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1.
M. Köttgen J. Leipziger K. -G. Fischer R. Nitschke R. Greger 《Pflügers Archiv : European journal of physiology》1994,428(2):179-185
The pH regulation in HT29 colon carcinoma cells has been investigated using the pH-sensitive fluorescent indicator 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). Under control conditions, intracellular pH (pHi) was 7.21±0.07 (n=22) in HCO
3
–
-containing and 7.21±0.09 (n=12) in HCO
3
–
-free solution. HOE-694 (10 mol/l), a potent inhibitor of the Na+/H+ exchanger, did not affect control pHi. As a means to acidify cells we used the NH
4
+
/NH3 (20 mmol/l) prepulse technique. The mean peak acidification was 0.37±0.07 pH units (n=6). In HCC
3
–
-free solutions recovery from acid load was completely blocked by HOE-694 (1 mol/l), whereas in HCO3
3
–
-containing solutions a combination of HOE-694 and 4,4-diisothiocyanatostilbene-2, 2-disulphonate (DIDS, 0.5 mmol/l) was necessary to show the same effect. Recovery from acid load was Na+-dependent in HCO
3
–
-containing and HCO
3
–
-free solutions. Removal of external Cl– caused a rapid, DIDS-blockable alkalinization of 0.33±0.03 pH units (n=15) and of 0.20±0.006 pH units (n=5), when external Na+ was removed together with Cl–. This alkalinization was faster in HCO
3
–
-containing than in HCO
3
–
-free solutions. The present observations demonstrate three distinct mechanisms of pH regulation in HT29 cells: (a) a Na+/H+ exchanger, (b) a HCO
3
–
/Cl– exchanger and (c) a Na+-dependent HCC
3
–
transporter, probably the Na+-HCO
3
–
/Cl– antiporter. Under HCO
3
–
— free conditions the Na+/H+ exchanger fully accounts for recovery from acid load, whereas in HCO
3
–
-containing solutions this is accomplished by the Na+/H+ exchanger and a Na+-dependent mechanism, which imports HCO
3
–
. Recovery from alkaline load is caused by the HCO
3
–
/Cl– exchanger.This study was supported by DFG Gr 480/10 相似文献
2.
Human glycophorins block in vitro invasion of Plasmodium falciparum merozoites into human erythrocytes. A segment of glycophorin A which appears to be involved in the inhibition, is at, or adjacent to, the membrane-spanning domain of the molecule. To study the role of hydrophobic interactions in the inhibition, a series of proteins were derivatized with lipophilic side groups, and tested for inhibitory activity. Glycophorin A became five times more inhibitory after derivatization with nitrobenzylfurazan groups. Bovine serum albumin was derivatized to different degrees with nitrobenzylfurazan, dinitrobenzyl, trinitrobenzyl, dansyl, disulfonic stilbene, and fluorescein groups. The presence of hydrophobic side groups on the protein rendered it highly inhibitory to invasion, whereas the presence of hydrophilic substitutes such as disulfonic stilbenes did not. Other soluble proteins such as human serum albumin, transferrin, ovalbumin, fetuin and casein derivatized with dinitrobenzyl groups, were also found to block invasion. Inhibition was not a result of toxic effects of the protein derivatives on parasite metabolism or development. A minimum of ten hydrophobic side groups per bovine serum albumin was required in order to elicit appreciable inhibition. The invasion blocking activity was highly correlated with the rate and affinity of binding of the derivatized macromolecules to heptyl-Sepharose. The latter provided a quantitative measure for the capacity of amphiphiles to undergo hydrophobic interactions with insoluble matrices. The results of the present study indicate that hydrophobic interactions may be an essential component in the invasion of P. falciparum merozoites into human erythrocytes. 相似文献
3.
Ma HP Zhou ZH Liang YY Saxena S Warnock DG 《Pflügers Archiv : European journal of physiology》2004,449(1):96-105
Using whole-cell patch-clamp techniques we found that ATP activated an outwardly rectifying current in Daudi human B lymphoma cells under acidic conditions. The substitution of Cl– for gluconate– shifted the reversal potential, while Cl– channel blockers, 4,4-diisothiocyanostibene-2,2-disulfonic acid (DIDS) and 9-anthracene carboxylic acid (9-AC), blocked the current, indicating that ATP induces this current by activating the outwardly rectifying chloride channel (ORCC). The effect of ATP on ORCC was mimicked by ADP, but not by other P2 receptor agonists such as ATPS (a poorly hydrolyzable analog of ATP), 2,3-O-benzoyl-4-benzoyl-ATP (BzATP), and UTP. The ATP-induced ORCC current was completely blocked by 100 M suramin (a P2 receptor antagonist), and was partially blocked by 100 M pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid tetrasodium (PPADS), which is another P2 receptor antagonist. Neither inactivation of G proteins nor elimination of extracellular Ca2+ affected the ATP-induced current, indicating that G protein-coupled P2Y receptors and Ca2+-permeable P2X receptors are not involved. Based on the pharmacological profile and the fact that acidic conditions are required for ATP to activate the ORCC, we suggest that acidic ATP activates the lymphocyte ORCC via a novel pathway, which is not associated with any previously described purinergic receptors. 相似文献
4.
Yoshitaka Saito Terutaka Ozawa Hiromu Hayashi Akinori Nishiyama 《Pflügers Archiv : European journal of physiology》1987,409(3):280-288
The mechanisms of Cl– transport and the effects of acetylcholine (ACh) and electrochemical Cl– potential changes across the basolateral plasma membrane on intracellular Cl– activity in the acinar cells of isolated mouse lacrimal glands were studied using double-barreled Cl–-selective microelectrodes. In the resting state, the basolateral membrane potential (V
m) was about –40 mV and intracellular Cl– activity was about 35 mmol/l. Addition of ACh (10–910–6 mol/l) hyperpolarizedV
m and decreased the Cl– activity in a dose-dependent manner. ACh (10–6 mol/l) hyperpolarizedV
m by 20 mV and decreased the cytosolic Cl– activity with an initial rate of 16.0 mmol/l · min. Reduction of the perfusate Cl– concentration to 1/9 control depolarizedV
m and decreased cytosolic Cl– activity at a rate of 1.9 mmol/l · min. AV
m hyperpolarization of 20 mV produced by DC injection to the adjacent cell decreased Cl– activity at a rate of 4.6 mmol/l · min. DIDS (1 mmol/l) hyperpolarizedV
m by 8 mV with little change in Cl– activity and increased the input resistance of the cells by 25%. DIDS decreased the rate of change in Cl– activity induced by low-Cl– Ringer to 35% of control, but had no effect on the ACh-evoked decrease in the Cl– activity. Furosemide (1 mmol/l) slightly hyperpolarizedV
m and decreased Cl– activity at a slow rate but affected Cl– movements induced by ACh or low-Cl– Ringer only slightly. Cl– uptake into the cells was inhibited partially by furosemide. The present results showed that ACh induces an increase in the Cl– permeability across the luminal plasma membrane and that the basolateral membrane possesses a DIDS-sensitive Cl– conductance pathway and a furosemide-sensitive Cl– uptake mechanism. 相似文献
5.
Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons 总被引:11,自引:0,他引:11
Wei L Xiao AY Jin C Yang A Lu ZY Yu SP 《Pflügers Archiv : European journal of physiology》2004,448(3):325-334
K+ and Cl– homeostasis have been implicated in cell volume regulation and apoptosis. We addressed the hypothesis that K+ and Cl– efflux may contribute to apoptotic cell shrinkage and apoptotic death in cultured cortical neurons. CLC-2 and CLC-3 chloride channels were detected in cultured cortical neurons. The Cl– channel blockers 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) inhibited the outwardly rectifying Cl– current, prevented apoptotic cell shrinkage, and mildly attenuated cell death induced by staurosporine, C2-ceramide, or serum deprivation. Cl– channel blockers, however, at concentrations that prevented cell shrinkage had no significant effects on caspase activation and/or DNA fragmentation. Cell death in the presence of a Cl– channel blocker was still sensitive to blockade by the caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk). Electron microscopy revealed that, although DIDS prevented apoptotic cell shrinkage, certain apoptotic ultrastructural alterations still took place in injured neurons. On the other hand, the K+ channel blocker tetraethylammonium (TEA), clofilium, or the caspase inhibitor z-VAD-fmk prevented cell shrinkage as well as caspase activation and/or DNA damage, and showed stronger neuroprotection against apoptotic alterations and cell death. The results indicate that neurons may undergo apoptotic process without cell shrinkage and imply distinct roles for Cl– and K+ homeostasis in regulating different apoptotic events. 相似文献
6.
Oxalate transport in cultured porcine renal epithelial cells 总被引:1,自引:0,他引:1
T. R. Wandzilak L. Calo S. D'Andre A. Borsatti H. E. Williams 《Urological research》1992,20(5):341-345
Summary Oxalate-containing kidney stones are the most common type (75%) of renal stones. In order to control oxalate excretion in the urine, a basic understanding of the cellular transport of oxalate is imperative. We have utilized the technique of continuous cell culture to establish and characterize a model system to study renal epithelial cell (LLCPK1) oxalate transport. Our data demonstrate that oxalate uptake in these cells is dependent on time, concentration and energy. TheK
m for oxalate uptake was 200 m. Oxalate uptake was decreased at lower temperatures and elevated in an acidic extracellular environment. Both anion exchange inhibitors DIDS and SITS inhibited oxalate oxalate uptake. Sulfate, chloride, and bicarbonate decreased oxalate uptake, as did the diuretics bumetanide and furosemide. There was no evidence for the co-transport of oxalate with sodium. Our data show that monolayers of cultured kidney epithelial cells are a valuable model system for study of the basic cellular mechanisms of oxalate transport. 相似文献
7.
Transmembrane acid extruders, such as electroneutral operating Na(+)/H(+)-exchangers (NHE) and Na(+)-dependent Cl(-)/HCO(3)(-)-exchangers (NCHE) are essential for the maintenance and regulation of cell volume and intracellular pH (pH(i)). Both of them are hypothesised to be closely linked to the control of excitability. To get further information about the relation of neuronal pH(i) and activity of cortical neurones we investigated the effect of NHE- and/or NCHE-inhibition on (i) spontaneous action potentials and epileptiform burst-activity (induced by bicuculline-methiodide, caffeine or 4-aminopyridine) and (ii) on pH(i) of CA3-neurones. NHE-inhibition by amiloride (0.25-0.5 mM) or its more potent derivative dimethylamiloride (50 microM) and NCHE-inhibition by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS, 0.25-0.5 mM) induced a biphasic alteration of neuronal activity: an initial, up to 30 min lasting, increase in frequency of action potentials and bursts preceded a growing and partially reversible suppression of neuronal activity. In BCECF-loaded neurones the pH(i), however, continuously decreased during either amiloride- or DIDS-treatment and reached its steady-state (DeltapH(i) up to 0.3 pH-units) when the neuronal activity was markedly suppressed. Combined treatment with amiloride (0.5 mM) and DIDS (0.5 mM) or treatment with harmaline alone (0.25-0.5 mM), which also continuously acidified neurones via inhibition of an amiloride-insensitive NHE-subtype, induced a monophasic and partially reversible suppression of neuronal activity. As an initial excitatory period failed to occur during combined NHE/NCHE-inhibition we speculate that its occurrence during amiloride- or DIDS-treatment resulted rather from disturbances in volume- than in pH(i)-regulation. The powerful inhibitory and anticonvulsive properties of NHE- and NCHE-inhibitors, however, very likely based upon intracellular acidification - as derived from our previous findings that a moderate increase in intracellular free protons is sufficient to reduce membrane excitability of CA3-neurones. 相似文献
8.
Zhu BM Miyamoto S Nagasawa Y Saitoh M Komori S Hashimoto K 《European journal of pharmacology》2003,460(1):43-50
The protective effects of Cl(-)/HCO(3)(-) exchange inhibitors, 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'isothiocyanato-stilbene-2,2'-disulfonic acid (SITS), against reperfusion-induced arrhythmias were investigated in anesthetized rats. Rats were subjected to 5-min occlusion of the left coronary artery followed by 10-min reperfusion. All drugs were intravenously administered 5 min before the onset of occlusion. DIDS (75 mg/kg) reduced the incidence of ventricular fibrillation and mortality to 0%, whereas SITS (75 mg/kg) only decreased these parameters to 60%. DIDS simultaneously decreased the mean blood pressure and heart rate, and prolonged PQ and QRS intervals, whereas SITS produced a weaker effect on these parameters and no change in QRS interval. Mexiletine (5 mg/kg), which had been demonstrated to suppress the arrhythmias and reduce the heart rate and mean blood pressure in this model, was shown to prolong PQ and QRS intervals. Verapamil (0.5 mg/kg) or diltiazem (0.4 mg/kg) suppressed the arrhythmias, simultaneously decreasing the heart rate and mean blood pressure and prolonging PQ interval. The results indicate that the protective effect of DIDS on reperfusion arrhythmias in the anesthetized rats is unlikely to be attributed to the inhibitory action on Cl(-)/HCO(3)(-) exchange, but possibly mediated by its blocking effects on cardiac ion channels, such as Na(+) or Ca(2+) channels. 相似文献
9.
BACKGROUND & AIMS: Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to prevent intestinal fluid secretion in cholera. We previously discovered low- affinity glycine hydrazide (GlyH) CFTR inhibitors that block CFTR at its external pore. The goal of this study was to develop potent CFTR inhibitors that are minimally absorbed and washed out of the intestinal lumen for application as antisecretory agents in cholera. METHODS: GlyH analogs (malonic hydrazides, MalH) were chemically conjugated to various lectins ("MalH-lectin") and purified. CFTR inhibition potency was measured by short-circuit current analysis, mechanism of action by patch-clamp, and antidiarrheal efficacy in closed-loop and suckling mouse models. RESULTS: By lectin conjugation, we improved CFTR inhibitory potency by approximately 100-fold (to 50 nmol/L) and retarded washout. High-affinity CFTR inhibition was abolished by MalH-lectin heat denaturation, protease digestion, or competition by mannose or unconjugated lectin. Patch-clamp analysis indicated CFTR inhibition by an external pore occlusion mechanism. Fluorescently labeled MalH-lectin remained membrane bound for >6 hours after washout, whereas washout occurred in a few minutes without the lectin. MalH-ConA and MalH-wheat (IC50 50-100 pmol) blocked cholera toxin-induced intestinal fluid secretion in closed intestinal loops in mice and greatly reduced mortality in a suckling mouse model of cholera. CONCLUSIONS: The high potency of MalH-lectin conjugates results from "anchoring" the CFTR-blocking MalH to cell surface carbohydrates by the lectin. The high-affinity, slow washout, and external site of action of the MalH-lectin conjugates support their further development as antisecretory drugs for enterotoxin-mediated secretory diarrheas. 相似文献
10.
Pharmacologic Properties of the Swelling-Induced Chloride Current of Dog Atrial Myocytes 总被引:4,自引:0,他引:4
Pharmacology of Swelling-Induced Chloride Current. Introduction: Swelling-induced chloride currents may contribute to cardiac electrical activity and cell volume regulation. Identification of selective Mockers would aid in understanding the functional contribution(s) of this current.
Methods and Results: Dog atrial cells were used to investigate the pharmacologic properties of the swelling-induced chloride current. Whole cell patch clamp was used. Swelling-induced chloride current was activated by osmotic stress. Initially, the chloride selectivity and calcium independence of the swelling-induced current in dog atrial cells was demonstrated. Subsequently, a number of putative chloride channel blockers were examined. Anthracene-9-earboxylic acid (1mM) and dideoxyforskolin (1000 μ) and extracellular cAMP (5mM) were found to partially inhibit the swelling-induced chloride current (∼50%, 80%, and 10% inhibition, respectively). Niflumic acid (100 μ), nitrophenylpropylamino benzoate (NPPB; 10 to 40 μ), and (+) 2-[(2-cydopentyl-6,7-dichloro-2,3-dihydro-2-melhyl-1-oxy-1H-inden-5-yl)oxy] acetic acid (indanyloxyacetic acid; IAA-94; 100 μ) could fully inhibit the swelling-induced chloride current without decreasing cell size. DIDS (100 μ) and dinitrostilbene disulfonic acid (DNDS;5 mM) fully inhibited outward currents but only partially inhibited inward current.
Conclusions: Niflumic acid, IAA-94, and NPPB were identified as full blockers of cardiac swelling-induced chloride current. Nonspecific effects were identified for each of the full blockers. Experiments that use these agents as functional antagonists should be carefully designed and interpreted with caution. 相似文献
Methods and Results: Dog atrial cells were used to investigate the pharmacologic properties of the swelling-induced chloride current. Whole cell patch clamp was used. Swelling-induced chloride current was activated by osmotic stress. Initially, the chloride selectivity and calcium independence of the swelling-induced current in dog atrial cells was demonstrated. Subsequently, a number of putative chloride channel blockers were examined. Anthracene-9-earboxylic acid (1mM) and dideoxyforskolin (1000 μ) and extracellular cAMP (5mM) were found to partially inhibit the swelling-induced chloride current (∼50%, 80%, and 10% inhibition, respectively). Niflumic acid (100 μ), nitrophenylpropylamino benzoate (NPPB; 10 to 40 μ), and (+) 2-[(2-cydopentyl-6,7-dichloro-2,3-dihydro-2-melhyl-1-oxy-1H-inden-5-yl)oxy] acetic acid (indanyloxyacetic acid; IAA-94; 100 μ) could fully inhibit the swelling-induced chloride current without decreasing cell size. DIDS (100 μ) and dinitrostilbene disulfonic acid (DNDS;5 mM) fully inhibited outward currents but only partially inhibited inward current.
Conclusions: Niflumic acid, IAA-94, and NPPB were identified as full blockers of cardiac swelling-induced chloride current. Nonspecific effects were identified for each of the full blockers. Experiments that use these agents as functional antagonists should be carefully designed and interpreted with caution. 相似文献