SEARCH · PubMed Health

Results for “Uncoupling Agents”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed1996

Oscillatory bursting of phasically firing rat supraoptic neurones in low-Ca2+ medium: Na+ influx, cytosolic Ca2+ and gap junctions.

1. Whole-cell patch recordings were obtained from supraoptic nucleus (SON) neurones in horizontal brain slices of adult male rats. Low-Ca2+ or Ca(2+)-free perifusion medium induced oscillatory bursting activity in all sixty-nine cells displaying both phasic firing and depolarizing after-potentials (DAPs). In fifteen non-phasic cells without DAPs, Ca(2+)-free medium produced little or no oscillatory bursting. 2. Typical bursts started with rapid membrane depolarization, resulting in a plateau with superimposed action potentials, and ended several hundred milliseconds later in swift repolarization. Prominent bursting was observed at membrane potentials from -50 to -70 mV, with maximum amplitudes of 12.2 +/- 0.7 mV (mean +/- S.E.M.) around -70 mV. Development of oscillatory bursting was dependent on reduction of [Ca2+]o, with a threshold for the bursting < or = 1.2 mM Ca2+. 3. Bursting was abolished by addition of TTX, Co2+, Ni2+ or Mg2+ into the Ca(2+)-free medium, or by replacement of external Na+ with choline or Li+. Low concentrations of TEA or increased [K+]o prolonged burst durations and enlarged oscillation amplitudes. 4. Voltage-clamp techniques were used to examine the persistent Na+ current (INaP), and revealed that low [Ca2+]o shifted the threshold for INaP activation in a negative direction and enhanced the amplitude of this current. These changes in INaP were abolished by adding Co2+ or Mg2+ to Ca(2+)-free medium. 5. Direct diffusion of BAPTA or heparin into neurones or bath application of ryanodine suppressed bursting. Oscillations were also eliminated by the uncoupling agents heptanol, halothane or acidification. 6. CNQX, APV, bicuculline, CGP35348 (GABAB receptor antagonist), promethazine, atropine, d-tubocurarine and suramin had no obvious effects on oscillatory bursting. Blockers of transient Ca2+, or hyperpolarization-activating cation currents also did not alter bursting activity. 7. These results suggest that intrinsic burst activity in SON neurons perifused with low-Ca2+ or Ca(2+)-free medium involves enhanced Na+ influx through persistent Na+ channels, and requires the presence of rapid intracellular Ca2+ mobilization that might also explain the selective existence of oscillatory bursting in phasically firing cells. Intercellular communication through gap junctions appears to be important in determining neuronal activity of the neuroendocrine cells in low-Ca2+ medium.

Action Potentials↗

PubMed1974

Demonstration of electrogenic Na+-dependent D-glucose transport in intestinal brush border membranes.

Na(+)-coupled D-glucose transport was studied in isolated membrane vesicles from intestinal brush borders. Concentration gradients of SCN(-), K(+), and H(+) were established between the intravesicular solution and the incubation medium and their influence on D-glucose uptake from the medium was measured. A gradient (medium > vesicle) of NaSCN, but not of KSCN, produced a transient overshoot of D-glucose uptake above the equilibrium level. Similarly, an increase of the membrane conductance with valinomycin (K(+)-conductance) or with uncoupling agents of oxidative phosphorylation (H(+)-conductance) induced an overshooting D-glucose uptake, provided a (vesicle > medium) K(+)-gradient or a H(+)-gradient, respectively, was present in each case. The transient overshoot is evidence that D-glucose was taken up against its concentration gradient (up to 10-fold). The gradients of SCN(-), K(+) (in the presence of valinomycin), and H(+) (in the presence of uncouplers) are thought to contribute to the "driving" force for this "active" D-glucose transport by changing the electrical potential across the vesicle membrane and thus making the inside more negative (with respect to the medium). These experiments, therefore, provide evidence that the Na(+)-coupled D-glucose translocation across the brush border membrane is an electrogenic process, i.e., the positive charge associated with Na(+) is not compensated by the co-movement of an anion or the counter-movement of a cation via the glucose "carrier". The results imply that an electrical potential across the brush border membrane may play an important role in determining the transport of D-glucose by intact cells.

Animals↗

PubMed1983

Negative inotropic effects of Na-salicylate and three congeners on the guinea-pig Langendorff heart.

In guinea-pig Langendorff hearts, Na-salicylate (1.9, 3.8 and 7.6 mmol/l) concentration-dependently reduced the contractile force (--9.1, --51.0 and --75.1%, respectively) and the coronary resistance. The influence of the uncoupling agent 2.4-dinitrophenol (0.02 mmol/l) was comparable to that of the largest concentration of Na-salicylate. From the three congeners of Na-salicylate that were tested, only 3.5-diiodosalicylate (0.03 mmol/l) reduced the contractility whereas Na-benzoate (42 mmol/l) and m-iodobenzoate (1.2 mmol/l) were inactive. These results suggest that the cardiac effects of salicylate-like compounds in vitro are caused by an uncoupling of the oxidative phosphorylation.

2,4-Dinitrophenol↗

PubMed1998

Effect of MI-D, a new mesoionic compound, on energy-linked functions of rat liver mitochondria.

MI-D (4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylami ne chloride), a new mesoionic compound, depressed the phosphorylation efficiency of liver mitochondria as deduced from an accentuated decrease of the respiratory control coefficient and ADP/O ratio. Analysis of segments of the respiratory chain suggested that the MI-D inhibition site is further on than complex I and between complexes II and III. The transmembrane electrical potential (delta psi) was collapsed dependent on MI-D concentration. ATPase activity was dramatically increased by MI-D in intact mitochondria, but inhibited in carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled mitochondria. These results suggest that MI-D acts as an uncoupler agent, a property closely related to its structural characteristics.

Adenosine Diphosphate↗

PubMed1989

Uncoupler resistance in Escherichia coli: the role of cellular respiration.

Bioenergetic properties of a mutant strain of Escherichia coli K12 designated TUV, which is resistant to the protonophoric uncoupling agent 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidiazole (TTFB) have been compared with those of its non-resistant parent, E. coli K12 Doc-S. Strain TUV grew and respired some 20-30% faster than strain Doc-S, and was cross-resistant to carbonylcyanide p-(trifluoromethoxy)phenylhydrazone and triphenyltin, but not to 2,4-dinitrophenol. Phosphorus nuclear magnetic resonance demonstrated the TTFB-mediated collapse of the transmembrane pH gradient at identical rates in starved cells of both strains, indicating that uncoupler access and function were unimpaired in the mutant under these conditions. Strain TUV displayed enhanced uncoupler resistance and maintained intracellular pH and ATP levels only when respiring. On the other hand, strain TUV also showed increased resistance to novobiocin, implying that its outer wall permeability had been lowered. We suggest that the active resistance of strain TUV results from the exclusion of uncoupler by the interaction of inner and outer membrane components in a manner modulated by the degree of cellular energization.

Adenosine Triphosphate↗

PubMed1991

Influence of extracellular pH on the accumulation and cytotoxicity of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea in human cell lines.

The effect of extracellular pH (pH(e)) on the accumulation and cytotoxicity of the diarylsulfonylurea antitumor agent N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (MPCU) has been examined. In a human colon adenocarcinoma cell line, GC3/C1, the initial rate of uptake of [3H]MPCU (2.4 microM) was increased by 4.5-fold as pH(e) was reduced from 7.4 to 6.5. Steady state levels of MPCU were inversely proportional to pH(e) and were 5-fold greater at pH 6.0 compared to 7.4. Similar results were obtained using Rh30 cells derived from an alveolar rhabdomyosarcoma. MPCU rapidly re-equilibrated after achieving steady state when pH(e) was altered, indicating that MPCU was not tightly bound within cells. In both cell lines, the uncoupling agent, carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), significantly reduced (GC3/C1) or completely inhibited (Rh30) accumulation of MPCU at each pH(e) examined. Sodium azide had the same effect on the accumulation of MPCU as FCCP. The effects of FCCP and azide appeared to be due to collapse of the pH differential across the mitochondrial inner membrane rather than the gradient across the plasma membrane. As extracellular pH (pH(e)) decreased, intracellular pH(pH(i)) also decreased in GC3/C1 cells, such that the greatest pH differential (pH(i) - pH(e)) was 0.2 units at pH(e) 6.0. Neither FCCP nor azide significantly altered this pH gradient, indicating a minor role, if any, for the plasma membrane pH gradient in accumulation of MPCU in GC3/C1 cells. The effect of pH(e) (7.4 to 6.0) on cytotoxicity of MPCU was determined after exposure of cells for 4 hr to various concentrations of MPCU in the presence of 10% fetal bovine serum. Decreasing the pH(e) from 7.4 to 6.0 increased the potency of MPCU by 4.7- and 4.5-fold in Rh30 and GC3/C1 cells, respectively. In cells exposed to drug/pH(e) combinations that resulted in 50% reduction in colony forming potential, the steady state levels of [3H]MPCU were similar (range 8.8 +/- 0.9 to 10.56 +/- 0.6 nmol/10(6) cells). These results demonstrate that decrease of pH(e) significantly enhanced the uptake of MPCU accumulation into an FCCP/azide-sensitive compartment, and cytotoxicity of this agent. These data further support the hypothesis that sequestration of diarylsulfonylureas into the FCCP/azide-sensitive compartment (probably mitochondria) was associated with its cytotoxicity. The role of pH(e) in determining therapeutic selectivity of diarylsulfonylureas is discussed.

Adenocarcinoma↗

PubMed1977

[Proton translocation in membranes of submitochondrial particles].

Effect of an electrophilous inhibitor, chlorophenacyl, on energy-dependent functions of submitochondrial particles is studied. Chlorophenacyl at concentrations up to 1 mM is found practically not to affect the generation of membrane potential under NADH and succinate oxidation and ATP hydrolysis and to be a strong inhibitor of oxidative phosphorylation and reverse electron transport. The mechanism of the inhibition of energy-dependent functions of submitochondrial particles with chlorophenacyl is different from that of electron transport inhibitor, energy transport inhibitors and classical uncoupling agents--protonophors. The data obtained are suggested to be due to the existence of two ways of proton translocation in submitochondrial particle membrane, phosphorylating and non-phosphorylating, the effect of chlorophenacyl being directed on phosphorylating way only.

Biological Transport↗

PubMed2002

Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.

The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.

Animals↗

PubMed1983

Use of carboxylic acids by Thiobacillus A2.

Thiobacillus A2 can grow on acetate, glycollate, succinate and citrate as sole carbon and energy sources. Results of growth and transport experiments indicated that separate transport systems existed for the four acids although acetate uptake by bacteria grown on glycollate was very rapid. Citrate was a potentially toxic substrate in that low concentrations had to be supplied to adapt organisms to growth on citrate following autotrophic culture on thiosulphate. Apparent Ks values for transport by whole organisms were around 10(-4) M. The effects of uncoupling agents, phosphate and arsenate, on acid uptake did not allow identification of the mechanisms of transport, but indicated energy-requiring processes possibly involving anion participation. The ratio of carbon assimilated from the -CH2- and the -COOH carbons of succinate was about 5:1, reflecting very rapid decarboxylation of succinate following uptake into the cell.

Acetates↗

PubMed1981

Role of energy metabolism in Mycoplasma pneumoniae attachment to glass surfaces.

Attachment values of Mycoplasma pneumoniae to glass are normally very low when tested in buffer containing bovine serum albumin (10 mg/ml). However, the addition of one of the metabolizable sugars glucose, fructose, or mannose increased attachment more than 10-fold. The effect was dose dependent with a distinct optimum at about 0.25 mg/ml. Higher concentrations reduced this effect. Not only the sugars themselves but also the products of their catabolism, pyruvate and phosphoenolpyruvate, enhanced attachment. Pyruvate was effective in the same range of concentrations as the sugars, whereas phosphoenolpyruvate enhanced attachment at a significantly lower concentration (0.001 mg/ml). Higher levels of these substances also resulted in a decrease of attachment. The glucose-induced increase could be partially inhibited by glucose analogs, especially by 3-O-methyl-glucopyranoside, and by various inhibitors or glycolysis. Furthermore, attachment was strongly reduced by the uncoupling agents carbonylcyanide m-chlorophenylhydrazone and 2,4-dinitrophenol, as well as by dicyclohexylcarbodiimide, an inhibitor of the membrane-bound Mg2+-adenosine triphosphatase, whereas the ionophore valinomycin increased attachment by about 30%. These findings provide strong evidence for coupling between the attachment process of M. pneumoniae to glass and the utilization of metabolic energy.

Chloramphenicol↗

PubMedDate not supplied

[The effect of oxidazable substrates and ATP on the sensitivity of certain energy-dependent functions submitochondrial particles to phospholipases A, C and D].

The effect of NADH, succinate and ATP on the sensitivity of a number of energy-dependent functions of submitochondrial particles ot phospholipases A, C and D has been studied. It has been shown that in the conditions of oxidation of NADH and succinate by oxygen and also of ATP hydrolysis, the decrease in the phosphorylating activity of the particles under the action of phospholipases C and D accelerates. No such acceleration has been observed with phospholipase A. For other two functions, i. e. reverse electron transfer (ATP-dependent NAD+ reduction by succinate) and ATP-dependent transhydrogenase reaction the results proved to be different. Oxidizable substrates and ATP promoted the maintenance of these functions in the presence of phospholipase A, but did not retard their suppression by phospholipases C and D. The effects of NADH, succinate and ATP on the sensitivity of different energy-dependent functions of submitochondrial particles to phospholipases A, C and D could be removed by the uncoupling agent carbonyl cyanide-m-chlorophenyl hydrazone. The conclusion is made that the effects revealed are associated with an increase in the sensitivity of coupling sites II PAND/OR III to phospholipases C and D and with a decrease in the sensitivity of sites I and IV to phospholipase A on energization of submitochondrial particles.

Adenosine Triphosphate↗

PubMed1997

Effects of heptanol on electrical activity in the guinea-pig vas deferens.

1. The effects of the putative intercellular uncoupling agent I-heptanol on electrical activity in the guinea-pig vas deferens were studied by use of intracellular and extracellular recording techniques. 2. At concentrations of 0.5, 1 and 2 mM, heptanol rapidly, monotonically and reversibly attenuated intracellularly recorded excitatory junction potential (e.j.p.) amplitude without affecting its time course, while spontaneous excitatory junction potentials (s.e.j.ps) were left unaffected. 3. Heptanol did not affect either the extracellularly recorded evoked excitatory junction current (e.j.c.), or the nerve terminal impulse that preceded it. These observations indicate that heptanol does not affect nerve impulse conduction, neurotransmitter release, or the postjunctional receptors involved in the production of the e.j.p. 4. E.j.ps appear to be suppressed by heptanol due to its intercellular uncoupling effects. Therefore, functional intercellular coupling may be necessary for the generation of the e.j.p. in smooth muscle.

Alcohols↗

PubMed1978

Uncouplers of oxidative phosphorylation. A structure-activity study of their inhibitor effect on passive chloride permeability.

Uncoupling agents inhibit chloride transport in red blood cells, which is a metabolism-independent process. An analysis of the molecular requirements shows that this inhibitory activity is closely correlated with the electronic and the hydrophobic bonding properties of phenols: the more lipophilic and the more electron-attracting the substituent groups are, the greater the activity they confer on the parent molecule. A recent structure-activity study concerning various classes of reversible inhibitors of chloride transport led to the same conclusion (Motais, R. and Cousin, J.L. (1977) in International Conference on Biological Membranes: Drugs, Hormones and Membranes (Bolis, L., Hoffman, J.F. and Straub, R.W., eds.), Raven Press, New York, in the press). The effects of substituents on the activity of phenols as uncouplers have been recently examined (Stockdale, M. and Selwyn, M.J. (1971) Eur. J. Biochem. 21, 565). The comparison of these results with our data shows that uncoupling depends more on electronic properties of phenols than does choloride inhibition.

Biological Transport↗

PubMed1975

Mitochondrial permeability to chloride ion.

It is generally accepted that the inner membrane of the mitchondrion is not penetrated by chloride ion, in contrast to other biological membranes which are chloride permeable. In this report mitochondrial permeablity to chloride ion has been reevaluated by the measurement of passive swelling in isotonic chloride-containing solutions in the presence of an uncoupling agent. Under these conditions, mitochondria prepared from rat liver or beef heart show a definite uptake of wide variety of chloride salts. Mitochondrial chloride transport appears to be electrogenic, as is the transmembrane movement of the other halides. Therefore, the mitochondrial inner membrane shares with other biological membranes a definite permeability to this ubiquitous anion.

Animals↗

PubMed2000

Gap junction-mediated coupling in the postnatal anterior subventricular zone.

We have studied gap junctional communication in the anterior subventricular zone (SVZa) of postnatal rodents, revealed by intercellular diffusion of dyes in brain slices. Extensive intercellular dye spread was evident in the SVZa. Coupling was not uniform, being characteristically larger in the outer borders of this layer, overlapping the previously described peripheral zone of concentration of S-phase cells. Intercellular spread of the dye was unaffected by acidification, but totally blocked by high Ca(2+) concentrations. In addition, application of some known uncoupling agents as carbenoxolone and halothane led to a marked reduction of dye spread in the SVZa. Our results demonstrate the presence of dye coupling mediated by gap junctions in the SVZa. Furthermore, the spatial organization of dye coupling in these slices strongly suggests the existence of cell compartments in the postnatal SVZa.

Animals↗

PubMedDate not supplied

[Effect of growth conditions on substrate phosphorylation during sulfite oxidation in Thiocapsa roseopersicina].

Cell extracts of Thiocapsa roseopersicina, strains BBS and SL, grown in the light under anaerobic conditions and in the dark under aerobic conditions on a medium containing thiosulphate produce ATP during oxidation of sulphite in the presence of AMP cytochrome c and inorganic phosphate. The uncoupling agent (m-chlorocarbonylcyanidephenylhydrazone) has no effect on the rate of ATP production, this being an evidence of substrate phosphorylation. The rate of ATP synthesis is higher in extracts of the cells grown in the dark under autotrophic conditions than in extracts of the cells cultivated in the light under anaerobic conditions or in the dark in the presence of thiosulphate and glucose.

Adenosine Monophosphate↗

PubMed1979

Toxic action of 2'-chloro-2,4-dinitro-5',6-di(trifluoromethyl) diphenylamine in the rat.

2'-Chloro-2,4-dinitro-5',6-di(trifluoromethyl)diphenylamine (CDTD) is a potent uncoupler of oxidative phosphorylation in isolated rat liver or brain mitochondria. The concentration of CDTD causing 50% uncoupling in vitro is dependent on the mitochdonrial protein concentration and is 2 nM at 0.9 mg protein/ml for rat liver mitochondria. Oxidative phosphorylation can be restored to CDTD uncoupled liver mitochondria by the addition of a 10 000-fold molar excess of bovine serum albumin to DCTD. Rats given a lethal dose (7.0 mumol/kg) of CDTD intrapertioneally show signs of toxicity typical of uncoupling agents. Mitochondria isolated from the livers of these rats show almost complete inhibition of ATP synthesis and mitochondria obtained from the livers of rats at various times after a single oral dose show maximal inhibition of ATP synthesis 4 h after dosing with complete recovery by about 24 h. A single oral administration of 58 mumol/kg or above, but not intraperitoneal injection, of CDTD into rats produced an increase in the water content of the brain and spinal cord. The additional fluid has been shown to contain Na+ ions. The increase in cerebral fluid is dose related, no effect being seen at 23 mumol/kg. This extra fluid is thought to be responsible for the hind limb weakness observed in these rats. These observations suggest that there are two facets to CDTD toxicity: early deaths (within 2 h), which appear to be due to uncoupling of oxidative phosphorylation, and delayed deaths, 2--3 days after dosing which are probably related to an increase in fluid in the brain and spinal cord.

Aniline Compounds↗

PubMed1985

Protonophoric properties of fluorinated arylalkylsulfonamides. Observations with perfluidone.

The acidity and lipophilicity of the fluorinated arylalkylsulphonamides are determined by the nature of the substituents on their aromatic rings. Herbicidal and anti-inflammatory effects of these compounds appear to increase with their lipophilicity. According to Mitchell's chemiosmotic theory, lipophilic weak-acid uncoupling agents act by transporting protons across the inner mitochondrial membrane and thus destroying the proton-electrochemical potential gradient required for ATP synthesis and ion transport. 1:1:1-Trifluoro-N-[2-methyl-4-(phenylsulphonyl) phenyl]methanesulphonamide (Perfluidone), a pre- and post-emergence herbicide (at 20 microM concentration), in isolated rat-liver mitochondria caused (1) a 2-fold stimulation of metabolic state-4 respiration, (2) a reduction of respiratory control ratio (RCR) by at least 50%, (3) an enhancement of latent ATPase activity by 40%, (4) a significant passive swelling of mitochondria in 0.15 N NH4Cl(delta A520 = -0.46 +/- 0.003), (5) proton intrusion during state-4 respiration (356 ng H+/min/mg protein; ng H+/min/mg protein with 5 microM perfluidone), and (6) at least 100% stimulation of oligomycin-inhibited respiration. These profiles are qualitatively comparable with those of the classical lipophilic weak-acid uncoupler, carbonylcyanide-trifluoro-methoxyphenylene hydrazone (FCCP), which acts by promoting the electrogenic transport of H+ ions across mitochondrial membrane.

Adenosine Triphosphatases↗