, and sodium orthovanadate only affected sperm motility. When spermatozoa were preincubated in a 'Ca2+-free' medium, quercetin and ethacrynic acid shortened capacitation time: spermatozoa incubated for 1 h in 100-200 microM-ethacrynic acid showed 60-80% acrosome reactions when Ca2+ was added. Such spermatozoa were able to fertilize zona-free hamster eggs. Our results therefore point to the possible involvement of a Ca2+-ATPase in the regulation of intracellular Ca2+ in spermatozoa. Cysteine and dithiothreitol, both disulphide reducing agents, prevented the effects of quercetin and ethacrynic acid, suggesting that sulphydryl groups may be important for the expression of Ca2+-ATPase activity. Lysophosphatidylserine (LS) also prevented the stimulatory effect of ethacrynic acid, an effect similar to that shown by LS on lysophosphatidylcholine (LC). It is argued that both LS and LC could exert their action through an effect on the Ca2+-ATPase.

Acrosome↗
PubMed1995

Loop diuretics act directly on adenylate cyclase in rat renal tubular basolateral membranes.

We have reported previously that loop diuretics, especially azosemide and ethacrynic acid, may act not only on the AVP receptor site, but also on the post-AVP receptor site in rat renal tubular basolateral membranes. The purpose of this study was to examine whether loop diuretics (furosemide, azosemide, ethacrynic acid) affect the post-AVP receptor components, using GTP-gamma S, forskolin and cholera toxin as tools acting distal to the receptor. Adenylate cyclase activity stimulated by 10(-9)M AVP was inhibited more potently by azosemide and ethacrynic acid than by furosemide at the concentration of 10(-3) M. Azosemide and ethacrynic acid at concentrations above 10(-4) M also significantly decreased the enzyme activity that was stimulated by 10(-7) M GTP-gamma S and 10(-5)M forskolin, while significant inhibition by furosemide was observed only at 10(-3)M. In addition, the inhibitory effect of these loop diuretics on cholera toxin-stimulated enzyme activity was almost similar to the results observed in AVP-, GTP-gamma S- or forskolin-stimulated the enzyme activity. From these results, we conclude that loop diuretics, especially azosemide and ethacrynic acid, directly affect adenylate cyclase in part as well as the AVP receptor site.

Adenylyl Cyclases↗
PubMed2000

A role of glutamate in drug-induced ototoxicity: in vivo microdialysis study combined with on-line enzyme fluorometric detection of glutamate in the guinea pig cochlea.

The time course of the changes in perilymphatic glutamate was determined during the application of kanamycin and ethacrynic acid, which are known to damage the hair cells in the inner ear. For the continuous recording of glutamate, the microdialysis technique combined with an enzyme-linked fluorometric assay was used. In guinea pigs receiving a loading dose of 800 mg/kg of kanamycin subcutaneously followed 3 h later by an i.v. injection of 40 mg/kg of ethacrynic acid, a marked glutamate release was clearly found about 2 h after the injection of ethacrynic acid. Injection of kanamycin or ethacrynic acid alone did not produce any change in the perilymphatic glutamate. The morphological changes induced by the administration of both drugs indicated that the collapsing hair cells might release glutamate into the perilymphatic space. The present findings provide additional evidence that glutamate acts as an aggravating factor in aminoglycoside-induced ototoxicity.

Animals↗
PubMed1994

Thermodynamic characterization of drug binding to human serum albumin by isothermal titration microcalorimetry.

Binding sites on human serum albumin (HSA) for anionic drugs and fatty acids have been thermodynamically characterized by microcalorimetry. The binding and the thermodynamic parameters were directly computed from the calorimetric titration data at 37 degrees C in a phosphate buffer (pH 7.4) using one- and two-class binding models. From compensation analyses plotting the molar enthalpy change (delta Hm,i) versus those of the molar free energy (delta Gm,i) and molar entropy (delta Sm,i) for each class of binding sites, HSA binding sites were classified into groups S1, S2, and S3. Group S1 included high-affinity binding sites for site II-bound drugs, such as ibuprofen, flufenamic acid, and ethacrynic acid, and short- or medium-length alkyl-chain fatty acids; group S2 included low-affinity binding sites of site II-bound drugs and long-length alkyl-chain fatty acids; and group S3 contained the high-affinity binding sites for site I-bound drugs, such as phenylbutazone, oxphenbutazone, and warfarin, and long-length alkyl-chain fatty acids. High- and low-affinity bindings sites for salicylic acid and acetylaslicylic acid agreed with the regions of groups S3 and S2, respectively. Groups S1 and S2 were characterized by large negative values of delta Hm,i and delta Sm,i, reflecting van der Waals interaction and hydrogen-bonding formation in low dielectric media, and the main force to stabilize the binding complex in group S3 was a hydrophobic interaction, characterized by a small negative delta Hm,i and minor or positive values of delta Sm,i (entropy-driven).

Anions↗
PubMed1984

Stimulation of K+ fluxes by diuretic drugs in human red cells.

Two different families of diuretic drugs--(i) (aryloxy)acetic acid diuretics (ethacrynic acid, tienilic acid and (--)-indacrinone) and (ii) furopyridines [(+/-)-BN 50157 and (+/-)-cycletanide]--stimulate K+ movements across human red cell membranes. The kinetic properties of this effect (K+-specificity, saturability, optical isomerism, antagonism by structural analogues, etc.) strongly suggest that it is mediated by a K+-transport system with a specific binding site for some diuretic drugs. The stimulated K+ fluxes are resistant to ouabain, bumetanide and quinine, thus suggesting that they are not mediated by the Na+,K+-pump, Na+,K+-cotransport or by the Ca2+-dependent K+-permeability ('Gardos effect'). The replacement of Cl- by NO3- ions can either decrease, increase or have no effect on the stimulated K+ fluxes, depending on the diuretic drug. Although not conclusive, these observations suggest that the K+ fluxes are not mediated by stimulation of a chloride-dependent K+ carrier. The study of structural analogues showed that the intensity of the stimulation of K+ fluxes is strongly correlated with the magnitude of the natriuretic effect. Curiously, some antiallergic furopyridines are able to inhibit K+ fluxes.

Bumetanide↗
PubMed2000

Use of a three-factor interpretive optimisation strategy in the development of an isocratic chromatographic procedure for the screening of diuretics in urine samples using micellar mobile phases.

Screening of diuretics in urine is feasible through direct injection of the samples into the chromatographic system and isocratic reversed-phase liquid chromatography (RPLC) with micellar-organic mobile phases of sodium dodecyl sulfate (SDS) and 1-propanol. The surfactant coverage of the chromatographic column makes the addition of organic competing amines less necessary than in conventional aqueous-organic RPLC to achieve well-shaped peaks. Also, the range of elution strengths of micellar mobile phases required to elute mixtures of hydrophobic and hydrophilic diuretics is smaller. This allows the isocratic separation of the diuretics within adequate analysis times. An interpretive methodology is applied to optimise the resolution of a mixture of 15 diuretics of diverse polarity and acid-base behaviour (althiazide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenoic acid, chlorthalidone, ethacrynic acid, furosemide, piretanide, probenecid, torasemide, triamterene, trichloromethiazide and xipamide), using pH and concentrations of surfactant and organic modifier in the mobile phase as separation factors. Twelve diuretics were resolved in 25 min using 0.055 M SDS-6.0% 1-propanol at pH 3.0. The mixture of 15 diuretics was also resolved with two mobile phases showing complementary behaviour: 0.05 M SDS-5.6% 1-propanol at pH 5.4 and 0.11 M SDS-5.4% 1-propanol at pH 4.2. The results were applied to the analysis of urine samples with limits of detection similar to those usually reported for aqueous-organic RPLC, taking into account that the samples were injected without any previous treatment to separate or preconcentrate the analytes.

Calibration↗
PubMed1995

2,4-Dichlorophenoxyacetic Acid and Related Chlorinated Compounds Inhibit Two Auxin-Regulated Type-III Tobacco Glutathione S-Transferases.

Two auxin-inducible glutathione S-transferase (GST, EC 2.5.1.18) isozymes from tobacco (Nicotiana tabacum, White Burley) were partially characterized. GST1-1 and GST2-1 are members of a recently identified new type of plant GST isozymes that we will here refer to as type III. Both enzymes were active, with 1-chloro-2,4-dinitrobenzene as a substrate, when expressed in bacteria as fusion proteins. The apparent Km for 1-chloro-2,4-dinitrobenzene was found to be 0.85 [plus or minus] 0.25 mM for GST1-1 and 0.20 [plus or minus] 0.15 mM for GST2-1. The apparent Km for glutathione was similar for both enzymes, 0.40 [plus or minus] 0.15 mM. The in vitro activity of both enzymes could be inhibited by the synthetic auxin 2,4-dichlorophenoxyacetic acid, with an apparent Ki of 80 [plus or minus] 40 [mu]M for GST1-1 and 200 [plus or minus] 100 [mu]M for GST2-1. The GST1-1 was also inhibited by structurally related substances, such as 2,4-dichlorobenzoic acid, with a roughly similar Ki. The nonchlorinated structures benzoic acid and phenoxyacetic acid did not inhibit. p-Chloroisobutyric acid, or clofibric acid, an auxin-transport inhibitor, was found to be an active inhibitor as well. The strongest inhibitor identified, however, was a phenylacetic acid derivative, ethacrynic acid, which showed an apparent Ki of 5 [plus or minus] 5 [mu]M for both enzymes. This substance is a known inducer as well as a substrate of specific mammalian GSTs. The results presented here indicate that the type III plant GSTs might be involved in the metabolism or transport of chlorinated substances that are structurally related to auxins. The possibility that auxins are endogenous ligands or substrates for GSTs is discussed.

Journal Article↗
PubMed1983

Oxygenation alters red cell folate levels.

Folate activity is consistently higher in deoxygenated than oxygenated human blood as measured by both radioassay and Lactobacillus casei growth. Red cell, but not serum, folate levels are rapidly mutable: when fully oxygenated, the mean red cell folate level of 15 samples was 489 ng/ml; after deoxygenation the mean rose to 553 ng/ml; following re-oxygenation the mean returned to 488 ng/ml. Transport of folate across the red cell membrane apparently does not contribute to these changes in folate levels, since agents known to inhibit permeation (N-ethyl-maleimide, p-chlormercuriphenyl sulfonic acid and ethacrynic acid) do not affect the rise with deoxygenation. Moreover, new synthesis of folate compounds seems unlikely, since the changes are observed in energy-depleted cells. Instead, direct binding of folate to haemoglobin is suggested by experiments in which the rise with deoxygenation was not seen in red cells exposed to carbon monoxide or treated with cyanate. Similar changes also occur in vivo: canine red cell, but not serum folate levels are significantly higher (P less than 0.05) in samples collected from five different veins compared with blood from the paired artery (carotid-jugular, renal, mesenteric, splenic, femoral) of four animals. Thus red cell folate levels are predictably influenced by the levels of oxygenation of the erythrocyte both in vitro and in vivo, possibly by reversibly binding to haemoglobin.

Animals↗
PubMed1994

Pharmacological classification and renal actions of diuretics.

Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium.

Diuretics↗
PubMed1995

Acute hyperoxic injury attenuates the relaxing effects of "loop" diuretics and salbutamol on large airways of newborn guinea pigs.

We have previously found an age-dependent relaxing effect of furosemide in normal fetal, newborn, and adult guinea pig airways with fetal trachea exhibiting the greatest relaxation and adult tissue the least. This study was designed to expand upon this finding by determining if in vivo hyperoxic exposure would influence in vitro airway relaxation mediated by the loop diuretics, furosemide and ethacrynic acid, and the beta 2-adrenoceptor agonist, salbutamol. Newborn guinea pigs were raised in > 95% FiO2 until ill; controls in room air. Isometric relaxation to 3 x 10(-5) M furosemide, 3 x 10(-6) M ethacrynic acid, or 10(-8)-10(-6) M salbutamol was recorded in 3 x 10(-6) M histamine-constricted airway rings. Ethacrynic acid, like furosemide, relaxed newborn guinea pig airways. Hyperoxia did not alter the contractile effect of 3 x 10(-6) M histamine but did significantly decrease the relaxing effect of furosemide, ethacrynic acid, and salbutamol. Loop diuretic mediated airway relaxation was accentuated in HEPES buffer when compared with Krebs, whereas salbutamol-mediated relaxation was unaffected. These results suggest that hyperoxia nonspecifically decreases airway responsiveness to the relaxing agents studied.

Albuterol↗
PubMed1977

Diuretics and the renal adenylate cyclase system.

1 The relationship between the diuretic effectiveness and the effect on the renal adenylate cyclase of three diuretics, acetazolamide, frusemide and ethacrynic acid, was examined. The hypothesis that acetazolamide and parathyroid hormone (PTH), inhibit renal carbonic anhydrase by a cyclic adenosine 3',5'-monophosphate (cyclic AMP)-dependent mechanism was also tested.2In vitro, acetazolamide, frusemide and ethacrynic acid at high concentrations (10(-3)M) all produced some inhibition of basal and stimulated rat kidney plasma membrane adenylate cyclase. The effect of acetazolamide was much less than that of frusemide and ethacrynic acid. These plasma membrane effects were reproduced in studies of cyclic AMP formation in isolated kidney tubules of rats.3 Intravenous injections of acetazolamide did not change the total cyclic AMP content of the kidneys of rats killed by microwave irradiation.4 Acetazolamide produced a diuresis in the rat and a slight inhibition of the antidiuretic effect of Pitressin. Frusemide produced a diuresis and greatly reduced the antidiuretic response to Pitressin. Ethacrynic acid was ineffective as a diuretic in the rat and actually enhanced the antidiuretic response to Pitressin.5 In investigating the possible influence of diuretics and PTH on the activity and state of phosphorylation of carbonic anhydrase it was found that: there was no correlation between the ability of diuretics to inhibit carbonic anhydrase activity and to inhibit carbonic anhydrase phosphorylation; neither PTH nor cyclic AMP (in the presence of adenosine triphosphate, Mg(2+), K(+) and incubation at 37 degrees C) inhibited rat cortex homogenate carbonic anhydrase activity.6 It seems unlikely that any of the tested diuretics exerts its pharmacological effect by means of changes in kidney cyclic AMP metabolism.

Acetazolamide↗
PubMed1994

Pharmacological advances in the treatment of glaucoma.

Glaucoma is a potentially blinding disease. The goal of glaucoma therapy is to reduce intraocular pressure to a predetermined target level. There are currently 5 classes of compounds used for the medical management of glaucoma. Four classes that appear promising for the long term management of glaucoma are in different phases of clinical investigation, and include the topically active carbonic anhydrase inhibitors, selective alpha 2-adrenergic agonists, prostaglandins and ethacrynic acid. The topically active carbonic anhydrase inhibitor dorzolamide (MK-507) is effective and well tolerated in clinical trials of up to 1 year's duration. Animal studies have demonstrated that this drug lowers intraocular pressure by reducing aqueous humour formation. The selective alpha 2-adrenergic agonists, brimonidine and apraclonidine, have been shown to be effective in reducing intraocular pressure in the short term. Long term effectiveness of these agents is under investigation. Prostaglandins (PG) of the PGF2-alpha isopropylester series caused marked reductions of intraocular pressure in laboratory and clinical trials. The newest prostaglandin analogue, latanoprost (PhXA41), effectively lowered intraocular pressure and was well tolerated in clinical trials of up to 4 weeks' duration. Prostaglandins reduce intraocular pressure by enhancing uveoscleral outflow. Ethacrynic acid enhanced traditional outflow facility and lowered intraocular pressure when applied topically or intracamerally in laboratory studies and clinical trials. Corneal adverse effects of ethacrynic acid have been noted. Reformulation of ethacrynic acid ointment may resolve this problem. These 4 classes of compounds will enhance our options for the medical management of glaucoma. They may be used instead of or in combination with some of the drugs currently in use, and may be better tolerated.

Administration, Topical↗
PubMed1979

Effect of diuretics on ADP incorporation in kidney mitochondria.

The effect of diuretics on incorporation of ADP in mitochondria isolated from rabbit renal cortex and medulla was examined. Inhibition of incorporation of [14 C]ADP into both types of mitochondria was observed following pretreatment with furosemide, ethacrynic acid and meralluride at high drug concentrations (7.5 x 10-4 M furosemide and ethacrynic acid, 6.4 x 10-3 M meralluride). At lower concentrations (7.5 x 10-5 M furosemide and ethacrynic acid, 6.4 x 10-4 M meralluride), only entry of ADP in medullary mitochondria was inhibited. Chlorothiazide, 1.7 x 10-3 M, did not inhibit incorporation of ADP into either mitochondrial preparation. Atractyloside, a classic inhibitor of ADP-ATP exchange, showed inhibition in both preparations. Furosemide, injected in vivo inhibited incorporation of ADP into medullary but not cortical mitochondria. These results are consistent with the possibility that loop diuretics may reduce tubular sodium reabsorption by inhibiting ADP-ATP exchange across the mitochondrial membrane, thereby depriving active transport processes of ATP. The differential action on cortical and medullary mitochondria by loop diuretics is consistent with their predominant site of action in the tubule and with the different morphologic characteristics of both types of mitochondria.

Adenosine Diphosphate↗
PubMed1976

Effect of single dose of diuretics on renal magnesium excretion in man, with special reference to their site of action.

The administration of a single dose of furosemide, ethacrynic acid and polythiazide to healthy individuals under conditions of maximum water diuresis produces a significant increase in renal magnesium excretion. Elevated Mg excretion displayed a direct correlation to renal sodium excretion after furosemide (r=0.689, p less than 0.001), ethacrynic acid (r=0.869, p less than 0.001) and polythiazide (r=0.586, p less than 0.01). The slopes of the various regression lines did not differe significantly from each other or from the slope of the regression line characterizing this correlation for mannitol (r= 0.603, p less than 0.01). A significant linear correlation was likewise found between the excretion of Mg and total osmotically active substances after furosemide (r=0.783, p less than 0.001), ethacrynic acid (r=0.88, p less than 0.001) and polythiazide (r=0.646, p less than 0.01). The regression lines of the given correlations did not differ significantlyfrom each other, but their slopes were significantly higher than that of the regression line for the correlation after mannitol (r=0.454, p less than 0.01). The findings indicate that tubular Mg transport is influenced both by a decrease in tubular Na resorption in the diluting segment (polythiazide) and by an effect on Na resorption in the parts of the nephron proximal to the diluting segment of the nephron (furosemide, ethacrynic acid).

Adult↗
PubMed1992

Comparative effects of loop diuretics on AVP-receptor binding and AVP-sensitive adenylate cyclase activity.

The effects of loop diuretics (azosemide, ethacrynic acid and furosemide) on arginine vasopressin (AVP) receptor-adenylate cyclase components were compared in rat renal basolateral membranes. AVP binding was inhibited by these loop diuretics at concentrations above 10(-4) M. At the IC50 of azosemide and ethacrynic acid, the Kd values were significantly increased, while the Bmax values remained unchanged. These findings indicate an inhibitory effect of loop diuretics at high concentrations on the AVP binding to its receptors. Both the basal (AVP-unstimulated) and AVP-stimulated cyclic AMP productions were also inhibited by addition of these drugs. The inhibitions of the AVP binding and AVP-sensitive adenylate cyclase activity were dose-dependent. The above findings suggest that loop diuretics, especially azosemide and ethacrynic acid, can inhibit the basal and AVP-sensitive adenylate cyclase activities directly and also indirectly via the AVP receptor, at least in part. Comparing the loop diuretics, azosemide exerts a similar effect to ethacrynic acid, and they have a more potent antagonistic effect than furosemide with respect to AVP adenylate cyclase activation.

Adenylyl Cyclases↗
PubMed1988

Properties of the macula densa mechanism for renin release in the dog.

To study the macula densa mechanism for renin release, both the macula densa and the haemodynamic mechanisms were activated in anaesthetized dogs with denervated kidneys, either by renal arterial constriction to a renal arterial pressure (RAP) of 52 +/- 2 mmHg or by ureteral occlusion to a ureteral pressure of 95-105 mmHg, 20-25 mmHg below RAP. Renal arterial constriction increased renin release from 0.3 +/- 0.2 to 16 +/- 4 micrograms AI min-1. At low RAP, renin release was subsequently reduced to 7 +/- 3 micrograms AI min-1 when sodium excretion was raised far above control values by plasma volume expansion and acetazolamide infusion. Ethacrynic acid (3 mg kg-1 body wt.) restored renin release to pre-expansion values, and a large dose (25 mg kg-1 body wt.) prevented renin release from falling even after unclamping the artery. During ureteral occlusion with stopped glomerular filtration, plasma volume expansion, acetazolamide and ethacrynic acid infusion did not alter renin release. On the other hand, beta-adrenergic stimulation by isoproterenol raised renin release equally (by 30-40 micrograms AI min-1) before and after plasma volume expansion, during both renal arterial constriction and ureteral occlusion. Indomethacin (10 mg kg-1 body wt.) abolished renin release induced by ethacrynic acid infusion and ureteral occlusion. We conclude that the macula densa mechanism for renin release is inactivated by high NaCl reabsorption during plasma volume expansion and acetazolamide infusion, reactivated by inhibition of NaCl reabsorption with ethacrynic acid and completely inhibited by indomethacin. The degree of activation does not influence the renin release induced by beta-adrenergic stimulation.

Acetazolamide↗