Amiloride Directly Inhibits the Na,K-ATPase Activity of Rabbit Kidney Proximal Tubules

Soltoff, Stephen P.; Mandel, Lazaro J.

doi:10.1126/science.6302840

Cited by 171 publications

(77 citation statements)

References 23 publications

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“…Amiloride is known to inhibit a number of Na' transport systems, including the tight epithelial Na' channel (Hamilton & Eaton, 1985), Na'-H' exchange system (Kinsella & Aronson, 1980), the Na'-Ca2+ exchange system (Schellenberg et al, 1983) and Na+/ K+-ATPase (Soltoff & Mandel, 1983). In the present experiments we found that amiloride blocked GABAinduced Ic, in a competitive manner, indicating the direct action ofthe drug on GABA-binding sites.…”

Section: Resultssupporting

confidence: 58%

Effects of diuretics on GABA‐gated chloride current in frog isolated sensory neurones

Inomata

Ishihara

Akaike

1988

British J Pharmacology

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Effects of three diuretics (furosemide, amiloride and α‐human atrial natriuretic polypeptide (α‐hANP)) on GABA‐activated chloride current (ICl) were investigated in frog isolated sensory neurones, following suppression of Na+, K+ and Ca2+ currents, by use of a ‘concentration‐clamp’ technique. Furosemide inhibited the GABA‐activated ICl in a non‐competitive manner and facilitated the inactivation phase, while amiloride inhibited the GABA response in a competitive manner, both inhibitions being concentration‐dependent. α‐hANP had no effects on the GABA‐induced ICl. The reversal potential of GABA‐activated ICl (EGABA) was not shifted in the presence of amiloride or furosemide. The results suggest that amiloride may act at the GABA binding site while furosemide may act on the GABA‐gated chloride channel.

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Section: Resultssupporting

confidence: 58%

Effects of diuretics on GABA‐gated chloride current in frog isolated sensory neurones

Inomata

Ishihara

Akaike

1988

British J Pharmacology

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“…In the low millimolar range, however, amiloride targets Na + -K + -ATPase, directly inhibiting its activity (Soltoff & Mandel 1983). At an amiloride concentration of 2.5 mM, we observed a 20 to 60% inhibition of Na + -K + -ATPase activity across species, tissues, and treatments.…”

Section: Discussionmentioning

confidence: 77%

“…At an amiloride concentration of 2.5 mM, we observed a 20 to 60% inhibition of Na + -K + -ATPase activity across species, tissues, and treatments. Using 2 mM amiloride, Soltoff & Mandel (1983) observed a 30 to 45% inhibition of Na + -K + -ATPase activity in isolated rabbit kidney proximal tubules. We have therefore used amiloride as an additional pharmacological tool to demonstrate reduced ATP-dependent enzymatic activity in gill and muscle tissue of deep-sea Tanner crabs.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of enzyme activities linked to acid–base regulation in a deep-sea and a sublittoral decapod crab species

2008

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When compared to the sublittoral Dungeness crab Cancer magister, the deep-sea Tanner crab Chionoecetes tanneri exhibited lower activities of enzymes involved in some of the processes essential for efficient acid -base regulation. Tissue enzymatic activities were compared between Dungeness crabs held in normoxia and Tanner crabs held in hypoxia -both treatments mimicking typical habitat oxygen levels. In the posterior gill, activities of all forms of ATPase and carbonic anhydrase (CA) were approximately 2-to 13.2-fold lower in Tanner crabs than in Dungeness crabs. CA activity in the heart and white muscle was also significantly lower in hypoxic deep-sea Tanner crabs, while ATPase activity in these 2 tissues was similar between the 2 treatments. Diagnostically, enzymatic activities were compared when both species were held in normoxic seawater, with additional significant differences found in specific white muscle ATPase fractions (amiloride-and N-ethylemaleimide [NEM]-sensitive ATPases) and tissue buffering (β) capacity. When both species were acclimated to normoxia, C. tanneri exhibited mass specific rates of oxygen consumption significantly lower (4.5-fold) than C. magister. Under short-term, strongly hypercapnic conditions (1% CO 2 ), the Dungeness crab displayed reduced (30 to 40%) branchial ATPase activities, while enzymatic activities in the Tanner crab gill, muscle and heart were refractive to short-term (24 h) hypercapnia, suggesting a minimal ability to tune branchial function to changing environmental conditions. These results support our hypothesis that the deep-sea Tanner crab has a reduced capacity for active transport of acid -base relevant ions, particularly at the gill, and is therefore at a marked disadvantage with respect to iono-and acid -base regulatory capacity. These results add to a growing database documenting the limited ability of deep-sea megafauna to compensate for internal acid -base disruptions associated with introduction of anthropogenic CO 2 into the deep sea.

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“…In other cell types, these concentrations have also been shown to inhibit Na conductive pathways (46), Na/Ca exchange (47), Na/K ATPase activity (48), and bicarbonate transport (49), and to penetrate the cell interior to affect protein synthesis (17). Thus, a question arises as to the specificity of amiloride for the Na/H exchanger of human neutrophils: whether the effect of amiloride on O2 production is related solely to abrogation of Na/H exchange rather than to some other property.…”

Section: Resultsmentioning

confidence: 99%

Intracellular pH modulates the generation of superoxide radicals by human neutrophils.

Simchowitz¹

1985

J. Clin. Invest.

161

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The relationship of intracellular pH (pH1) to superoxide radical (02) generation was investigated in chemotactic factor-stimulated human neutrophils. Exposure of cells to 100 nM N-formylmethionyl-leucyl-phenylalanine (FMLP) caused activation of Na/H exchange which, in 140 mM Na medium (pHo 7.40), led to a rise in pH1 from 7.22 to 7.80. This pH, change was sensitive to amiloride (apparent K1 78 MM), an inhibitor of Na/H countertransport. The time course of the alkalinization was similar to that of FMLP-stimulated 02 production, which was complete by 5 min. In the presence of 1 mM amiloride, which nearly blocked the pH, transient elicited by FMLP, or in the absence of external Na, where intracellular acidification was observed in FMLP-stimulated cells, 02-release was still roughly 25-45% of normal. Thus, an alkalinization cannot be an obligatory requirement for 02-generation. By independently varying either pH0, pH1, or the internal or external concentrations of Na, both the direction and magnitude of the FMLP-induced pH, transients could be altered. In each instance, the amount of 02-release correlated directly with pHi and was enhanced by intracellular alkalinization.In the absence of FMLP, a rise in pH, to 7.7-7.8 by exposure of cells to 30 mM NH4CI, 10 MM monensin (a Na/H exchanging ionophore), or after a prepulse with 18% CO2 did not result in 02 generation. Thus, these results imply that an alkalinization per se is not a sufficient trigger. Neutrophils exposed to 4 nM FMLP exhibited a threefold slower rate of alkalinization (reaching pHj 1 7.80 by 20-30 min) as compared to that obtained with 100 nM FMLP and did not release significant amounts of 02 under normal incubation conditions. However, these cells could be induced to generate 0°when the degree of alka tion was enhanced by internal Na depletion or by pretreatment with 18% Co2. Together, these results indicate a modulating effect of pH3 on 02 production and suggest that other functional responses of neutrophils may be regulated by their pH1.

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Amiloride Directly Inhibits the Na,K-ATPase Activity of Rabbit Kidney Proximal Tubules

Cited by 171 publications

References 23 publications

Effects of diuretics on GABA‐gated chloride current in frog isolated sensory neurones

Effects of diuretics on GABA‐gated chloride current in frog isolated sensory neurones

Comparison of enzyme activities linked to acid–base regulation in a deep-sea and a sublittoral decapod crab species

Intracellular pH modulates the generation of superoxide radicals by human neutrophils.

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