Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00514 (Amiloride)
 1,513 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purified basolateral membrane vesicles (BLMVs) were prepared from Atlantic lobster (Homarus americanus) hepatopancreas using a Percoll density gradient technique. Enrichments of the Na+/K+-ATPase and alkaline phosphatase activities of these vesicles were 15.4- and 1.2-fold, respectively. The presence of amiloride-sensitive Na+/H+ exchange was demonstrated. Contrary to electrogenic 2Na+/1H+ exchange on apical membranes from the same tissue, kinetic studies of Na+ transport by these basolateral membranes indicate an electroneutral antiport with a Km of 28±1.7 mmol l-1 and a Jmax of 1.74±0.13 µmol mg-1 min-1. Amiloride interacted at a single binding site (Ki=39 µmol l-1) and external Li+ was shown to be an effective competitive inhibitor of the exchange process (Ki=493 µmol l-1). The presence of a membrane-potential-sensitive, Na+-accepting ion channel was also demonstrated. The basolateral Na+/H+ exchanger physiologically resembles members of the NHE family of Na+/H+ antiporters described in vertebrates and departs from the apical electrogenic system previously described in lobster. Whether or not the basolateral Na+/H+ antiporter is an NHE isoform remains to be determined.
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PMID:Characterization of a basolateral electroneutral Na+/H+ antiporter in Atlantic lobster (Homarus americanus) hepatopancreatic epithelial vesicles 931 72

The enzyme involved in outward K+ transport in insect epithelia belongs to the family of V-ATPases. Evidence has been reported relating the generation of the K+ gradient to a primary electrogenic proton transport via a distinct electrophoretic nH+/K+ antiport. The subject of this paper is the transport of K+ at a thread hair sensillum of the cockroach in situ. We recorded changes in the voltage and resistance of the ion-transporting membrane and of shifts in pH caused by inhibition of energy metabolism and by putative inhibitors of a proton/cation exchanger. The results are supplemented by previous determinations of the K+ activities in the same preparation. 1. In cockroach hair sensilla, the ion transport generates a membrane voltage of 105 mV. We found that the transport rendered the positive output compartment alkaline with respect to the cytoplasm by 1.0 pH unit compared with the pH at equilibrium distribution, and we infer that proton transport cannot be the process that energizes the generation of the K+ gradient. 2. The ion transport created an electrochemical potential difference for protons, DeltaetaH, of approximately 4.5 kJ mol-1, while the potential difference for K+, DeltaetaK, amounted to approximately 11 kJ mol-1. Both potential differences are directed to the cytosol. It follows from DeltaetaK/DeltaetaH that an antiport would have to be electrophoretic to drive K+ by DeltaetaH and it should, therefore, contribute to the membrane conductance. Amiloride and harmaline did not significantly change the pH in the adjacent spaces and did not affect the voltage or the resistance of the transporting membrane. Previous determinations of the impedance have shown that the ATP-independent conductance of this membrane is small, supporting the conclusion that it lacks an electrophoretic antiport. From these results, we deduce that K+ transport in cockroach sensilla is not secondary to a proton transport and an electrochemical proton gradient. The phenomena observed match the performance of a primary, electrogenic, cation-translocating ATPase of the type deduced from analyses of the short-circuit current at the midgut epithelium of lepidopteran larvae. The validity of the H+ transport/antiport hypothesis is discussed.
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PMID:A primary cation transport by a V-type ATPase of low specificity 931 11

The effects of two ionizable cryptands, the Na-selective (221)C10 and the K-selective (222)C10, and of valinomycin, FCCP and nystatin on K+ fluxes in opossum kidney (OK) cells have been quantified. The Na,K-ATPase (ouabain-sensitive 86Rb influx) was stimulated by nystatin (> or = 20%), and inhibited by the other ionophores (50-80%), by barium (K-channel blocker) (61%) and by amiloride (Na entry blocker) (34%). The Vmax of the Na,K-ATPase phosphatase activity was unmodified by the ionophores, indicating the absence of direct interaction with the enzyme. The ATPi content was unmodified by the inhibitors and nystatin, but was lowered by (221)C10 (47%), (222)C10 (75%), valinomycin (72%) and FCCP (88%). Amiloride was found to partially remove the inhibition caused by (222)C10 (51%) and valinomycin (49%). Rb efflux was stimulated by nystatin (32%), unmodified by valinomycin, and was inhibited by (221)C10 (19%), (222)C10 (19%) and FCCP (10%). Barium (39%) and amiloride (32%) inhibited this efflux and, in their presence, the nystatin effect persisted, whereas that of the other ionophores vanished. At pH 6.4, the Rb efflux decreased by 14% of its value at pH 7.4, with no additional inhibition by cryptands. Cryptands are shown to inhibit the pH-sensitive K+-conductance, probably by inducing a K+-H+ exchange at the plasma membrane, and by uncoupling oxidative phosphorylation by inducing the entry of K+ and H+ (and possibly Ca2+) ions into the mitochondria.
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PMID:Potassium transport in opossum kidney cells: effects of Na-selective and K-selective ionizable cryptands, and of valinomycin, FCCP and nystatin. 937 11

Alveolar macrophages (m phi) participate in inflammatory and immune responses in acidic microenvironments such as the interstitial fluids of tumors and abscesses. Two plasmalemmal H+ extruders interact to control the acid-base status of alveolar m phi, namely a V-type H+ pump (V-ATPase) and a Na+/H+ exchanger. The present study examined the effects of extracellular pH (pHo) and H+ transport inhibitors on tumor necrosis factor-alpha (TNF-alpha) release induced by endotoxin (lipopolysaccharide) in rabbit alveolar m phi. The amount and activity of TNF-alpha in m phi-conditioned media were determined by enzyme-linked immunosorbent assay and L929 fibroblast bioassay, respectively. TNF-alpha release was suppressed progressively at lower pHo values (< or = 7.0). Also, bafilomycin A1 (a specific inhibitor of V-ATPases) significantly reduced the amount and activity of TNF-alpha in m phi-conditioned media (pHo 7.4). However, bafilomycin caused a significant increase in the nonspecific cytotoxicity (i.e. bioactivity insensitive to TNF-alpha antibody) of m phi-conditioned media. The effects of bafilomycin specifically on TNF-alpha release followed a time course similar to that of acidic pHo, suggesting that both treatments acted on similar events in the lipopolysaccharide signal transduction pathway. Amiloride (an inhibitor of Na+ transporters including the Na+/H+ exchanger) also suppressed TNF-alpha release but displayed a time course of action different from the acidic pHo or bafilomycin.
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PMID:Evidence for pH sensitivity of tumor necrosis factor-alpha release by alveolar macrophages. 950 Feb 96

It has been shown that short-term (hours) treatment with beta-adrenergic agonists can stimulate lung liquid clearance via augmented Na+ transport across alveolar epithelial cells. This increase in Na+ transport with short-term beta-agonist treatment has been explained by activation of the Na+ channel or Na+-K+-ATPase by cAMP. However, because the effect of sustained stimulation (days) with beta-adrenergic agonists on the Na+ transport mechanism is unknown, we examined this question in cultured rat alveolar type II cells. Na+-K+-ATPase activity was increased in these cells by 10(-4) M terbutaline in an exposure time-dependent manner over 7 days in culture. This increased activity was also associated with an elevation in transepithelial current that was inhibited by amiloride. The enzyme's activity was also augmented by continuous treatment with dibutyryl-cAMP (DBcAMP) for 5 days. This increase in Na+-K+-ATPase activity by 10(-4) M terbutaline was associated with an increased expression of alpha1-Na+-K+-ATPase mRNA and protein. beta-Adrenergic agonist treatment also enhanced the expression of the alpha-subunit of the epithelial Na+ channel (ENaC). These increases in gene expression were inhibited by propranolol. Amiloride also suppressed this long-term effect of terbutaline and DBcAMP on Na+-K+-ATPase activity. In conclusion, beta-adrenergic agonists enhance the gene expression of Na+-K+-ATPase, which results in an increased quantity and activity of the enzyme. This heightened expression is also associated with augmented ENaC expression. Although the cAMP system is involved, the inhibition of enhanced enzyme activity with amiloride suggests that increased Na+ entry at the apical surface plays a role in this process.
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PMID:Impact of beta-adrenergic agonist on Na+ channel and Na+-K+-ATPase expression in alveolar type II cells. 970 Jan 4

Stretching the renal pelvic wall increases ipsilateral afferent renal nerve activity (ARNA). This response is enhanced by inhibiting Na+-K+-ATPase with ouabain, suggesting a modulatory role for intracellular Na+ in the activation of mechanosensitive neurons. The messenger RNA for alpha-, beta-, and gamma-subunits of epithelial Na+ channels (ENaC) is found in collecting duct cells. Because ENaC subunits show homology with genes involved in mechanosensation, we examined whether ENaC mRNA could be found in the pelvic wall and whether the ARNA response to increased renal pelvic pressure was modulated by blockers of the Na+ channel. alpha-, beta-, and gamma-subunits are present in the pelvis. The messenger RNA for the beta- and gamma-subunits is readily detected by in situ hybridization throughout the uroepithelium. The ARNA response to increased renal pelvic pressure was reduced by 53 +/- 10% and 40 +/- 10% (P < 0.01) by renal pelvic perfusion with the inhibitors amiloride and benzamil, respectively. Amiloride inhibited the ouabain-induced enhancement of the ARNA response to increased renal pelvic pressure. The magnitude of this inhibition was inversely correlated with the magnitude of the amiloride-mediated blockade of the ARNA response to increased renal pelvic pressure (P < 0.001). Amiloride also reduced the ARNA response to renal pelvic administration of substance P, a mediator of the ARNA response to increased renal pelvic pressure. We conclude that the ENaC complex in the pelvic uroepithelium participates in the activation of renal pelvic mechanosensitive neurons.
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PMID:Amiloride-sensitive Na+ channels in pelvic uroepithelium involved in renal sensory receptor activation. 984 67

In the search for the mechanisms whereby water is transported across biological membranes, we hypothesized that in the airways, the hydration of the periciliary fluid layer is regulated by luminal-to-basolateral water transport coupled to active transepithelial sodium transport. The luminal-to-basolateral (JWL-->B) and the basolateral-to-luminal (JWB-->L) transepithelial water fluxes across ovine tracheal epithelia were measured simultaneously. The JWL-->B (6.1 microliter/min/cm2) was larger than JWB-->L (4.5 microliter/min/cm2, p < 0.05, n = 30). The corresponding water diffusional permeabilities were PdL-->B = 1.0 x 10(-4) cm/s and PdB-->L = 7.5 x 10(-5) cm/s. The activation energy (Ea) of JWL-->B (11.6 kcal/mol) was larger than the Ea of JWB-->L (6.5 kcal/mol, p < 0.05, n = 5). Acetylstrophanthidin (100 microM basolateral) reduced JWL-->B from 6.1 to 4.4 microliter/min/cm2 (p < 0. 05, n = 5) and abolished the PD. Amiloride (10 microM luminal) reduced JWL-->B from 5.7 to 3.7 microliter/min/cm2 (p < 0.05, n = 5) and reduced PD by 44%. Neither of these agents significantly changed JWB-->L. These data indicate that in tracheal epithelia under homeostatic conditions, JWB-->L was dominated by diffusion (Ea = 4.6 kcal/mol), whereas approximately 30% of JWL-->B was coupled to the active Na+,K+-ATPase pump (Ea = 27 kcal/mol).
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PMID:Bidirectional transepithelial water transport: measurement and governing mechanisms. 992 88

The inotropic and chronotropic effects of Amiloride (AMI) and Dichloro-benzamil Amiloride (DBC-AMI) were studied on the guinea pig isolated atria, also, the interaction between these drugs and Beta-methyl-Digoxin (BM-DIGO), epinephrine and low extracellular potassium (1 mM). AMI (10(-3) M) has a negative chronotropic and positive inotropic effects, not dependent on the autonomic system. DCB-AMI has a bimodal effect on the contractile force: increases it at low concentrations but causes a decrease at concentrations higher than 10(-6) M. The effect of AMI on the sinus frequency is unchanged by BM-DIGO. AMI (10(-3) M) decreases the inotropic effect of BM-DIGO and increases the toxic concentration of this drug on isolated tissues. The dose-response curve to epinephrine was not changed by AMI. Similar results were obtained using DCB-AMI (2 x 10(-7) M). The positive inotropic effect obtained by low extracellular potassium (1 mM) was not altered by AMI. The activity of the Mg(++)-dependent, Na+/K+ ATPase measured in the microsomal fraction obtained from guinea pig heart was diminished (10%) by AMI (10(-3) M). The drug did not affect the inhibition of the enzyme induced by ouabain. In conclusion, our experiments show multiple effects of AMI and DCB-AMI on the guinea pig heart. The inhibition of the Na+/Ca++ exchange explains them only partially. A slow channel blocking effect appears fundamental to interpret our results.
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PMID:[Effect of amiloride and its derivative dichlorobenzamil on guinea pig atria: interaction with other inotropic mechanisms]. 1051 38

The mechanism by which the intra-erythrocytic form of the human malaria parasite, Plasmodium falciparum, extrudes H(+) ions and thereby regulates its cytosolic pH (pH(i)), was investigated using saponin-permeabilized parasitized erythrocytes. The parasite was able both to maintain its resting pH(i) and to recover from an imposed intracellular acidification in the absence of extracellular Na(+), thus ruling out the involvement of a Na(+)/H(+) exchanger in both processes. Both phenomena were ATP-dependent. Amiloride and the related compound ethylisopropylamiloride caused a substantial reduction in the resting pH(i) of the parasite, whereas EMD 96785, a potent and allegedly selective inhibitor of Na(+)/H(+) exchange, had relatively little effect. The resting pH(i) of the parasite was also reduced by the sulfhydryl reagent N-ethylmaleimide, by the carboxyl group blocker N,N'-dicyclohexylcarbodiimide, and by bafilomycin A(1), a potent inhibitor of V-type H(+)-ATPases. Bafilomycin A(1) blocked pH(i) recovery in parasites subjected to an intracellular acidification and reduced the rate of acidification of a weakly buffered solution by parasites under resting conditions. The data are consistent with the hypothesis that the malaria parasite, like other parasitic protozoa, has in its plasma membrane a V-type H(+)-ATPase, which serves as the major route for the efflux of H(+) ions.
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PMID:pH regulation in the intracellular malaria parasite, Plasmodium falciparum. H(+) extrusion via a V-type H(+)-ATPase. 1055 94

Split lamellae of the posterior gills of freshwater-adapted Chinese crabs (Eriocheir sinensis) were mounted in a modified Ussing-type chamber, and active and electrogenic absorption of Na(+) and Cl(-) were measured as positive (I(Na)) or negative (I(Cl)) short-circuit currents. Haemolymph-side addition of eyestalk extract stimulated I(Cl) by increasing both the transcellular Cl(-) conductance and the electromotive force for Cl(-) absorption. The effect was dose-dependent. Boiling the eyestalk extract did not change its effectiveness. The stimulating factor passed through dialysis tubing, indicating that it has a molecular mass of less than 2 kDa. R(p)cAMPS, a blocker of protein kinase A, reduced the stimulated I(Cl). Eyestalk extract stimulated I(Na) by increasing the transcellular Na(+) conductance at constant electromotive force. Amiloride-induced current-noise analysis revealed that stimulation of I(Na) was accompanied by an increase in the apparent number of open apical Na(+) channels at a slightly reduced single-channel current. In addition to the electrophysiological experiments, whole gills were perfused in the presence and in the absence of putative transport stimulators, and the specific activities of the V-ATPase and the Na(+)/K(+)-ATPase were measured. Eyestalk extract, theophylline or dibutyryl-cyclic AMP stimulated the activity of the V-ATPase, whereas the activity of the Na(+)/K(+)-ATPase was unaffected. The simultaneous presence of R(p)cAMPS prevented the stimulation of V-ATPase by eyestalk extract or theophylline.
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PMID:Active NaCl absorption across split lamellae of posterior gills of the chinese crab Eriocheir sinensis: stimulation by eyestalk extract. 1072 85


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