Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new amiloride research articles will be listed here shortly after becoming available to us.
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Medical research on amiloride
J Biol Chem. 2008 Jun 27;
de Seigneux S, Leroy V, Ghzili H, Rousselot M, Nielsen S, Rossier BC, Martin PY, Féraille E
Tubulo-interstitial inflammation is a common feature of renal diseases. We have investigated the relationship between inflammation and Na(+) transport in the collecting duct (CD) using the mCCD(cl1) and mpkCDD(cl4) principal cell models. Lipopolysaccaride (LPS) decreased basal and aldosterone-stimulated amiloride-sensitive transepithelial current in a time-dependent manner. This effect was associated with a decrease in Serum and Glucocorticoid-regulated Kinase 1 (SGK1) mRNA and protein levels, followed by a decrease in epithelial sodium channel (ENaC) alpha-subunit mRNA levels. The LPS-induced decrease in SGK1 expression was confirmed in isolated rat CD. This decreased expression of either SGK1 or ENaC alpha-subunit was not due to enhanced degradation of mRNA. In contrast, LPS inhibited transcriptional activity of the SGK1 promoter measured by luciferase-reporter gene assay. The effect of LPS was not mediated by inhibition of mineralocorticoid (MR) or glucocorticoid receptor (GR), since expression of both receptors was unchanged, and blockade of MR or GR by either spironolactone or RU486, respectively, did not prevent the down-regulation of SGK1. The effect of LPS was mediated by the canonical NF-kappaB pathway since overexpression of a constitutively active mutant inhibitor of nuclear factor kappaB kinase beta (IKKbeta) decreased SGK1 mRNA levels, and knock-down of p65 NF-kappaB subunit by small interfering RNA increased SGK1 mRNA levels. Chromatin immunoprecipitation showed that LPS increased p65 binding to two NF-kappaB sites along the SGK1 promoter. In conclusion, we show that activation of the NF-kappaB pathway down-regulates SGK1 expression and that this might participate in decreased ENaC alpha-subunit expression, ultimately resulting in decreased Na(+) transport.
Long-term growth of children with nephrogenic diabetes insipidus.
Pediatr Nephrol. 2008 Jun 27;
Lejarraga H, Caletti MG, Caino S, Jiménez A
Primary nephrogenic diabetes insipidus (NDI) is a genetic, chronic disease characterised by lack of distal renal tubule to antidiuretic hormone. The condition produces polyuria, polydipsia, and consequently, reduced caloric intake and growth failure. There is very scarce information on physical growth of affected children. The objective of the paper is to describe long-term growth of 14 patients from 11 families, studied retrospectively and followed for 3-16 years (median 11.6 years). Diagnosis was made on the basis of clinical and laboratory data and concentration test under pitressin. Patients were treated with indomethacin, thiazides, and amiloride. Weight and standing height was measured periodically at the Laboratory of Anthropometry, following standardised techniques. Information was obtained from clinical notes. The majority of children grew below the third centile of local standards, and many showed improvement of weight, height, and body mass index (BMI) over time. Mean height, weight, and BMI gain during follow-up was 1.72, 1.06, and 1.46 standard deviations (SDs), respectively. Three children who did not adhere to treatment showed growth delay. Height gain during the first 2 years of follow-up was inversely associated with height deficit at diagnosis. Further studies on growth at adolescence and in different mutations are recommended.
Pflugers Arch. 2008 Jun 26;
Bogdan R, Veith C, Clauss W, Fronius M
Epithelia, in general, and the lung epithelium, in particular, are exposed to mechanical forces, but little is known about their impact on pulmonary ion transport. In our present study, we employed transepithelial ion transport measurements on Xenopus lung preparations using custom-built Ussing chambers. Tissues were exposed to mechanical stress by increasing the water column (5 cm) at one side of the tissues. Apical exposure to hydrostatic pressure significantly decreased the short circuit current (I (SC): 24 +/- 1%, n = 152), slightly decreased the transepithelial resistance (R (T): 7 +/- 2%, n = 152), but increased the apical membrane capacitance (C (M): 16 +/- 6%, n = 9). The pressure-induced effect was sensitive to Na(+) (amiloride), Cl(-) (DIDS, NFA, NPPB) and K(+) channel blockers (Ba(2+), glibenclamide). Further on, it was accompanied by increased extracellular ATP levels. The results show that mechanical stress leads to an activation of Na(+), Cl(-), and K(+) conductances in a native pulmonary epithelium resulting in a net decrease of ion absorption. This could be of considerable interest, since an altered ion transport may contribute to pathophysiological conditions, e.g., the formation of pulmonary edema during artificial ventilation.
Am J Physiol Renal Physiol. 2008 Jun 25;
O'Connor PM, Lu L, Schreck C, Cowley Jr AW
The aims of the current study were to determine whether superoxide (O2(-)) production is enhanced in mTAL of Dahl salt-sensitive (SS) rats compared to a salt-resistant consomic control strain (SS.13(BN)) and to elucidate the cellular pathways responsible for augmented O2(-) production. Studies were carried out in 7-10 week old male SS and SS.13(BN)rats fed either a 0.4% NaCl diet or a 4.0% NaCl diet for 3 days prior to tissue harvest. Tissue strips containing mTAL were isolated from the left kidney, loaded with the O2(-) sensitive fluorescent dye DHE, superfused with modified Hanks solution and imaged at X60 magnification on a heated microscope stage. O2(-) production was stimulated in mTAL by incrementing superfusate NaCl concentration from 154 to 254 to 500mM. O2(-) production was enhanced in mTAL of SS rats compared to SS.13(BN)rats in response to incrementing bath NaCl. Addition of N-methyl-amiloride (100microM) or inhibition of NAD(P)H oxidase reduced O2(-) production in SS mTAL to levels observed in SS.13(BN)rats. Both amiloride and ouabain sensitive pathways of O2(-) production were elevated following three days of high (4.0%) NaCl feeding in mTAL of SS and SS.13(BN) rats. We conclude that mTAL from SS rats exhibit enhanced amiloride sensitive O2(-) production. The amiloride sensitive O2(-) response in mTAL is independent of active Na(+) transport and appears to be mediated by NAD(P)H oxidase. Amiloride sensitive O2(-) production is likely to contribute to augmented outer medullary O2(-) production observed in SS rats during both normal and high NaCl diets. Key words: free radicals, hypertension, kidney, NADPH oxidase, blood pressure.
Amiloride delays the onset of pilocarpine-induced seizures in rats.
Brain Res. 2008 May 15;
N'gouemo P
Recent evidence suggests that amiloride, a potent and nonselective blocker of acid-sensing ion channels, suppresses generalized seizures induced by maximal electroshock and pentylenetrazole. Here I further determined and quantified the effects of amiloride on the occurrence of limbic seizures and status epilepticus-induced by intraperitoneal administration of pilocarpine, a muscarinic acetylcholine receptor agonist. Pretreatment with various doses (5, 10, 30, 100, and 200 mg/kg) of amiloride significantly delayed the onset of the first episode of limbic seizures and the occurrence of status epilepticus following administration of pilocarpine (380 mg/kg). At the dose of 100 and 200 mg/kg, amiloride suppressed limbic seizures in 33% of pilocarpine-treated animals and significantly reduced the seizure severity score in 67% of the remaining animals. These findings suggest that amiloride may modulate seizure generation and propagation, probably via mechanisms involving acid-sensing ion channels in the pilocarpine model of temporal lobe epilepsy.
Blood Press. 2008; 17(1): 55-63
Obih P, Oyekan AO
This study evaluated the role of PPARalpha in renal function and whether PPARalpha knockout (KO) mice are hypertensive or salt-sensitive. We hypothesize that PPARalpha modulation of ion transport defines the capacity for sodium excretion (U(Na)V). PPARalpha KO and wild-type (WT) mice were placed on a normal salt (NS, 0.5% NaCl) or high salt (8% NaCl, HS) diet for 28 days and mean arterial blood pressure (MABP) and heart rate (HR) determined. In a group of anesthetized animals on NS diet, pressure natriuresis (P/N) was determined and in another group, acute sodium load (0.9% NaCl) was administered and U(Na)V compared in mice pretreated with amiloride (200 microg/kg) or hydrochlorothiazide (3 mg/kg), in vivo measurements of sodium hydrogen exchanger or Na-Cl-cotransporter activity, respectively. MABP and HR were similar in PPARalpha KO and WT mice placed on a NS diet (116+/-6 mmHg, 587+/-40 beats/min, KO; 116+/-4 mmHg, 551+/-20 beats/min, WT). HS diet increased MABP to a greater extent in KO mice (Delta = 29+/-3 vs 14+/-3 mmHg, p
Ann Acad Med Stetin. 2007; 53(2): 56-67
Banach B
INTRODUCTION: The aim of the study was to determine a role of intra-wall nervous and neurohormonal system in control of ion transport in airways, and to identify the control mechanisms, having effect on constant electric potential of this tissue named as PD, and the ones which have effect on reversible changes of this potential marked as dPD. Through the application of amiloride sodium ion transport blocker the importance of transepithelial sodium ion transport for transepithelial electric potential of airways was to be determined, as well as the other amiloride effects on isolated airways. The conditions for examination of secretion of the chlorides in airways have been determined and will be presented as chemical isolation of chloride currents with use of amiloride. MATERIAL AND METHODS: Experimental material consisted of 135 fragments of trachea wall obtained from 45 animals. Experiments consisted in measurements of transepithelial electric potential (PD) and resistance (R) of isolated trachea wall placed in Ussing apparatus, where the tissue separates two chambers filled up with isoosmotic complex electrolyte solution. The essential procedure applied in irritation of sensory receptors was directing the fluid jet from a peristaltic pump to mucous surface of isolated trachea. The jet consisted of fluid analogous to the one from the chamber, or it was modified as the experiment conditions required. RESULTS: Transepithelial transport way of sodium ions in trachea epithelium has the controlling effect in value modulation of transepithelial difference of electric potentials, as well as in induction of hyperpolarization after mechanical stimuli action, while at the same time the sodium transport at 40% is the exclusive carrier of hyperpolarization reaction.
Epithelial Na(+) channel delta subunit mediates acid-induced ATP release in the human skin.
Biochem Biophys Res Commun. 2008 Aug 15; 373(1): 155-158
Yamamura H, Ugawa S, Ueda T, Nagao M, Shimada S
The amiloride-sensitive epithelial Na(+) channel (ENaC) regulates Na(+) homeostasis in cells and across epithelia. Although we described that ENaCdelta is a candidate molecule for a pH sensor in the human brain, the physiological and pathological roles of ENaCdelta in non-neuronal tissues are still unknown. Here we show a novel physiological function of ENaCdelta in peripheral tissues in humans. Expression analyses at the level of mRNA clearly revealed that ENaCdelta was abundantly expressed in human epidermis and keratinocytes. In addition, ENaCdelta protein was detected in there. In cultured keratinocytes, acidic stress (pH 5.0) evoked ATP release, which was significantly reduced in the presence of 100muM amiloride or 10muM benzamil. In conclusion, ENaCdelta may be involved in the mechanism underlying pH sensing followed by the regulation of cell viability in the human skin.
J Cell Biochem. 2008 Jun 9;
Diaz-Velasquez CE, Castro-Muñozledo F, Kuri-Harcuch W
Pre-adipose 3T3-F442A cells exposed to fetal bovine serum or human growth hormone (adipogenic medium) become irreversibly committed to differentiation into adipocytes within 24-36 h. We show now that the action of the serine-threonine kinase inhibitor staurosporine is much more rapid since its addition in non-adipogenic medium resulted in commitment to adipocyte differentiation within 4-6 h. During this period, glycogen synthase kinase 3beta was activated. Commitment depended on an increase in the intracellular calcium concentration that was modulated in part by a T-type calcium channel since mibefradil, amiloride, and NiCl(2), which are selective blockers of the T-type channels, partially inhibited adipose differentiation. Studies of the inhibitory action of retinoic acid showed that a period of time after exposure to St was required in order to stabilize the commitment to adipose differentiation. It was concluded that the commitment of the cells consists of two stages. Commitment is promoted during the first one, and during the second there is a stabilization which still can be destabilized by the addition of retinoic acid or other drugs. The commitment becomes stable after 40 h of staurosporine treatment, and can no longer be prevented by retinoic acid. The identification of these two stages of commitment makes it possible to analyze in further detail early molecular events of the process and the nature of any other participating genes. J. Cell. Biochem. (c) 2008 Wiley-Liss, Inc.
Arch Biochem Biophys. 2008 May 27;
Taves J, Rastedt D, Canine J, Mork D, Wallert MA, Provost JJ
Matrix metalloproteinase 9 (MMP-9) plays a critical role in digesting the extracellular matrix and has a vital function in tumor metastasis and invasion; this protease activity is significantly increased in non-small cell lung cancers. The sodium hydrogen exchanger isoform 1 (NHE1) functions as a focal point for signal coordination and cytoskeletal reorganization. NHE1 is thought to play a central role in establishing signaling components at the leading edge of a migrating cell. Therefore, we studied the relationship between NHE1 and MMP-9 activity in Chinese hamster lung fibroblasts (CCL39) stimulated with phenylephrine (PE). We show that PE increases MMP-9 gelatinolytic activity in CCL39 cells. The inhibition of phospholipase D (PLD) signaling abrogated PE-induced MMP-9 activity. The role of PLD as an essential signaling intermediate was confirmed when the addition of permeable phosphatidic acid increased MMP-9 activity in the same cells. PE-induced invasion was increased 1.9-fold over controls and the PE response was lost when 1-butanol was used to block PLD signaling. Cells pre-treated with the NHE1 inhibitor, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) prior to PE addition resulted in a notable decrease in MMP-9 activation and cell invasion as compared to untreated PE-stimulated cells. CCL39 NHE1 null cells demonstrated no increase in MMP-9 protease activity or cell invasion in response to PE treatment. Reconstitution of NHE1 expression recovered the PE-induced activation of protease activity and cell invasion. MMP-9 processing was altered in cells expressing a proton transport defective NHE1 but retained the ability to respond to PE. Conversely, cells expressing an ezrin, radixin, moesin (ERM)-binding deficient NHE1 had a lower MMP-9 activity and the protease did not respond to PE addition. Parallel studies on NCI-H358 non-small cell lung cancer (NSCL) cells showed that PE stimulated both MMP-9 activity and cell invasion in an NHE1 dependent manner. This work describes for the first time a PE-induced relationship between NHE1 and MMP-9 and a new potential mechanism by which NHE1 could promote tumor formation and metastasis.