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At least 19 recordsLinked to original sources
PubMed1989

Modulation of doxorubicin resistance by valinomycin (NSC 122023) and liposomal valinomycin in Chinese hamster ovary cells.

Recently, we have reported that the toxicity of the membrane-active agent valinomycin (VM) can be reduced with maintenance and/or enhancement of its antitumor activity by incorporation in liposomes (S. S. Daoud and Juliano, Cancer Res., 46:5518-5525, 1986). Since the underlying defect(s) in multidrug resistance reside mainly in the cell membrane, it seems reasonable to attempt to overcome multidrug resistance with membrane-active drugs. Here, we report on the in vitro restoration of Adriamycin (ADR) sensitivity in a resistant Chinese hamster ovary cell line (CHRC5) by treatment with nontoxic doses of valinomycin or of liposomal valinomycin. During a 1-h drug exposure, the sensitivity of CHRC5 to ADR was enhanced 21- to 28-fold when 20 or 40 nM VM was present, doses which are not toxic to CHRC5 cells. At the same time, modest synergistic toxicity could be seen in the parent drug-sensitive cell line (AUX B1). At 100 nM VM, the sensitivity of CHRC5 to ADR was restored to almost that of the sensitive AUX B1 cells. The effects of liposomal VM on ADR sensitivity were similar to the effects produced by free VM. At nontoxic doses and with continuous exposure of the drug, valinomycin was highly active in restoring ADR sensitivity in CHRC5 cells. In cells treated for 72 h, valinomycin enhanced the sensitivity to ADR 208- to 250-fold in CHRC5 and 3- to 5-fold in AUX B1 cells. Measurements of ADR uptake and efflux indicate that, unlike other multidrug resistance modifiers, valinomycin exerts its actions in modulating ADR resistance by mechanism(s) other than increasing intracellular accumulation of Adriamycin. The possible mechanisms of the restoration of ADR sensitivity by valinomycin are discussed.

Animals↗
PubMed1975

[Action of valinomycin in vivo on Ehrlich ascites tumor cells. A change in the ultrastructure of the tumor cells under the influence of valinomycin].

It was found with the help of electron microscopy that valinomycin administered to mice with Ehrlich ascitic tumors in a dose inhibiting the proliferating activity induced impairements in the mitochondria. The changes were similar to those under the effect of valinomycin in vitro. An increase in the antibiotic dose resulted in more pronounced and irreversible changes not only in the mitochondria but also in other structures of the tumor cells.

Animals↗
PubMed1975

[In vivo action of valinomycin on Ehrlich ascites tumor cells. Inhibition of the proliferative activity of the tumor cells under the action of valinomycin].

It was shown that repeated administrations of valinomycin in doses of 1.0 and 0.01 gamma/gm to mice with Ehrlich ascitic tumors inhibited the ascite development. The radioautographic study using 3H-thimidine showed that 24 hours after the administration of valinomycin in doses of 0.1 and 0.01 gamma/gm transference of the cells into the phase of DNA synthesis was inhibited--inhibition of the tumor cell mitotic activity took place.

Animals↗
PubMed1976

Valinomycin inhibition of the inward slow current of cardiac muscle.

Valinomycin (10(-6) M), a K+ ionophore and uncoupler of oxidative phosphorylation, produced pronounced shortening of the action potential plateau in young (3 day) and old (15-19 day) embryonic chick hearts and isolated perfused guinea pig hearts. The rate of rise of the action potential was usually not affected. Dimethylsulfoxide (DMSO) (2 percent), The vehicle for valinomycin, did not cause plateau shortening. In chick hearts, diminution of the plateau by valinomycin at 10(-6) M usually occurred by 1 hr; larger doses produced prominent effects within 15 min. Young embryonic hearts were more resistant to valinomycin, and 20x10(-6) M for 1-2 hr was necessary to produce a significant diminution in plateau. Several agents were able to partially relengthen the plateau shortened by valinomycin. In both young and old hearts, the resting potential was not increased by valinomycin, even though young hearts have a low resting potential because of a low K+ conductance (gK). In guinea pig, 10(-6) M valinomycin markedly shortened the plateau within 5-10 min. Contractions were abolished, i.e., the hearts became electromechanically uncoupled. When hearts were perfused with 27 mM K+ to depolarize the cells to about -40 mV to inactivate fast Na+ channels, catecholamines or methylxanthines rapidly induced slowly rising (about 10 V/sec), overshooting, plateau-like responses with accompanying contractions. Valinomycin rapidly (within 2-5 min) abolished these slow responses and contractions. Hearts perfused with 10(-6) M valinomycin or 10(-5) dinitrophenol became nearly entirely depleted of ATP within 2-10 min. These results suggest that valinomycin blocks the slow inward current indirectly through ATP depletion, the slow cation channels requiring metabolic energy. The possibility that resting gK or kinetics of changes in gK during the plateau is also affected by valinomycin cannot be excluded.

Action Potentials↗
PubMed1975

Valinomycin shortening of action potential of embryonic chick hearts.

The effects of valinomycin, an agent known to increase the K+ conductance (gK) of lipid bilayer membranes and to be an uncoupler of oxidative phosphorylation, were examined on young (3 days old) and old (15-19 days old) embryonic chick hearts. In the old hearts, valinomycin produced pronounced shortening of the action potential plateau, and often only the spike component remained. The rate of rise of the action potential was usually not affected (slightly diminished sometimes). Addition of dimethylsulfoxide (2 percent), the vehicle for the valinomycin, did not cause shortening of the plateau. The diminution of the plateau by valinomycin at 1 mug/ml was usually obtained after incubation for 1 h; larger doses produced prominent effects within 15 min. The threshold concentration was about 0.1 mug/ml. Cooling, isoproterenol, Ba++, Sr++, and tetraethylammonium partially relengthened the plateau shortened by valinomycin. Lowering of external K+ also lengthened the plateau slightly in the presence of valinomycin. Young embryonic hearts were more resistant to valinomycin, and it was necessary to incubate with 20-40 mug/ml for 1-2 h to produce a significant diminution in plateau. In both young and old hearts, the resting potential was not increased by valinomycin, even though young hearts have a low resting potential (similar to minus 40 mV) mainly because of a low gK. These results suggest that the kinetics of the changes in gK during the action potential plateau may be more greatly affected by valinomycin than the steady-state gK of the resting membrane. In addition to such a direct effect on the sarcolemma, valinomycin could also exert an indirect effect by blocking the slow inward current through ATP depletion.

Action Potentials↗
PubMed1986

Effect of valinomycin on thyroid iodide transport and TSH-stimulated cAMP formation.

The K+ ionophore valinomycin, in concentrations as low as 0.1 microM, induces an inhibition of thyroid-stimulating hormone (TSH)-stimulated cAMP formation in cat and pig thyroid slices and isolated, trypsin-collagenase-dispersed beef thyroid cells. Valinomycin was also shown to inhibit histamine and prostaglandin E1 stimulation of thyroid cAMP formation. The inhibitory effect of valinomycin could be partially overcome by elevated (81 mM) K+ concentrations. In the absence of valinomycin, the ability of TSH to stimulate thyroid cAMP formation was dependent on extracellular K+. Chronic removal or addition of K+ to medium bathing thyroid sections was accompanied by inhibition of TSH-stimulated cAMP formation. Maximum TSH stimulation was observed at an extracellular K+ of 2.7 mM. Valinomycin had no significant effect on thyroid ATP content but did reduce the ATP-to-ADP ratio. However, chronic removal of K+ had no effect on either ATP or the ATP-to-ADP ratio. Varying extracellular Na+ from 26 to 144 mM or addition of tetrodotoxin did not affect TSH action. Valinomycin addition to thyroid slices was associated with a reduction in iodide transport as measured by the ratio of tissue to extracellular iodide concentrations. The effect of valinomycin on iodide transport was accompanied by an increase in iodide efflux that was not greater than that observed with perchlorate ion, suggesting a reduced recirculation of released iodide in valinomycin-treated tissue. These findings suggest that alterations in thyroid cell K+ permeability or intracellular K+ concentration may be accompanied by changes in TSH-induced stimulation of thyroid cAMP formation.

Adenine Nucleotides↗
PubMed1976

Modification of valinomycin-mediated bilayer membrane conductance by 4,5,6,7-tetrachloro-2-methylbenzimidazole.

The compound 4,5,6,7-tetrachloro-2-methylbenzimidazole (TMB), has been found to markedly modify the steady-state valinomycin-mediated conductance of potassium (K+) ions through lipid bilayer membranes. TMB alone does not contribute significantly to membrane conductance, being electrically neutral in solution. In one of two classes of experiments (I), valinomycin is first added to the aqueous phases, then changes of membrane conductance accompanying stepwise addition of TMB to the water are measured. In a second class of experiments (II), valinomycin is added to the membrane-forming solution, followed by TMB additions to the surrounding water. In both cases membrane conductance shows an initial increase with increasing TMB concentration which is more pronounced at lower K+ ion concentration. At TMB concentrations in excess of 10(-5) M, membrane conductance becomes independent of K+ ion concentration, in contrast to the linear dependence observed at TMB concentrations below 10(-7) M. This transition is accompanied by a change of high field current-voltage characteristics from superlinear (or weakly sublinear) to a strongly sublinear form. All of these observations may be correlated by the kinetic model for carrier-mediated transport proposed by Läuger and Stark (Biochim. Biophys. Acta 211:458, 1970) from which it may be concluded that valinomycin-mediated ion transport is limited by back diffusion of the uncomplexed carrier at high TMB concentrations. Experiments of class I reveal a sharp drop of conductance at high (greater than 10(-5) M) TMB concentration, not seen in class II experiments, which is attributed to blocked entry of uncomplexed carrier from the aqueous phases. Valinomycin initially in the membrane is removed by lateral diffusion to the surrounding torus. The time dependence of this removal has been studied in a separate series of experiments, leading to a measured coefficient of lateral diffusion for valinomycin of 5 x 10(-6) cm2/sec at 25 degrees C. This value is about two orders of magnitude larger than the corresponding coefficient for transmembrane carrier diffusion, and provides further evidence for localization of valinomycin in the membrane/solution interfaces.

Benzimidazoles↗
PubMed1975

Direct measurement of the membrane potential of Ehrlich ascites tumor cells: lack of effect of valinomycin and ouabain.

The membrane potential of Ehrlich ascites tumor cells and the effects of valinomycin and ouabain upon it have been determined. The membrane potential in control cells was 12.0 mV, inside negative. Neither valinomycin nor ouabain alone affected this value. However, valinomycin and ouabain in combination resulted in a slight hyperpolarization of the membrane. Concomitant determinations of cellular Na+, K+ and Cl- showed that valinomycin induced net losses of K+ and Cl- and a net gain in Na+ when compared to ouabain-inhibited cells. K+ permeability was increased by approximately 30% in the presence of valinomycin. In addition, valinomycin caused a rapid depletion of cellular ATP. Inhibition of Na/K transport by ouabain was without sparing effect on the rate of ATP depletion. Possible mechanisms for the electroneutral increase in K+ permeability induced by valinomycin are discussed.

Adenosine Triphosphate↗
PubMed1987

Valinomycin, a degranulating agent in rat mast cells which inhibits calcium-uptake.

The effect of valinomycin on both, mast cell histamine release and on calcium (45Ca)-uptake processes was examined. Pleural and peritoneal mast cells were purified in isotonic Percoll (pH = 7) and mixed populations were used in the experiments. Valinomycin (10(-9)-10(-5) M) stimulated histamine release in isolated rat mast cells when the incubation medium contained high K+ concentrations (Tris-K+ with 150 mM K+), but not in other media such as Tris-Na+ (120 mM Na+) or Tris-sucrose (300 mM sucrose). In contrast, in the absence of valinomycin, elevated K+ levels in the external environment did not activate mast cell secretion. Optimum response in valinomycin-treated mast cells was obtained when the cells were incubated for 60 min. Also valinomycin (10(-5) M) induced substantial inhibition of 45Ca-uptake while lower doses (10(-9)-10(-7) M) did not affect or only slightly increased uptake. In this paper valinomycin is shown to be a degranulating agent eliciting mediator release in mast cells incubated in the presence of high K+ levels, which does not require extracellular calcium and inhibits 45Ca uptake. The possibility that valinomycin acts as a K+ ionophore, as in other secretory systems, is discussed.

Animals↗
PubMed1988

Location and ion-binding of membrane-associated valinomycin, a proton nuclear magnetic resonance study.

Valinomycin, incorporated in small unilamellar vesicles of perdeuterated dimyristoylphosphatidylcholine, reveals several well-resolved 1H-NMR resonances. These resonances were used to examine the location, orientation and ion-binding of membrane-bound valinomycin. The order of affinity of membrane-bound valinomycin for cations is Rb+ greater than K+ greater than Cs+ greater than Ba2+, and binding is sensitive to surface change. The exchange between bound and free forms is fast on the NMR time scale. The intrinsic binding constants, extrapolated to zero anion concentration, are similar to those determined in aqueous solution. Rb+ and K+ show 1:1 binding to valinomycin, whereas the stoichiometry of Cs+ and Ba2+ is not certain. Paramagnetic chemical shift reagents and nitroxide spin label relaxation probes were used to study the location and orientation of valinomycin in the membrane. Despite relatively fast exchange of bound cations, the time average location of the cation-free form of valinomycin is deep within the bilayer under the conditions of these experiments. Upon complexation to K+, valinomycin moves closer to the interfacial region.

Barium↗
PubMed1992

Valinomycin and excitation-contraction coupling in skeletal muscle fibres of the frog.

1. Experiments were carried out on intact frog skeletal muscle fibres to study the role of H+ and K+ as counter-ions during the release of Ca2+ from the sarcoplasmic reticulum (SR). A specific focus was to test whether valinomycin, a potassium ionophore, markedly reduces or abolishes H+ counter-ions fluxes across the SR membrane in response to electrical stimulation. 2. Single twitch fibres, mounted on an optical bench apparatus and stretch to long sarcomere length (3.6-4.0 microns), were activated by single action potentials (16 degrees C). Two optical signals related to excitation-contraction coupling were measured: (i) the 'second component' of the intrinsic birefringence signal, which is closely related to the myoplasmic free [Ca2+] transient, and (ii) the transient myoplasmic alkalization (delta pH) detectable from the pH indicator Phenol Red, a signal thought to reflect the movement of protons from the myoplasm into the SR in partial electrical exchange for released Ca2+. 3. Exposure of a fibre to 5 microM-valinomycin produced a slight, progressive decrease in the amplitude of the birefringence signal, approximately 5-6% per hour. This result suggests that, if anything, the peak rate at which Ca2+ is released from the sarcoplasmic reticulum is slightly decreased by valinomycin. 4. The amplitude of the Phenol Red delta pH signal, measured after exposure of a fibre to valinomycin for a period of at least 60 min, averaged 0.0020 +/- 0.0002 (+/- S.E.M.); this value is slightly smaller than, but not significantly different from (P greater than 0.05; two-tailed t test) that measured in fibres not exposed to valinomycin (0.0025 +/- 0.0002). This result does not support the idea that valinomycin, but virtue of increasing the flux of K+ into the SR, markedly reduces the flux of protons during Ca2+ release. 5. Our findings of minimal changes in the birefringence and delta pH signals are consistent with the idea that, at the time of Ca2+ release, the potassium conductance of the SR membrane is large and not substantially increased by the addition of valinomycin to Ringer solution.

Action Potentials↗
PubMed1979

Kinetics of ion transport in lipid membranes induced by lysine-valinomycin and derivatives.

Lysine-valinomycine and two N epsilon-acyl derivatives are compared with respect to their potency to transport Rb+ ions across thin lipid membranes. Lysine-valinomycin acts as a neutral ion carrier only above a pH of about 7 of the aqueous solutions, while at lower pH the molecules seem to be positively charged due to a protonation of the epsilon-NH2 group of the lysine residue. A kinetic analysis based on voltage jump relaxation experiments and on the nonlinearity of the current-voltage characteristics showed that the conductance increment delta per carrier molecule for uncharged lysine-valinomycin is similar to that of natural valinomycin. The attachment of a rather bulky side group such as the dansyl or para-nitrobenzyloxycarbonyl group reduced delta by approximately one order of magnitude. Some of the relaxation data of the valinomycin analogues were influenced by an unspecific relaxation of the pure lipid membrane. This structural relaxation represents a limitation to the possibility of analyzing specific transport systems in thin lipid membranes by the voltage jump or charge pulse techniques. It is shown that the time dependence of this structural relaxation--which was first published by Sargent (1975)--is at variance with a three capacitor equivalent circuit of the membrane, which was suggested by Coster and Smith (1974) on the basis of a.c. measurements. A modified equivalent circuit has been found to represent a satisfactory analogue for the current relaxation in the presence of valinomycin. It turned out, however, that such an equivalent circuit provides little insight into the molecular mechanism of transport.

Biological Transport↗
PubMed1975

Increase of potassium flux by valinomycin in embryonic chick heart.

The effect of different concentrations of the antibiotic valinomycin, was determined on 42K efflux and Na, K content of embryonic chick hearts. Valinomycin produces an increase of K efflux which is progressive in time and markedly dependent on the concentration of external K (0-5 mM) and valinomycin (10(-8) to 10(-5) M). The changes in K efflux is not due to a reversal of the Na-K pump mechanism, secondary to ATP depletion: i) the increase of K efflux by valinomycin persists in the absence of external Na ions. ii) analysis of Na and K content and 42K influx measurements with and without valinomycin indicate that active K influx is not inhibited in a solution containing 0.5 mM K and only slightly decreased in a solution containing 5 mM K. Valinomycin, acting as a K carrier, presumably increases K conductance of the cell membrane resulting in a rise in K efflux.

Animals↗
PubMed1979

The effect of surface charge density on valinomycin-K+ complex formation in model membranes.

The model membrane approach was used to investigate the surface charge effect on the ion-antibiotic complexation process. Mixed monolayers of valinomycin and lipids were spread on subphases containing K+ or Na+. The surface charge density was modified by spreading ionizable valinomycin analogs on aqueous subphases of different pH or by changing the nature of the lipid (neutral, negatively charged) in the mixed film. Surface pressure and surface potential measurements demonstrated that a neutral lipid (phosphatidylcholine) or positively charged valinomycin analogs didn't enhance the anti-biotic complexing capacity. However, a maximal complexation is reached for a critical lipid concentration in the valinomycin-phosphatidylserine mixed film. The role of the surface charge on the valinomycin complexing properties was examined in terms of the Gouy-Chapman theory. As a consequence of the negative charge of the lipid monolayer, the K+ concentration near the surface is larger than the bulk concentration, by a Boltzmann factor. A good agreement was observed between the experimental results and the theoretical predictions. Conductance measurements of asymmetric bilayers containing a neutral lipid (egg lecithin) on one side and a negatively charged lipid (phosphatidyl-serine) on the other, confirm the role of the surface charge. Indeed, addition of K+ to the neutral side of the bilayer containing valinomycin had no effect on the conductance whereas addition of K+ to the charged side of the bilayer caused a 80-fold conductance increase.

Kinetics↗
PubMed1991

The influence of valinomycin induced membrane potential on erythrocyte shape.

In addition to previous observations indicating that membrane potential changes generated by various Donnan- and Nernst-potentials lead to erythrocyte shape transformations, we show in this paper that diffusion potential change, induced by valinomycin, governs erythrocyte shape transformations. In low KCl-medium valinomycin, transferring the positive Nernst-potential into a negative diffusion potential, transforms stomatocytes into echinocytes. Using modified erythrocytes with a reversed K/Na ratio, even positive diffusion potentials can be induced by valinomycin. In these cases, stomatocytes can be generated by valinomycin. It is shown that, additionally, valinomycin in large concentrations is itself stomatocytogenic, and that the fluorescent dye diS-C3-(5) also induces stomatocytes. This, however, is a side effect which does not contradict the potential dependence of shape transformation. Using non washed erythrocytes, resuspended in plasma, valinomycin, inducing negative diffusion potential, transforms most erythrocytes to echinocytes despite the stomatocytogenic effect of albumin.

Albumins↗
PubMed1978

Transport of organic anions through the erythrocyte membrane as K+-valinomycin complexes.

K+, Rb+, or Cs+ complexes of valinomycin form ion pair complexes with picric acid and trinitrobenzenesulfonate (TNBS). The formation of a picrate-K+-valinomycin complex is supported by spectral evidence. These complexes have zero net charge and readily permeate the intact erythrocyte membrane. The K+-valinomycin complex has been used to convert the nonpenetrating TNBS into a penetrating covalent probe, making it as useful vectorial probe to measure accessible amino groups of proteins and phospholipids on both sites of the erythrocyte membrane. The enhanced transport of TNBS into the cell by valinomycin is dependent on external K+ in the medium. The entry of TNBS into the cell is manifested by an increased labeling of hemoglobin and membrane phosphatidylethanolamine (PE). Stilbeneisothiocyanatedisulfonate (SITS) and anilinonaphthalenesulfonate (ANS) inhibit both the basal and K+-valinomycin stimulated labeling of PE and hemoglobin by TNBS. The data suggest two independent effects of ANS and SITS, one mediated by an inhibition of the anion transport protein and another by the incorporation of these hydrobic anions into the cell membrane with an increase in negative charge on the membrane which leads to an inhibition of TNBS permeation into the cell by electrostatic repulsion.

Anilino Naphthalenesulfonates↗
PubMed1986

Flux ratio of valinomycin-mediated K+ fluxes across the human red cell membrane in the presence of the protonophore CCCP.

The ratio of valinomycin-mediated unidirectional K+ fluxes across the human red cell membrane, has been determined in the presence of the protonophore carbonylcyanide m-chlorophenylhydrazone, CCCP, using the K+ net efflux and 42K influx. The driving force for the net efflux (Vm - EK+) has been calculated from the membrane potential, estimated by the CCCP-mediated proton distribution and the Nernst potential for potassium ions across the membrane. An apparent driving potential for the K+ net efflux has been calculated from the K+ flux ratio, determined in experiments where the valinomycin and CCCP concentrations were varied systematically. This apparent driving force, in conjunction with the actual driving force calculated on basis of the CCCP estimated membrane potential, is used to calculate a flux ratio exponent, which represents an estimate of the deviation of valinomycin-mediated K+ transport from unrestricted electrodiffusion, when protonophore is present. In the present work, the flux ratio exponent is found to be 0.90 when the CCCP concentration is 5.0 microM and above, while the exponent decreases to about 0.50 when no CCCP is present. The influence of CCCP upon the rate constants in the valinomycin transport cycle is discussed. The significance of this result is that red cell membrane potentials are overestimated, when calculated from valinomycin-mediated potassium isotope fluxes, using a constant field equation.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1986

Potassium transport in the rabbit renal proximal tubule: effects of barium, ouabain, valinomycin, and other ionophores.

Potassium fluxes in a suspension of rabbit proximal tubules were monitored using a potassium-sensitive extracellular electrode. Ouabain (10(-4) M) and barium (5 mM) were used to selectively quantitate the potassium efflux pathway (105 +/- 5 nmol K+ X mg protein-1 X min-1) and the sodium pump-related potassium influx (108 +/- 7), respectively. These equal and opposite fluxes suggest that potassium accumulation in the cell occurs mainly through the sodium pump and that potassium efflux occurs mainly through barium-sensitive potassium channels. Thus the activity of the sodium pump (Na,K-ATPase) in the basolateral membrane of the proximal tubule is balanced by the efflux of potassium, presumably across the basolateral membrane, which has a high potassium permeability. In addition, the effect of valinomycin and other ionophores was examined on potassium fluxes and several metabolic parameters [oxygen consumption (QO2), ATP content]. The addition of valinomycin to the tubules produced a net efflux of potassium which was quantitatively equivalent to the efflux produced by the addition of ouabain. The valinomycin-induced efflux was mainly due to the activity of valinomycin as a mitochondrial uncoupler, which indirectly inhibited the sodium pump by allowing a rapid reduction of the intracellular ATP. Amphotericin, nystatin, and monensin all produced large net releases of intracellular potassium. The action of the ionophores could be localized to the plasma or mitochondrial membrane and classified into three groups, as follows: those which demonstrated full mitochondrial uncoupler activity (FCCP, valinomycin), those which had no uncoupler activity (amphotericin B, nystatin); and those which displayed partial uncoupler activity (monensin, nigericin).

Animals↗