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At least 19 recordsLinked to original sources
PubMedDate not supplied

Mitochondrial uncoupling agents. Effects on membrane permeability of molluscan neurons.

Agents which uncouple oxidative phosphorylation in mitochondria were applied to identified neurons in an isolated ganglion of the marine mollusc Navanax inermis. Aromatic monocarboxylic acids, acetanilides, benzamides, benzaldehydes and phenols all caused a rapid, reversible, dose-dependent increase in the membrane potential and conductance of the neurons tested. These events were due primarily to an increase in the membrane's conductance to potassium, relative to chloride. All active compounds also produced a reversible, dose-dependent decrease in the permeability of alkali-cations relative to potassium. The relative activity of congeners in each group of substances was directly correlated with the octanol-water partition coefficients of the various compounds, indicating that hydrophobicity was important in determining drug effect and suggesting that steric requirements were minimal. The results suggest that the observed changes in membrane electrical properties and cation selectivity are due to an increase in the membrane's anionic field strength caused by the hydrophobic interaction of anionic and nonionic agents with the neuronal membrane.

Animals↗
PubMed1998

Effect of uncoupling agents on AT1 receptor affinity for antagonist analogs of angiotensin II.

AT1 receptor is responsible for most of the physiological effects of Angiotensin II (Ang II). AT1 receptor belongs to the G-protein-coupled receptor (GPCR) family, and it mediates its actions through the coupling of the Gq/11 protein with phospholipase C beta. Classical pharmacology has used the sensitivity of GPCR ligands to uncoupling agents as a criteria to discriminate agonists (which are sensitive) from antagonists (which are insensitive). In this study, the uncoupling agents GTP gamma S and pentosan sulfate (PS) (a low molecular weight polyanion) were used to further characterize the molecular interactions between Ang II analogs and the AT1 receptor. We show that some Ang II antagonists are sensitive to the conformational change of the AT1 receptor induced by uncoupling agents. These results demonstrate that there is no direct relationship between the intrinsic activity of a ligand and its affinity for different conformations of the AT1 receptor and that the sensitivity of GPCR ligands to uncoupling agents can not be used as a criteria to discriminate agonists from antagonists.

Adrenal Cortex↗
PubMed1979

Morphological alterations in the mitochondria of Amoeba proteus induced by uncoupling agents.

Ultrastructural changes in mitochondrial morphology were observed in amoebae exposed to the uncoupling agents dinitrophernol (DNP), pentachlorophenol (PCP), and m-chlorocarbonyl cyanide phenylhydrazone (CCCP). These alterations occurred with rapidity and were present before whole-cell activity changes could be detected. They included changes in profile shape and overall dimensions, matrix density changes, and alterations to the cristal membranes, so that distinction between control Type I and Type II conformations was eliminated and a form with intermediate characters generated. It is proposed that, in producing these altered forms, the uncoupling agents are acting by suppressing the control functional states of the mitochondria. At the end of the uncoupler treatment all alterations were shown to be reversible, i.e. in cells transferred back to normal culture medium, mitochondrial profiles identical to those in control cells were again evident with time. These effects on the mitochondria could be produced whether the uncoupler was introduced externally by total cell exposure, or to the inside of the cell by microinjection. The importance of precisely defining conditions for treatments and at disrupting cell activity was evident. Thus, an uncoupler, which is a weak acid, proved to be more effective in whole cell treatments if applied at a pH near to it pKa - so ensuring its penetration across the outer cell membrane.

Amoeba↗
PubMedDate not supplied

[Effect of oxidative phosphorylation inhibitors and uncoupling agents on cAMP activity].

Uncouplers of oxidative phosphorylation increased the speed of substrate oxidation and ATP hydrolysis and raised cAMP induced neuron membrane current. Different inhibitors decreased it. Both effects support the hypothesis that a signal of intracellular injected cAMP spreads to the neuron membrane as a mechanical signal. This signal propagated to the membrane along microtubules which according to this hypothesis serve as a sound generator with metabolic heat pumping.

Animals↗
PubMed1980

Effects of metabolic and transport inhibitors on sodium transport and CO2 production of toad bladders: use of an uncoupling agent to distinguish between effects on transport and metabolism.

Agents that directly inhibit sodium transport secondary reduce the rat of metabolism. Conversely, agents that directly inhibit energy metabolism cause a secondary inhibition of active transport. The aim of the present investigation was to distinguish between these two effects with an uncoupling agent, 2,4-dinitrophenol (DNP). The rates of sodium transport (TNa) and CO2 production (QCO2) by paired urinary hemibladders from Dominican toads were simultaneously measured. DNP alone inhibited TNa, but stimulated QCO2 of the hemibladders, consistent with its action as an uncoupling agent. Ouabain, which directly inhibits sodium transport, inhibited TNa and QCO2 of toad hemibladders; the subsequent addition of DNP stimulated QCO2 to a rate similar to that of the control hemibladders. The metabolic inhibitors antimycin A and rotenone also inhibited TNa and QCO2; in contrast to the results with ouabain, the subsequent addition of DNP did not stimulate QCO2 in the presence of antimycin A or rotenone. Therefore, the respiratory response to DNP clearly distinguishes between direct inhibition of metabolism and direct inhibition of active transport. This approach may be useful for the investigation of the mechanism of action of drugs, hormones and other biological phenomena.

Animals↗
PubMed1982

Effect of uncoupling agents of oxidative phosphorylation on the spontaneous release of transmitter from insect motor nerve terminals.

1. The effect of uncoupling agents of oxidative phosphorylation, potassium warfarin and carbonylcyanide-p-trifluoromethoxy-phenylhydrazone (p-CCP), on the spontaneous release of transmitter was studied at the neuromuscular junction of cockroach muscles. 2. The agents produced a large increase in the frequency of occurrence of miniature excitatory postsynaptic potentials (MEPSPs). This increase also was observed in calcium-free saline. 3. The results may be explained on the hypothesis that the increase in the spontaneous release is due to the increase in free calcium concentration derived from an intracellular origin in the terminal. The mitochondria may play an important role in regulating the intracellular calcium concentration in the nerve terminals of insect muscles.

Animals↗
PubMed1985

Effects of the uncoupling agents FCCP and CCCP on the saltatory movements of cytoplasmic organelles.

Two potent uncoupling agents, carbonylcyanide-4-trifluoromethoxyphenylhydrazone (FCCP) and carbonylcyanide-3-chlorophenylhydrazone (CCCP) inhibit the movement of organelles in neurites of chick sensory neurones in culture. FCCP applied for 30 minutes at 10 microM reduces the number of moving organelles by 78% and a similar treatment with CCCP causes a reduction of 47%. At 100 microM either compound abolishes all directed movements both in neurites and in cultured 3T3 cells. These effects are probably not due to the discharge of proton gradients since 2,4-dinitrophenol (DNP), at concentrations shown to uncouple mitochondria by the discharge of the permeant cationic fluorescent probe rhodamine 123, fails to inhibit cytoplasmic movements. The inhibition of cytoplasmic movements by FCCP and CCCP is likely to be a consequence of their inhibitory action on a variety of enzymes, including dynein and myosin ATPases, through a reaction with sulfhydryl groups.

Adenosine Triphosphatases↗
PubMed1974

Effect of uncoupling agents and respiratory inhibitors on the growth of Streptococcus agalactiae.

2,4-Dinitrophenol, dicoumarol, carbonylcyanide, m-chlorophenyl-hydrazone and pentachlorophenol all depressed aerobic molar growth yields of Streptococcus agalactiae to values equal to, or less than, those supported by substrate level phosphorylation. When the only source of energy was from substrate phosphorylation (anaerobic growth conditions), there was also a severe depression of the molar growth yield by the same four uncoupling agents. These results indicate that the effect of these agents is to uncouple both substrate and oxidative phosphorylation in S. agalactiae. Amytal inhibited glucose utilization, reduced the amount of O(2) used per mole of substrate and reduced the molar cell yield to that supported by substrate phosphorylation. Atebrin inhibited the respiration rate, but final O(2) consumed per mole of substrate was unchanged, and the respiration was coupled to biosynthesis. Rotenone had no effect on respiration, substrate utilization, or on molar growth yields.

Adenosine Triphosphate↗
PubMed1989

Fall in intracellular pH and increase in resting tension induced by a mitochondrial uncoupling agent in crayfish muscle.

1. The influence of the mitochondrial uncoupling agent carbonylcyanide-m-chlorophenylhydrazone (CCCP) upon resting tension and intracellular pH (pHi) was studied in the dactyl opener muscle of the crayfish. pHi was measured with liquid sensor H+-selective microelectrodes. 2. CCCP (10(-6)-10(-5) mol l-1) induced a reversible, tonic contracture which was associated with a depolarization of the membrane potential. Both effects were augmented by a fall and inhibited by a rise in extracellular pH. The action of CCCP on tension was not mimicked by cyanide + oligomycin or by cyanide + dicyclohexylcarbodiimide nor was it inhibited by pre-exposure to these agents. 3. CCCP produced an initial alkalosis of less than 0.1 units and thereafter a fall in pHi of 0.4-0.6 units during which the sarcolemmal H+ driving force decreased from 61 to 15 mV. The apparent influx of H+ due to CCCP had a maximum of 2.7 mequiv l-1 min-1. The CCCP-induced acidosis was unaffected by iodacetate (0.5 mmol l-1) but it was inhibited by a depolarization of the membrane potential. 4. The contraction caused by CCCP was not due to the simultaneous fall in pHi since an intracellular acidosis of equal magnitude, produced by propionate (50 mmol l-1), did not lead to force generation. In addition, propionate had an inhibitory effect on the depolarization and contracture caused by CCCP. 5. Both the depolarization and the contracture caused by CCCP were inhibited by gamma-aminobutyric acid (GABA). The contracture was blocked by Cd2+, Mn2+ and by a nominally Ca2+ -free medium but not by a pre-exposure to caffeine (20 mmol l-1). Cd2+ and Mn2+ had no influence on the fall of pHi caused by CCCP. 6. It is concluded that CCCP induces a sarcolemmal H+ conductance which leads to a fall in pHi and to a depolarization of the membrane potential. This depolarization activates sarcolemmal, voltage-dependent calcium channels and thereby induces an increase in tension. The initial alkalosis produced by CCCP may be due to a transient uptake of H+ by mitochondria.

Animals↗
PubMed2004

Fluoride curcumin derivatives: new mitochondrial uncoupling agents.

The mitochondrial effects of two fluoride curcumin derivatives were studied. They induced the collapse of mitochondrial membrane potential (DeltaPsi), increased mitochondrial respiration, and decreased O(2)*- production and promoted Ca(2+) release. These effects were reversed by the recoupling agent 6-Ketocholestanol, but not by cyclosporin A, an inhibitor of the permeability transition pore (PTP), suggesting that these compounds act as uncoupling agents. This idea was reinforced by the analysis of the physico-chemical properties of the compounds indicating, that they are mainly in the anionic form in the mitochondrial membrane. Moreover, they are able to induce PTP opening by promoting the oxidation of thiol groups and the release of cytochrome c, making these two molecules potential candidates for induction of apoptosis.

Animals↗
PubMed2004

The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord.

The purpose of this study was to investigate the potential neuroprotective efficacy of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in rats following a mild to moderate spinal cord contusion injury. Animals received intraperitoneal injections of vehicle (DMSO) or 5 mg/mL of DNP prior to injury. Twenty-four hours following surgery, mitochondrial function was assessed in mitochondria isolated from spinal cord synaptosomes. In addition, synaptosomes were used to measure indicators of reactive oxygen species formation, lipid peroxidation, and protein oxidation. Relative to vehicle-treated animals, pretreatment with DNP maintained mitochondrial bioenergetics and significantly decreased reactive oxygen species levels, lipid peroxidation, and protein carbonyl content following spinal cord injury. Furthermore, pretreatment with DNP significantly increased the amount of remaining white matter at the injury epicenter 6 weeks after injury. These results indicate that treatment with mitochondrial uncoupling agents may provide a novel approach for the treatment of secondary injury following spinal cord contusion.

2,4-Dinitrophenol↗
PubMed1979

Uncoupling agents distinguish between the effects of metabolic inhibitors and transport inhibitors.

In studies with toad bladders, the uncoupling agent 2,4-dinitrophenol (DNP) reversed the inhibition of CO2 production produced by direct inhibition of transport. In contrast, DNP did not reverse the inhibition of CO2 production brought about by metabolic inhibitors. Therefore, the response to DNP distinguished between inhibition of transport and metabolism; this approach may be useful for the investigation of factors that regulate active transport.

Animals↗
PubMed2005

The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.

It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.

2,4-Dinitrophenol↗
PubMed1996

Octanol, a gap junction uncoupling agent, changes intracellular [H+] in rat astrocytes.

Octanol rapidly closes gap junction channels but its mechanism of action is not known. Because intracellular [H+], pHi, also affects the conductance of gap junctions, we studied octanol's effects on pHi in cultured rat astrocytes, which are highly coupled cells. Octanol (1 mM) caused an acid shift in the pHi of 90% of rat hippocampal astrocytes which averaged -0.19 +/- 0.09 pH units in magnitude. In 58% of the cells tested, a biphasic change in pHi was seen; octanol produced an initial acidification lasting approximately 10 min that was followed by a persistent alkalinization. The related gap junction uncoupling agent, heptanol, had similar effects on pHi. Octanol-induced changes in pHi were similar in nominally HCO(3-)-free and HCO(3-)-containing solutions, although the rate of initial acidification was significantly greater in the presence of HCO3-. The initial acidification was inhibited in the presence of the stilbene DIDS, an inhibitor of Na+/HCO3- cotransport, indicating that octanol caused acidification by blocking this powerful acid extruder. The alkalinization was inhibited by amiloride which blocks the Na+/H+ exchanger (NHE), an acid extruder, suggesting that the alkaline shift induced by octanol was caused by stimulation of NHE. As expected, octanol's effects on astrocytic pHi were prevented by removal of external Na+, which blocks both Na+/HCO3- cotransport and NHE. Octanol had only small effects on intracellular Ca2+ (Ca2+i) in astrocytes. Hepatocytes which, like astrocytes, are strongly coupled to one another, showed no change in pHi with octanol application. Fluorescence recovery after photobleaching (FRAP) was used to study the effect of changes in astrocyte pHi on degree of coupling in hippocampal astrocytes. Coupling was decreased by intracellular acid shifts approximately -0.2 pH units in size. Octanol's effects on astrocyte pHi were complex but a prompt initial acidification was nearly always seen and could contribute to the uncoupling action of this drug in astrocytes. Because octanol uncouples hepatocytes without changing their pHi, this compound clearly can influence gap junctional conductance independent of changes in pHi.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1995

Biphasic effects of gap junctional uncoupling agents on the propagation of retinal spreading depression.

The spreading depression wave of Leão (SD) propagates in the nervous tissue at 3-10 mm/min and is accompanied by an increase of intracellular Ca2+ concentration and a decrease in the extracellular milieu. Recently the spread of Ca2+ waves with propagating velocities of the same order of magnitude has been detected in cultures of nerve cells. It has been suggested that these waves, which can be blocked by gap junctional agents, are related to SD. The present experiments describe some effects of heptanol and octanol (10 microM to 10 mM), well-known uncoupling agents of gap junctions, on the slow voltage changes and the velocity of propagation of Leão's phenomenon in isolated chick retina: 1) a 50 to 700 microM concentration of these alcohols in the superfusate solutions increased the velocity, whereas high concentrations (1 to 10 mM) decreased and subsequently halted the spread; 2) the recovery period of the slow voltage changes of SD was shorter in the presence of alcohol and its amplitude was larger during faster SD waves. These effects were observed in the retina during successive individual waves as well as in the course of circling SD. All of these effects were reversible, without any sign of damage to the retina. In the concentration range of 50 microM to 10 mM, methanol, ethanol, butanol and cyclo-hexanol had no effect on retinal SD. These data suggest the involvement of gap junctions in Leão's wave. This involvement is complex and its functional effects together with other factors that influence the velocity of propagation of SD are being investigated.

Animals↗
PubMed2003

Effects of heart isolation, voltage-sensitive dye, and electromechanical uncoupling agents on ventricular fibrillation.

We tested whether the interventions typically required for optical mapping affect activation patterns during ventricular fibrillation (VF). A 21 x 24 unipolar electrode array (1.5 mm spacing) was sutured to the left ventricular epicardium of 16 anesthetized pigs, and four episodes of electrically induced VF (30-s duration) were recorded. The hearts were then rapidly excised and connected to a Langendorff perfusion apparatus. Four of the hearts were controls, in which 24 additional VF episodes were then mapped. In the remaining 12 hearts, four VF episodes were mapped after isolation, four more episodes were mapped after exposure to the voltage-sensitive dye di-4-ANEPPS, and six more episodes were mapped after exposure to the electromechanical uncoupling agents diacetyl monoxime (DAM; 20 mmol/l, n = 6) or cytochalasin D (CytoD; 10 micromol/l, n = 6). VF episodes were separated by 4 min. VF activation patterns were quantified using custom pattern analysis algorithms. From comparisons with time-corrected control data, all interventions significantly changed VF patterns. Most changes were broadly consistent with slowing and regularization due to loss of excitability. Heart isolation had the largest effect on VF patterns, followed by CytoD, DAM, and dye.

Animals↗