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At least 19 recordsLinked to original sources
PubMed1992

In vivo potentiation of ricin toxicity by monensin delivered through liposomes.

Monensin, a carboxylic ionophore, which is known to raise intravesicular pH, was intercalated in liposomes and its effect on the toxicity of ricin in mice was studied. The toxicity of ricin in vivo was found to be significantly enhanced by the administration of monensin intercalated in liposomes (liposomal monensin). The observed enhancement of the toxicity of ricin by monensin was highly dose-dependent and was maximal when ricin was injected within 60 min of monensin injection. The survival time was found to be reduced in the range of 8-20 h, depending on the dose of ricin used, by liposomal monensin. Stability of liposomes containing monensin as inferred from the release of entrapped calcein or FITC-dextran under both in vivo and in vitro conditions was comparable to that observed for liposomes without monensin. Liposomal monensin remains in circulation for 2 h and was cleared from the blood stream after 4 h. In contrast, 15 min was required for the clearance of monensin when administered in free form. Studies on the distribution of liposomal monensin and 125I-ricin in various tissues have revealed that monensin is mainly localized in the liver and spleen which are also the major sites for ricin accumulation. Our observation on the substantial enhancement of ricin toxicity in vivo by liposomal monensin strongly supports the potential usefulness of the latter as a potentiating agent in the enhancement of the toxicity of immunotoxin or hormonotoxin for selective elimination of cancer cells.

Animals↗
PubMed1992

Monensin intercalation in liposomes: effect on cytotoxicities of ricin, Pseudomonas exotoxin A and diphtheria toxin in CHO cells.

Monensin, a carboxylic ionophore was intercalated in liposomes (liposomal monensin) and its effect on cytotoxicities of ricin, Pseudomonas exotoxin A and diphtheria toxin in CHO cells was studied. Intercalation of monensin in liposomal bilayer is found to have no effect on its stability and interaction with cells. Liposomal monensin (1 nM) substantially enhance the cytotoxicities of ricin (62-fold) and Pseudomonas exotoxin A (11.5-fold) while it has no effect on diphtheria toxin. This observed effect is highly dependent on the liposomal lipid composition. The potentiating ability of monensin (1 nM) in neutral vesicles is significantly higher (2.2-fold) as compared to negatively charges vesicles. This ability is drastically reduced by incorporation of stearylamine in liposomes and is found to be dependent on the density of stearylamine as well as on the concentration of serum in the medium. Monensin in liposomes containing 24 mol% stearylamine has a very marginal effect on the cytotoxicity of ricin (7.5-fold) which is further reduced (1.5-fold) in the presence of 20% serum. The uptake of 125I-gelonin from neutral vesicles is significantly higher (approximately 2.0-fold) than that from the negative vesicles. The uptake from positive vesicles is highly dependent on the concentration of stearylamine. The reduction in the lag period (30 min) of ricin action by monensin in neutral and negative vesicle is comparable with free monensin. However, monensin in positive vesicle has no effect on it. These studies have suggested that liposomes could be used as a delivery vehicle for monensin for selective elimination of tumor cells in combination with hybrid toxins.

ADP Ribose Transferases↗
PubMed1992

Practical usage concentrations of monensin have non-specific actions other than as a sodium ionophore in rat parotid acinar cells.

Monensin is used as a sodium ionophore to examine the effect of Na+ on cellular function in a variety of cell types. In the present study, we investigated the effects of different concentrations of monensin on the signal transduction system in exocrine parotid acinar cells. Monensin increased cytosolic free Na+ concentration, measured by the Na+ indicator sodium-binding benzofuran isophthalate in a concentration-dependent manner (0.01 to 100 microM). Likewise, monensin concentration-dependently increased amylase release and intracellular Ca2+ concentration in the presence and the absence of extracellular Ca2+. Low concentrations (0.01 to 1 microM) of monensin did not release Ca2+ from non-mitochondrial intracellular pools in permeabilized cells with saponin but high concentrations (10 and 100 microM) of monensin which are of practical usage did. Monensin itself did not change the cyclic AMP accumulation, whereas high concentrations (10 and 100 microM) but not low concentrations (0.01 to 1 microM) of monensin inhibited cyclic AMP accumulation elevated by isoproterenol in the presence and absence of extracellular Na+. These results indicate that high concentrations of monensin, which are practically used, have nonspecific actions in rat parotid acinar cells, and lower concentrations of monensin are recommended for use as a sodium ionophore.

Adenosine Triphosphate↗
PubMed1978

Effects of monensin on in vivo rumen propionate production and blood glucose kinetics in cattle.

Four rumen-fistulated steers (154 to 253 kg), fed two different diets in succession, were used to determine effects of monensin on rumen propionate production rates and blood glucose kinetics as determined by single-injection isotope-dilution techniques. A high-roughage and a high-grain diet, with and without 150 mg of monensin daily, were fed isoenergetically at 2-hour intervals. Monensin increased rumen propionate pool sizes from 32 to 57 g for the high-roughage diet and from 37 to 66 g for the high-grain diet and increased rumen propionate production rates from 441 to 659 g/day for the high-roughage diet and from 510 to 899 g/day for the high-grain diet. Molar percentages of rumen propionate were increased significantly by monensin in the high-grain diet. Blood glucose pool sizes were not changed significantly by either monensin or isoenergetic diets. Monensin increased irreversible losses of glucose from 582 to 677 g/day for the high-grain diet. Monensin tended to increase glucose total entry rates for both diets and to increase irreversible loss of glucose for the high-roughage diet but the differences were not significant. Thus, increases in glucose kinetics are minor in contrast to major increases of rumen propionate production caused by monensin.

Animals↗
PubMed1992

Enhancing potency of liposomal monensin on ricin cytotoxicity in mouse macrophage tumor cells.

Monensin, a carboxylic ionophore, which is known to disrupt intracellular trafficking of proteins was intercalated in liposomes and its effect on the stability of liposomes and cytotoxicities of ricin and Pseudomonas exotoxin A in mouse macrophage tumor cells J774A.1 was studied. Stability of liposomes containing monensin was comparable to liposomes without monensin. The cytotoxicity of ricin and Pseudomonas exotoxin A was significantly enhanced by 1nM liposomal monensin (15.7 and 3.6 fold respectively). The enhancing potency of monensin in neutral and negative vesicles was found to be similar, while it was drastically reduced in positive vesicles. The specific uptake of 125I-gelonin from neutral and negative vesicles was not significantly different, whereas from positive vesicles no uptake was observed. Serum strongly influenced the binding at 4 degrees C of positive vesicles as well as the enhancing potency of monensin in these vesicles. Monensin in neutral and negative vesicles significantly reduced the lag period of ricin action, while in positive vesicles, it had no effect. These studies clearly indicate that liposomes could be used as a delivery vehicle for monensin.

ADP Ribose Transferases↗
PubMed1992

Monensin can transport calcium across cell membranes in a sodium independent fashion in the crayfish Procambarus clarkii.

Monensin, a Na(+)-selective ionophore, enhances transmitter release when applied to crustacean and frog neuromuscular junctions. Monensin is believed to raise intracellular sodium ([Na+]i) which in turn elevates intracellular calcium ([Ca2+]i). Using the fluorescent indicator fura-2, we measured [Ca2+]i in crayfish Procambarus clarkii presynaptic terminals during monensin application in normal Ringer, zero-calcium Ringer and zero-sodium Ringer to determine if [Ca2+]i increases with monensin application and if so by what mechanism. In normal Ringer, monensin, 10 microM and 100 microM, elevated [Ca2+]i by 440 nM and 7 microM respectively. This rise in [Ca2+]i was dependent on external calcium, as [Ca2+]i did not increase in zero-calcium Ringer. However, in a zero-sodium Ringer, monensin (10 microM) elevated [Ca2+]i by 370 nM. It is important to recognize that monensin, thought to be a sodium-selective ionophore, can transport calcium across the cytoplasmic membrane in a sodium-independent manner.

Animals↗
PubMed1977

Effect of monensin on rumen metabolism in vitro.

The effect of Monensin (Rumensin, Eli Lilly & Co.) in incubations with mixed rumen microorganisms metabolizing carbohydrate or protein substrates was investigated. Monensin partly inhibited methanogenesis and increased propionate production, although the effect was not always statistically significant. Incubations with substrates specific for methane bacteria suggest that inhibition of methanogenesis by Monensin was not due to a specific toxic action on the methanogenic flora, but rather to an inhibition of hydrogen production from formate. Total and net microbial growth were considerably decreased by addition of Monensin, although the amount of substrate fermented was not altered, resulting in lowered values of microbial growth efficiency. In incubations with casein, Monensin lowered protein degradation in line with a lowered ammonia production, whereas a slight accumulation of alpha-amino nitrogen was observed. The results suggest that besides an influence of Monensin on the rumen carbohydrate fermentation pattern, another reason for the beneficial effects observed in vivo might be decreased food protein degradation in the rumen, altering the final site of protein digestion in the animal. Also, the possibility of a decrease in rumen microbial growth efficiency has to be considered when using Monensin as a food additive.

Animals↗
PubMed1992

Na+-H+ antiport and monensin effects on cytosolic pH and iodide transport in FRTL-5 rat thyroid cells.

Na+-H+ exchange may proceed via an endogenous antiporter or by exposure to the Na+ ionophore monensin. We investigated the characteristics of Na+-H+ exchange induced by antiporter stimulation and by monensin in FRTL-5 rat thyroid cells. We also examined the effects of intracellular pH (pHi) changes on iodide uptake and efflux. pHi was determined using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The resting pHi was 7.33 +/- 0.02 units; this level correlated directly with extracellular pH. In acid-loaded cells, Km for external Na+ activation of the antiporter was 7.1 mM and maximum velocity was 0.3801 delta pH units/min. Dimethylamiloride was 42 times more potent than amiloride in inhibiting sodium-dependent recovery in acidified cells. Metabolic inhibition reduced the initial alkalinization rate. Monensin increased pHi, and this response was dependent on extracellular Na+ and HCO3- but not on antiporter function. Low-dose monensin (1 microM) and 1 mM NH4Cl enhanced 125I uptake. High-dose monensin (100 microM), but not NH4Cl, reduced iodide uptake. Neither NH4Cl nor monensin altered 125I efflux. Thus FRTL-5 cells possess an amiloride-sensitive Na+-H+ exchanger, which is not essential for maintaining basal pHi but is affected by ATP depletion. Monensin also alkalinizes these cells but independently of the antiporter. Iodide uptake, but not efflux, is affected by changes in intracellular Na+ and H+ levels.

Amiloride↗
PubMed1992

Monensin inhibits the binding of 3H-flunitrazepam to and reveals the intracellular passage of GABAA/benzodiazepine receptor.

Effects of monensin were examined on the intracellular processing of the GABAA/benzodiazepine receptor (GABAA/BZDR) in neuron cultures derived from embryonic chicken brain, using 3H-flunitrazepam as the probe for the benzodiazepine modulator site on the receptor. Incubation of cultures with 0.1 or 1 microM monensin for 3 h blocked the binding of 3H-flunitrazepam by about 18%. Loss of ligand binding was due to a reduction in the number of binding sites, with no significant changes in receptor affinity. The general cellular protein synthesis and glycosylation in the cells were inhibited by 26% and 56%, respectively, in the presence of 1 microM monensin, as detected by assaying the incorporation of 3H-leucine and 3H-galactose. In contrast, an increase was observed for mannose incorporation by the cultures in the presence of the drug. Moreover, the results from in situ trypsinization of the cultures following monensin treatment showed that monensin did not alter the distribution of intracellular and surface receptors. The data suggest that monensin induces the down-regulation of GABAA/BZDR by generating abnormal glycosylation of the receptor and interrupting its transport within the Golgi apparatus, as well as from the Golgi apparatus to the intracellular pool and cell membrane. The galactosylation of receptor proteins may be important for the maturation of the receptor.

Animals↗
PubMed1979

Mechanism of monensin-induced hyperpolarization of neuroblastoma-glioma hybrid NG108-15.

Addition of the ionophore monensin to mouse neuroblastoma-rat glioma hybrid NG108-15 cells leads to a 20 to 30-mV increase in the electrical potential across the plasma membrane as shown by direct intracellular recording techniques and by distribution studies with the lipophilic cation [3H]-tetraphenylphosphonium+ (TPP+) [Lichtshtein, D., Kaback, H.R. & Blume, A.J. (1979) Proc. Natl. Acad. Sci. USA 76, 650-654]. The effect is not observed with cells suspended in high K+ medium, is dependent upon the presence of Na+ externally, and the concentration of monensin that induces half-maximal stimulation of TPP+ accumulation is approximately 1 microM. The ionophore also causes rapid influx of Na+, a transient increase in intracellular pH, and a decrease in extracellular pH, all of which are consistent with the known ability of monensin to catalyze the transmembrane exchange of H+ for Na+. Although ouabain has no immediate effect on the membrane potential, the cardiac glycoside completely blocks the increase in TPP+ accumulation observed in the presence of monensin. Thus, the hyperpolarizing effect of monensin is mediated apparently by an increase in intracellular Na+ that acts to stimulate the electrogenic activity of the Na+,K+-ATPase. Because monensin stimulates TPP+ accumulation in a number of other cultured cell lines in addition to NG108-15, the techniques described may be of general use for studying the Na+,K+ pump and its regulation in situ.

Animals↗
PubMedDate not supplied

Characterization of the coronary vasodilator and hemodynamic actions of monensin, a carboxylic ionophore.

The effects of monensin on coronary blood flow (CBF) and other hemodynamic parameters were studied in anesthetized dogs. A dose-response relationship was established, and it was found that the lowest doses of monensin (5-25 micrograms/kg) produced a dose-dependent increase (3-5x) in CBF with a concomitant decrease in total peripheral resistance (TPR). Pretreatment with diphenhydramine, atropine, indomethacin, or propranolol resulted in no reduction in peak increase in CBF or in the duration of response to monensin. However, the response was partially blocked by aminophylline. Large doses (100 and 200 micrograms/kg) produced a dose-dependent increase in cardiac output, aortic pressure, and LV dP/dt max. The duration of these effects was dose-dependent, ranging from 60 to 120 min or longer. Heart rate remained unchanged with all doses of monensin. Pretreatment with propranolol, H87/07 (a cardioselective beta-blocker), and D-600 given alone or in combination significantly reduced, but did not completely abolish, the monensin-induced increase in LV dP/dt max and aortic pressure responses. The increase in CBF in the left anterior descending coronary artery was not significantly affected by these drug pretreatments. Thus, our studies indicate that monensin has two distinct pharmacological effects--in the lower dose range (less than 25 micrograms/kg) it produces a direct relaxation of the blood vessels resulting in an increase in CBF and a decrease in TPR; at high doses (greater than 25 micrograms/kg) it increases myocardial contractility and aortic blood pressure.

Animals↗
PubMed1979

Ovine coccidiosis: comparison of the effects of monensin and aureomycin on lambs infected with coccidia.

Lambs naturally infected with mixed species of Eimeria were fed monensin (30 mg/kg of feed) and aureomycin (10 mg/kg of feed) separately and in combination. An evaluation was made of the efficacy of the treatments in the suppression of oocyst production. Comparisons were made of the parasitic damage to the intestinal surface. Performance of the lambs was measured by weight gains and feed efficiency. Monensin given separately or in combination with aureomycin produced decreases in oocyst counts that were not significantly different from those in the lambs given only aureomycin. Body weight gains and feed efficiency were best in the aureomycin-treated group, and less so in the monensin-treated and the control groups. Animals fed the monensin-aureomycin combination had the poorest weight gains and feed efficiency. Scanning electron microscopy indicated that the groups fed monensin or aureomycin separately had morphologically normal intestinal surfaces. This was in contrast to the control group and the group fed the monensin-aureomycin combination, wherein there was disrupted intestinal surface morphology.

Animals↗
PubMed1992

Effect of monensin on the sulfation of heparan sulfate proteoglycan from endothelial cells.

Monensin is a monovalent metal ionophore that affects the intracellular translocation of secretory proteins at the level of trans-Golgi cisternae. Exposure of endothelial cells to monensin results in the synthesis of heparan sulfate and chondroitin sulfate with a lower degree of sulfation. The inhibition is dose dependent and affects the ratio [35S]-sulfate/[3H]-hexosamine of heparan sulfate from both cells and medium, with no changes in their molecular weight. By the use of several degradative enzymes (heparitinases, glycuronidase, and sulfatases) the fine structure of the heparan sulfate synthesized by control and monensin-treated cells was investigated. The results have shown that among the six heparan sulfate disaccharides there is a specific decrease of the ones bearing a sulfate ester at the 6-position of the glucosamine moiety. All other biosynthetic steps were not affected by monensin. The results are indicative that monensin affects the hexosamine C-6 sulfation, and that this sterification is the last step of the heparan sulfate biosynthesis and should occur at the trans-Golgi compartment.

Animals↗
PubMed1992

Effect of monensin on the neuronal ultrastructure and endocytic pathway of macromolecules in cultured brain neurons.

1. The endocytic pathway of horseradish peroxidase (HRP) was investigated in the perikarya of cultured neurons by electron microscopy and enzyme cytochemistry. The tracer was observed in endocytic pits and vesicles, endosomes, multivesicular bodies, and lysosomes. It took approximate 15 min for the transfer of HRP from the exterior of the cell to the lysosomes. 2. Monensin induced distension of the Golgi apparatus and formation of intracellular vacuoles. When neurons were incubated with both monensin and HRP for 30 to 120 min, the number of HRP-labeled endosomes was greater than that in the monensin-free group, whereas the reverse was seen for HRP-positive lysosomes. The formation of HRP-positive lysosomes in monensin-treated cells was blocked by 47 to 79%. 3. These results indicate that the intracellular transport of the endocytosed macromolecule is pH dependent. It is also possible that the export of lysosomal enzymes is inhibited by monensin, resulting in an accumulation of the endosomes and a reduction of the lysosomes.

Animals↗
PubMed1979

[Investigations concerning the use of the rumen fermentation regulator monensin in feeding fattening bulls].

In two digestion experiments with wethers and seven feeding experiments with 198 fattening bulls with rations rich in (greater than 55% of the dry matter intake from roughage), the influence of the antibiotic monensin on the digestibility of the ration, on rumen-physiologic characteristic values and on fattening and slaughtering results was investigated. The digestibility of the organic matter and the crude nutrients was not significantly influenced by the use of monensin (20 mg/kg dry matter). The administration of 200 mg monensin per fattening bull and day resulted in an increase of the molar concentration of propionate in the rumen fluid by 9.7 mol%, the concentration of acetate and butyrate decreased by 7.3 resp. 2.8 mol %. On an average of the seven experiments the intake of dry matter was diminished by 5.1% through the use of monensin, the live weight increase remained almost unaffected (3.0% additional increase), feed and energy requirement per kg live weight were improved by 7.9%. The fattening results do not always correspond in the various experiments. The results of the dressing of the carcass, the composition of the carcass and the quality of the meat remained unaffected by the administration of monensin.

Animal Nutritional Physiological Phenomena↗
PubMed1992

Effect of monensin on fermentation of hay and wheat bran investigated by the Rumen Simulation Technique (Rusitec). 1. Basal parameters of fermentation.

An experiment was performed with Rumen Simulation Technique (Rusitec) in which the fermentation of mixed ration of hay (12.8 g/d) and wheat bran (3.2 g/d) was compared with the fermentation of the same diet in the presence of 2, 5 and 10 mg of monensin/d. The duration of the experiment was 12 days. During the first six days the fermentation conditions in Rusitec were stabilized. Monensin significantly depressed the digestibility of dry matter and fibre digestion--neutral detergent fibre (NDF), acid detergent fibre (ADF) and cellulose but only after using 2 mg monensin/d. Addition of monensin depressed the production of VFAs--acetate, butyrate and isovalerate and acetate:propionate ratio. Production of propionate was increased and production of methane and CO2 was decreased in the presence of monensin. It can be explained by changes in the production of VFAs and redistribution of metabolic hydrogen. The recovery of nitrogen was satisfactory (about 100%) and its distribution in the effluent was increased by monensin. The recovery of protein (measured as alpha--NH2 groups) and distribution of protein in the effluent and residues was increased with the increasing dose of monensin.

Animal Feed↗
PubMed1977

Effects of lasalocid and monensin in combination with roxarsone on lesion reduction and oocyst suppression in chicks infected with Eimeria tenella field isolates.

The anticoccidial activity of lasalocid, monensin, and roxarsone, alone and in combination, was evaluated against eleven Eimeria tenella recent field isolates. Lasalocid was used at 0.0075. 0.01, and 0.0125% activity drug in feed; monensin at 0.0099 and 0.0121%; and roxarsone at 0.005%. Further studies with lasalocid 0.0075%, monensin 0.0099% and roxarsone 0.005 and 0.0025% combinations were carried out against three E. tenella field isolates selected from the aforementioned strains. Lasalocid and monensin each exhibited a high degree of anticoccidial activity at all concentrations tested. Lasalocid and monensin fed in combination with roxarsone showed, in addition to high anticoccidial activity a further reduction in gross lesions and oocysts production, more pronounced at 0.005% level of roxarsone than at 0.0025%, compared to either medication alone or the roxarsone combinations. These positive effects were noted with all strains tested. The practical aspects of these findings are discussed.

Administration, Oral↗
PubMed1977

Comparison of anticoccidial efficacy, resistance and tolerance of narasin, monensin and lasalocid in chicken battery trials.

The anticoccidial efficacy, host tolerance, and projected resistance development of the three polyether antibiotics, monensin, narasin, and lasalocid were compared. The efficacy of narasin against different coccidial strains was found to parallel that of monensin in as much as strains which were refractory to monensin were also refractory to narasin. In contrast, lasalocid easily controlled some strains which were not well controlled by either narasin or monensin and failed to control one strain readily controlled by these two antibiotics. In growing chicks, lasalocid at the projected use level of 75 p.p.m. and narasin at an efficacious level of 100 p.p.m. were both better tolerated than monensin at the recommended use level of 121 p.p.m. The frequency of mutants resistant to each of these polyether compounds was found to be less than 8.6 X 10(-9) per drug sensitive oocyst for one strain of Eimeria tenella. This corresponds to less than 0.036 and 0.148 as frequent as mutants of this strain resistant to glycarbylamide or to amquinate, respectively.

Animals↗