Sodium channel blockers for cystic fibrosis
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Background People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over‐absorption of sodium results in the dehydration of the liquid that lines the airway surface and is a primary defect in people with CF. Objectives To determine whether the topical administration of drugs that block sodium transport improves the respiratory condition of people with CF. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture ion transport agents for unpublished or follow‐up data. Most recent search of the Group's register: 26th August 2009. Selection criteria Published or unpublished randomised controlled trials (RCTs) or quasi‐randomised controlled trials of sodium channel blockers compared to placebo or another sodium channel blocker or the same sodium channel blocker at a different dosing regimen. Data collection and analysis Two authors independently extracted data. Meta‐analysis was limited due to differing study designs. Main results Five RCTs, with a total of 226 participants, examining the topical administration of the short‐acting sodium channel blocker, amiloride, compared to placebo were identified as eligible for inclusion in the review. In three studies over six months, there was a significant difference found in the difference in relative change in FVC in favour of placebo (weighted mean difference 1.51% (95% confidence interval ‐2.77 to ‐0.25), although heterogeneity was evident. A two‐week study demonstrated that hypertonic saline with amiloride pre‐treatment did not result in a significant improvement in respiratory function or mucus clearance, in contrast to pre‐treatment with placebo. There were no significant differences identified in other clinically relevant outcomes. Authors' conclusions We found no evidence that the topical administration of a short‐acting sodium channel blocker improves respiratory condition in people with cystic fibrosis and some limited evidence of deterioration in lung function.Keywords:
Amiloride
Sodium channel blocker
The modifying effects of amiloride on the thermosensitivity of Chinese hamster V-79 cells were examined under both neutral (pH 7.3) and acidic (pH 6.6) conditions. Amiloride, a diuretic drug, is known to inhibit the Na+/H+ exchange activity. Under the extracellular pH of 7.3, amiloride (0.1-0.5 mM) enhanced the thermal cell killing powers of 42 degrees C hyperthermia with increasing concentration and exposure time of the drug. The age response of cells to 42 degrees C hyperthermia in the presence or absence of amiloride (0.5 mM) showed that amiloride sensitized cells to heat, especially those at G1-S boundary through middle S phases. On the other hand, the lowering of extracellular pH to 6.6 enhanced cell killing by 42 degrees C hyperthermia. When cells were exposed to 42 degrees C hyperthermia in the presence of amiloride at pH 6.6, cell survival decreased still more. The thermosensitizing effects of the lowered pH at 6.6 and amiloride appeared to be additive. From these results, it is suggested that the thermosensitization by amiloride is probably due, in part, to the inhibition of cellular Na+/H+ exchange activity. The present study proposes the possibility that amiloride may be useful as a hyperthermic sensitizer in a clinical treatment of cancer.
Amiloride
Chinese hamster
Epithelial sodium channel
Intracellular pH
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The kinetics of inhibition by amiloride of the integrated chorda tympani response were investigated in rats subjected to lingual stimulation with NaCl. In one series of experiments the time of exposure to amiloride was varied at fixed amiloride concentration. Exposure to 10(-4) M amiloride for 2 s reduced the response to 0.5 M NaCl by approximately 50%. The time course of recovery from amiloride inhibition was first order (relaxation time approximately equal to 4 min) for all exposure times. For exposure to 10(-4) M amiloride for less than or equal to 30 s recovery was better than 90% in 20 min. Not all of the chorda tympani response was inhibited by amiloride. With 0.5 M NaCl there was a 70% reduction in response, whereas at 0.05 M NaCl the reduction was only 30%. Parallel effects of amiloride were seen in the short-circuit current of an in vitro preparation of canine lingual epithelium. Amiloride reduced the short-circuit current by the same percentage as it inhibited the chorda tympani response. These results suggest that gustatory transduction is mediated in part by an apical membrane transport system that can be inhibited by amiloride. There exists, however, a second transducing element that is amiloride insensitive. A model is developed, assuming, in part, that the neural response reflects the flows of Na through amiloride-sensitive apical pathways.
Amiloride
Chorda
Epithelial sodium channel
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Amiloride and its derivatives (benzamil, dichlorobenzamil, 5-(N,N-dimethyl)-amiloride, 5-(N-ethyl-N-isopropyl)-amiloride, (N,N-hexamethylene)- amiloride and 5-(N-methyl-N-isobutyl)-amiloride) are commonly used as selective blockers of Na+/Ca++ exchange or Na+/H+ exchange. Very little information is currently available regarding their effects on cardiac performance. It was observed that addition of amiloride or any of the selected derivatives to the coronary perfusate of the right ventricular wall produced a potent depressive effect on peak developed tension and the rates of tension generation and dissipation. The concentrations at which this occurred are those that are commonly used in ischemia or hypoxia studies. Significantly, the depressive action of the drugs increased with the perfusion duration and never achieved a stable level. An initial, transient positive inotropic effect was observed with some of the drugs. If the drug concentration and perfusion time was limited, the effects were reversible. All of the drugs except amiloride produced extra systoles. The drugs were capable of blocking Ca++ transients in isolated cardiomyocytes but had little effect on intracellular pH. The drugs lengthened the action potential duration and decreased the action potential amplitude and upstroke velocity. Their effects on cardiac performance may involve a complex inhibition of Ca++ influx and K+ efflux in addition to a stimulation of a nonselective cation current. It is concluded that amiloride and its analogs have striking effects on cardiac performance which may be unrelated to their capacity to inhibit Na+/Ca++ or Na+/H+ exchange. In summary, the use of these drugs is not normally recommended in cell or tissue perfusion experiments because of their nonselectivity. However, if the drug concentration and perfusion time is controlled carefully, interpretable data may be obtained in some cases.
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Intracerebroventricular infusions of an amiloride analog, benzamil, reduce blood pressure in several rat models of hypertension. This effect has been attributed to an inhibition of amiloride-sensitive Na + channels in the brain. This study examines whether intracerebroventricular benzamil would prevent the onset of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats and whether this effect correlates with an inhibition of ion transport through the known amiloride-sensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na + channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 μg/h icv) did significantly attenuate the increase in blood pressure induced by DOCA treatment. This antihypertensive effect, however, was not associated with an alteration in a blood-brain barrier ion transport as assessed by measurements of blood-to-brain 22 Na transport and cerebral spinal fluid Na + and K + concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na + channels, also attenuated the increase in blood pressure induced by DOCA-salt treatment. Comparisons of the effects of benzamil, dimethyl amiloride, and 3,4-dichlorobenzamil, another amiloride analog, suggest that these antihypertensive effects are mediated by an inhibition of Na + /Ca 2+ exchange in the brain.
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Epithelial sodium channel
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To test the hypothesis that liquid formation in the foetal lung reflects the balance between Cl- secretion and Na+ absorption by the respiratory tract epithelium, we studied the independent and combined effects of selective ion transport inhibitors on basal production of lung liquid in foetal lambs. We prepared 19 foetal lambs (gestation 125 +/- 4, term = 147 days) with chronic indwelling catheters for subsequent measurement of luminal liquid production over time (JV). Using an impermeant tracer technique, we measured JV before and after tracheal instillation of 2 different inhibitors of ion transport: bumetanide, a Na(+)-K(+)-2Cl- co-transport inhibitor, and amiloride, a Na+ transport inhibitor. In 7 foetuses we sequentially added bumetanide (10(-4) M) and 2 different concentrations of amiloride (10(-6) M, 10(-4) M) to the liquid within the lung lumen. After we gave bumetanide, JV decreased from 12 +/- 4 ml/h to 0 +/- 5 ml/h and subsequently increased during the 2 periods of amiloride exposure (10(-6) M: 6 +/- 5 ml/h; 10(-4) M: 7 +/- 7 ml/h). In 5 control studies we gave bumetanide, followed by only amiloride vehicle. JV for all time periods in the control studies was similar to the experimental group, demonstrating no effect of amiloride. In 5 foetuses we administered the 2 concentrations of amiloride before bumetanide. There was no change in JV with either concentration of amiloride (baseline: 13 +/- 2 ml/h; 10(-6) M amiloride: 15 +/- 5 ml/h; 10(-4) M amiloride: 13 +/- 6 ml/h).(ABSTRACT TRUNCATED AT 250 WORDS)
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Bumetanide
Epithelial sodium channel
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Amiloride
Sodium–hydrogen antiporter
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By using the Sperber technique in nonanesthetized chickens, it was found that amiloride was actively secreted by the renal tubule. This active secretion could be blocked by the simultaneous infusions of the organic cations guanidine, quinine and mepiperphenidol, but not by the organic anion probenecid. This suggested that amiloride was transported by the organic cation transport system of the renal tubule. A significant part of the amiloride which bypassed the infused kidney was taken up by the peripheral tissues, resulting in a recovery of amiloride smaller than that of simultaneously infused p-aminohippurate. During the infusion of amiloride, a dose-dependent ipsilateral mild natriuresis was observed. A maximum ipsilateral antikaliuretic effect and increase in pH were found when 5 X 10(-9) mol/kg.min of amiloride were reaching the infused kidney. It is concluded that amiloride is secreted from blood to urine by the proximal tubule and exerts it natriuretic and kaliuretic effects at the luminal surface of the distal tubule.
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Tubule
Probenecid
Epithelial sodium channel
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Amiloride and amiloride analogs have been extensively used as inhibitors of Na+-selective transport proteins. The interaction of amiloride analogs with the epithelial Na+ channel, Na+/H+ exchanger, and Na+/Ca2+ exchanger is summarized. The potential use of amiloride analogs as biochemical probes for amiloride-sensitive transport proteins, and as immunologic tools for development of antibodies directed against these proteins is discussed, as are some of the limitations and problems encountered using amiloride analogs as "specific" inhibitors of defined transport proteins.
Amiloride
Epithelial sodium channel
Anion exchanger
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Amiloride-sensitive sodium channels in taste buds appear to play a key role in the response to NaCl stimulation, at least in adult rats. The researchers examined whether neonatal rats, which display an exaggerated preference for hypertonic NaCl solutions, lack functional amiloride-sensitive sodium channels. NaCl intake was significantly reduced by amiloride pretreatment, but water and ammonium chloride, NH4Cl, were unaffected. The researchers assessed whether the early appearance of amiloride sensitivity was mediated by effects on chorda tympani (CT) activity by sectioning the CT before testing. CT transection reduced intake of NaCl solutions and eliminated evidence of amiloride sensitivity. Amiloride sensitivity was also assessed by recording of whole-nerve CT activity at 8-11 days of age; the response to NaCl stimulation was significantly suppressed by amiloride. These data indicate that amiloride-sensitive sodium channels develop earlier than previously believed.
Amiloride
Epithelial sodium channel
Chorda
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To investigate the mechanism by which amiloride inhibits urinary acidification, its effects on H+ secretion were examined in the isolated urinary bladder of the fresh water turtle. In short-circuited turtle bladders amiloride inhibited H+ secretion by 30% and Na+ transport by 100%. Maximal inhibition was reached at 10(-4) M amiloride for both transport systems. In contrast to amiloride, ouabain did not affect H+ secretion despite complete inhibition of Na+ transport. In bladders first treated with ouabain amiloride failed to inhibit H+ secretion and in bladders first treated with amiloride, the inhibition of H+ secretion was partially reversed by ouabain. The inhibition of H+ secretion by amiloride is attributed to hyperpolarization of the luminal cell membrane and the imposition of a voltage opposing the movement of protons in the active transport pathway.
Amiloride
Epithelial sodium channel
Hyperpolarization
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