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PubMed1993

Nonselective cation channels: physiological and pharmacological modulations of channel activity.

Cation channels play a major role in fast and sustained cellular responses to hormones and neurotransmitters. They contribute to depolarization of the membrane and--in most cases--to an increase in the intracellular Ca2+ concentration. Nonselective cation channels presumably form a large family of diverse channels which are modulated by various extracellular and intracellular signals. Structure and regulation of ligand-operated and cyclic nucleotide-activated nonselective cation channels found in synapses and sensory receptor cells, respectively, are well documented; none of the structures of other cation channels are known. Except for ligand-operated and stretch-activated channels, G-proteins form the link between the involved receptors and signalling cascades stimulating nonselective cation channels. Observed in numerous cellular systems is hormonal activation of cation channels by hormones or neurotransmitters interacting with heptahelical receptors inducing a phosphoinositide breakdown (PI response); several pathways stimulated within the PI response may generate signals involved in cation channel activation. Pharmacological modifications of nonselective cation channels by inorganic and organic blockers are so far extremely limited; various blockers have been described but unfortunately lack high specificity for these channels.

Animals↗
PubMed1993

Divalent cation-dependent adhesion at the myotendinous junction: ultrastructure and mechanics of failure.

Junctional microfibrils, which span the lamina lucida of the vertebrate myotendinous junction, are thought to function in force transmission at the junction. This hypothesis has been tested by disrupting junctional microfibrils through elimination of extracellular divalent cations, and determining the effects of this treatment on the ultrastructure and mechanics of whole frog skeletal muscles passively stretched to failure. Muscles incubated in divalent cation-free solution failed exclusively in the lamina lucida of the myotendinous junction, while control muscles all failed within the muscle fibres, several millimetres away from the junction. Failure sites from divalent cation-free muscles incubated with antibodies against collagen type IV, laminin, and tenascin showed no labelling of the avulsed ends of the muscle fibres, indicating that remnants of junctional microfibrils observed on the cell surface are not composed of any of these extracellular proteins. All three proteins were present on the tendon side of the failure site, confirming that the lamina densa remains attached to the tendon. Breaking stress for control muscles was 3.47 x 10(5) N m-2, and for divalent cation-free muscles, 1.84 x 10(5) N m-2, or approximately half the control value. Breaking strain averaged 1.17 for divalent cation-free muscles and 1.39 for controls, although the difference was not significant. We conclude that junctional microfibrils are components of a divalent cation-dependent adhesion mechanism at the myotendinous junction. In addition, ultrastructural analysis of divalent cation-free fibres stretched just short of failure suggests that a second, divalent cation-independent mechanism persists along the non-junctional cell surface, and can transmit substantial passive tension from myofibrils laterally to the extracellular matrix, bypassing the failed myotendinous junction.

Animals↗
PubMed1999

Inhibition by steroids of [14C]-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells.

Effects of some naturally occurring steroids and synthetic analogues on the cation flux through the cation channel of the 5-HT3 receptor and the voltage-gated and tetrodotoxin-sensitive sodium channel were studied in N1E-115 mouse neuroblastoma cells by measuring the 2-min influx of the organic cation [14C]-guanidinium. The cation fluxes in intact cells were either induced by 2 min exposure of the cells to 5-hydroxytryptamine (5-HT, 100microM) or to veratridine (1 mM). Influx of [14C]-guanidinium through both channels was concentration-dependently inhibited by all compounds studied. The rank order of potency for inhibition of the 5-HT3 receptor-induced cation flux was clomiphene approximately/= cyproterone acetate > estradiol > progesterone approximately/= allotetrahydrodeoxycorticosterone > alfaxalone approximately/= testosterone > aldosterone > dexamethasone. With the exception of dexamethasone and testosterone, which were more potent at the voltage-dependent sodium channel, and progesterone and testosterone, which were about nearly equipotent in inhibiting both cation channels, the steroids were twofold (alfaxalone, allotetrahydrodeoxycorticosterone) to 107-fold (cyproterone acetate) more potent at the 5-HT3 receptor channel than at the voltage-gated sodium channel. The potencies of the steroids (and the synthetic analogues) for inhibition of the 5-HT3 receptor-induced [14C]-guanidinium influx were correlated with their lipophilicity (log P values). A similar correlation between log P values and pIC50 values for the steroid-induced inhibition of the veratridine-evoked cation influx through the voltage-gated sodium channel was only found when cyproterone acetate (a compound with extremely low inhibitory potency at this channel) was not included in the regression analysis. The results indicate that both the 5-HT3 receptor channel and the voltage-gated sodium channel are targets for steroids. The relationship between most of the compounds in inhibiting both cation channels and lipophilicity is compatible with a common mechanistic principle in steroid-induced inhibition of the two channels, i.e. a nonspecific hydrophobic interaction with certain membrane lipids in the neighbourhood of the two channels.

Animals↗
PubMed2004

Protamine enhances uptake of cationic liposomes in angiogenic microvessels.

INTRODUCTION: Cationic liposomes have been shown to target angiogenic endothelial cells of solid tumours. Supposing a charge-related mechanism might be responsible for liposome-endothelial interaction, we investigated the effect of intravenous pre-injection of the charged molecules protamine, a polycationic protein, and fucoidan, a polyanionic polysaccharide on the accumulation of cationic liposomes within the blood vessels of a solid tumour. MATERIALS AND METHODS: Experiments were performed using the amelanotic hamster melanoma A-Mel-3 growing in a dorsal skinfold chamber of hamsters. Accumulation of fluorescently-labelled cationic liposomes was quantified by intravital macroscopy and digital image analysis of tumour (t) and surrounding normal host tissue (n) over an observation period of 6 h. All animals received an i.v. injection of cationic liposomes. Animals of the control group were pre-treated with an i.v. injection of 0.9% saline, while animals of group 2 received positively charged protamine and animals of group 3 negatively charged fucoidan prior to liposome injection. RESULTS: In control animals i.v. injection of cationic liposomes revealed a preferential targeting of the tumour vessels, indicated by a maximal t/n ratio of 2.2 +/- 0.24 and a maximal fluorescence intensity (fmax) corresponding to the tumour of 66 +/- 12 [% standard]. While there were no significant differences of liposome accumulation within normal host tissue, accumulation of cationic liposomes within the tumour was significantly enhanced after the pre-administration of protamine (fmax: 117 +/- 12 [% standard]). The t/n ratio was significantly increased in protamine pre-treated animals (5.3 +/- 1.7) in comparison to control and fucoidan treated animals. In contrast, pre-injection of fucoidan resulted in reduced maximal fluorescence intensities in tumour (47 +/- 8 [% standard]) and normal surrounding host tissue. CONCLUSION: Pre-administration of protamine increases the accumulation of cationic liposomes in a solid tumour animal model causing an increased selectivity of cationic liposomes in targeting angiogenic microvessels.

Animals↗
PubMed1989

Role of carboxyl residues and membrane lipids in cation binding to bacteriorhodopsin.

To investigate the site specificity of cation binding to bacteriorhodopsin, carboxyl groups were chemically modified in purple membrane preparations from Halobacterium halobium. Cation binding followed by EPR and visible spectroscopy has led us to the conclusion that two cations bind to the surface regions and that at least one cation binds to carboxyl groups in the protein interior. Conformational freedom is necessary for the cooperative conversion of deionized blue species to cation-reconstituted purple species. Studies of white membranes from the JW-5 strain showed that a higher content of charged lipids results in the binding of approximately 100 more color-regulating cations and in negative cooperativity in the blue-to-purple species conversion. A greater dependence of protein structure on these bound cations suggests a role for cations in the modulation of opsin-lipid interaction.

Bacteriorhodopsins↗
PubMed1976

Kinetics of ion translocation across charged membranes mediated by a two-site transport mechanism. Effects of polyvalent cations upon rubidium uptake into yeast cells.

(1) The effect of surface charge upon the kinetics of monovalent cation translocation via a two-site mechanism is investigated theroretically. (2) According to the model dealt with, typical relations are expected for the dependence of the kinetic parameters of the translocation process upon the concentration of a polyvalent cation, differing essentially from those derived for the case in which the membrane carries no excess charge. (3) Even when a polyvalent cation does not compete with the substrate cation for binding to the translocation sites, apparently competitive inhibition may occur when the membrane is negatively charged. (4) The model is tested experimentally by studying the effects of the polyvalent cations Mg2+, Sr2+, Ca2+, Ba2+ and Al3+ upon Rb+ uptake into yeast cells at pH 4.5 A good applicability is found. (5) Equimolar concentrations of polyvalent cations reduce the rate of the Rb+ uptake into yeast cells in the order Mg2+ less than Sr2+ less than Ca2+ less than Ba2+ less than Al3+. (6) The conclusion is reached that the reduction in the rate of Rb+ uptake caused by the polyvalent cations applied results mainly from screening of the negative fixed charges on the membrane surface and binding to these negative sites rather than competition with Rb+ for the transport sites. (7) The results of our investigation indicate the affinity of the alkaline-earth cations for the negative fixed charges on the surface to the yeast cell membrane increases in the orther Mg2+ less than Sr2 less than Ca2+ less than Ba2+. (8) Probably mainly phosphoryl groups determine the net charge on the membrane of the yeast cell at a medium pH of 4.5.

Aluminum↗
PubMed1985

Differential interaction of cations with the thiamine and biotin transport proteins of Lactobacillus casei.

Lactobacillus casei cells contain separate and specific binding proteins which mediate the cellular uptake of thiamine and biotin. In buffered salt solutions, these proteins exhibit a very high affinity for their vitamin substrate. Dissociation constants (Kd values) at pH 7.5 are 0.03 and 0.15 nM for thiamine and biotin, respectively. Optimal binding of biotin requires the presence of cations. This cation dependence is substantial since the Kd for biotin is 60-fold higher in a buffer containing 0.1 mM K-Hepes, compared with a buffer composed of 50 mM K-Hepes and 5 mM MgCl2. Measurements of Kd versus cation concentration showed that Mg2+ is 300-fold more effective than K+ in promoting biotin binding. The extent of cation dependence decreases as the pH is reduced from 7.5 to 5.0, suggesting that protons can partially fulfill the cation requirement. In contrast, binding of thiamine to the thiamine transport protein shows no dependence on the ionic composition of the medium. These results suggest that the transport protein for the anionic vitamin, biotin, contains a binding site for cations. Cotransport of both the vitamin and cation into the cell might then occur during the normal transport cycle, allowing the cellular uptake of the vitamin to occur against the membrane potential. Conversely, the cationic vitamin, thiamine, does not appear to be transported into the cell as a complex with other ions.

Biotin↗
PubMed1990

Inhibition of transport system b0,+ in blastocysts by inorganic and organic cations yields insight into the structure of its amino acid receptor site.

The most conspicuous, Na(+)-independent amino acid transport process in preimplantation mouse blastocysts was provisionally designated system b0,+ because it accepts some cationic and zwitterionic amino acids about equally well as substrates. Although system b0,+ is not Na(+)-stimulated, it has not been determined if it is inhibited by Na+, or if its activity is affected by most other ions. Therefore, we measured uptake of amino acids by blastocysts in isotonic solutions of different ionic and nonionic osmolites. Na(+)-independent L-leucine uptake was unaffected by the ion concentration, but L-lysine transport was several-fold faster in isotonic solutions of non-electrolytes than in similar solutions of inorganic and organic salts or zwitterions. The Km value for 'Na(+)-independent' L-lysine transport was about 10-fold higher in isotonic salt solutions than in solutions of nonionic osmolites, whereas the Km value for L-leucine transport was about the same in either type of solution. Therefore, inorganic and organic cations and the cationic portions of zwitterions appear to compete with cationic but not zwitterionic amino acids for system b0,+ receptor sites. The cation, harmaline, was a particularly strong competitive inhibitor of 'Na(+)-independent' L-lysine uptake by system b0,+, even in isotonic salt solutions, whereas it inhibited L-leucine uptake noncompetitively. Moreover, harmaline appeared to compete with inorganic cations for the lysine receptor sites of system b0,+. Harmaline also has been found by other investigators to competitively inhibit L-lysine uptake by the Na(+)-independent system asc1 in horse erythrocytes, whereas it noncompetitively inhibits alanine uptake by the same system. Similarly, harmaline noncompetitively inhibits L-alanine uptake by the Na(+)-dependent system ASC in human erythrocytes, but it appears to compete for binding with L-alanine's cosubstrate, Na+. In addition, others have found that the positively-charged side chains of cationic amino acids seem to take the place of Na+ needed near side chains in order for zwitterionic amino acids to be transported by systems ASC and y+. We conclude that system b0,+ may be similar to systems asc1, ASC and y+, and that each of these systems may be a variant of the same ancestral transport process. We speculate that since it appears to accept a broader scope of substrates and to interact with a wider variety of cations than do systems asc1, ASC or y+, system b0,+ may more closely resemble the proposed ancestral transport process than any of the other contemporary systems.

Amino Acids↗
PubMed1995

Cation-sensitive pore formation in rehydrated erythrocytes.

Rehydration of red blood cells (RBC) in isotonic media after dehydration in hypertonic electrolyte or nonelectrolyte saline leads to their posthypertonic hemolysis (PH). Ca2+ ions at a concentration of more than 5 mM stimulated hemolysis of RBC treated by hypertonic sucrose but not NaCl if rehydration was carried out in the presence of cations. Zn2+ produced a more complex response of stimulation followed by inhibition as a concentration is increased. Mg2+, Ca2+, Zn2+, EDTA and sucrose exhibited only inhibition when added to isotonic NaCl media immediately after onset of rehydration or later on. At low ionic strength inhibition produced by divalent cations was markedly reduced and sucrose was ineffective. An equimolar concentration of EDTA abolished the inhibition of PH by Zn2+ ions if they were introduced into the isotonic media after the cells, but activated hemolysis when rehydration was carried out in the presence of ions. The same divalent cations prevented shape transformation and hemolysis induced by melittin if they interacted with the plasma membrane prior to the addition of melittin. Subsequent chelation of cations by EDTA triggers the full sequence of events characteristic to the action of melittin alone and resulted in cell spherulation followed by hemolysis. Inhibition of melittin-induced hemolysis produced by all cations was reversible because EDTA abolished the action of divalent cations and even stimulated hemolysis in isotonic sucrose. Similarities in the mode of action of divalent cations and EDTA on posthypertonic hemolysis which is attributed to endogenous stimuli and melittin-induced hemolysis as far as the exogenous agent is concerned imply that in both cases common intrinsic mechanisms are involved in the process of cation-sensitive pore formation in erythrocyte membranes, while differences indicate that more complex pores are formed during posthypertonic injury.

Cations, Divalent↗
PubMed1994

Effect of divalent cations on lipid organization of cardiolipin isolated from Escherichia coli strain AH930.

Escherichia coli strain AH930 is a lipid biosynthetic mutant, which is unable to synthesize phosphatidylethanolamine. Instead it produces large amounts of phosphatidylglycerol and cardiolipin and has an absolute requirement for certain divalent cations. Cardiolipin was isolated from this mutant strain and its interaction with divalent cations was studied by various biophysical techniques. Monolayer measurements showed that the cations decrease the molecular surface area of cardiolipin in the order Ca2+ approximately Mg2+ > Sr2+ > Ba2+. 31P-NMR and X-ray diffraction measurements demonstrated a comparable sequence for the ability of the cations to promote HII phase formation in dispersions of the E. coli cardiolipin: Ca2+ and Mg2+ induced HII phase formation at 50 degrees C, Sr2+ at 75 degrees C, while Ba2+ was found to be unable to promote HII phase formation in the temperature range measured. Furthermore, all divalent cations were found to increase the temperature at which the transition to the liquid-crystalline phase takes place, which was below 5 degrees C for the lipid in the absence of divalent cations. In the presence of Sr2+, Mg2+ and Ba2+ and at 25 degrees C two lamellar phases were observed, one corresponding to a liquid-crystalline phase, the other to either a gel or a crystalline phase. In the presence of Ca2+ at 25 degrees C and even at 45 degrees C no evidence for a liquid-crystalline phase was obtained and only a crystalline phase could be observed. The ability of the different cations to promote HII phase formation in the isolated E. coli cardiolipin was found to correlate with their ability to support growth of the mutant strain (De Chavigny, A., Heacock, P.N., Dowhan, W. (1991) J. Biol. Chem. 266, 5323-5332), suggesting that cardiolipin with divalent cations can replace the role of phosphatidylethanolamine in the mutant strain, and that this role involves the preference of these lipids for organization in non-bilayer lipid structures.

Cardiolipins↗
PubMed1985

Activation and inactivation of bovine caudate acetylcholinesterase by trivalent cations.

Kinetic analysis of the interaction of trivalent cations with mammalian brain acetylcholinesterase revealed at least three distinct concentration-dependent effects on enzyme activity. Acetylcholinesterase was purified from bovine caudate nucleus by affinity chromatography to a specific activity of 1.1 mmoles acetylthiocholine X hr-1 X (mg protein)-1. The cations studied included the chloride salts of lanthanum, terbium, yttrium and scandium in low and high ionic strength buffers (2 mM Pipes +/- 0.1 M NaCl). At low ionic strength, high affinity noncompetitive or allosteric activation was observed at very low cation concentrations (1-10 microM); at higher concentrations (50-200 microM) these cations were noncompetitive inhibitors; and at 200-500 microM they exerted a mixed competitive-noncompetitive inhibition. Activation by low cation concentrations was not evident in high ionic strength buffers, while enzyme inhibition by all the trivalent cations was similar at low and high ionic strength. Inhibition by all of the multivalent cations was fully reversed by a 10-fold excess of EDTA or by a 100-fold dilution of the inhibited enzyme. The water-soluble carboxyl group affinity reagent, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, was shown to specifically block the activating effect of the multivalent cations supporting the suggestion that the beta- or "activator" peripheral anionic sites (P1) involve a carboxyl group outside the enzyme active site.

Acetylcholinesterase↗
PubMed1988

Phosphatidylinositol kinase of bovine adrenal chromaffin granules. Modulation by hydrophilic and amphiphilic cations.

The effects of hydrophilic and amphiphilic cations on the activity of phosphatidylinositol (PI) kinase (EC 2.7.1.67) of chromaffin granule ghosts were investigated. The cations studied can be divided into two groups, i.e. (i) compounds with a biphasic response (stimulation and inhibition), and (ii) those with a selective stimulatory effect on the enzyme activity. The cationic amphiphile trifluoperazine belongs to the first group, and stimulated the enzyme activity, maximal at 80 microM (2-fold), with a progressive inhibition at higher concentrations. This biphasic response was shared by a number of structurally related cationic amphiphiles, i.e. the tricyclic antidepressants, imipramine and desipramine, the phenothiazine, chlorpromazine, the miconazole derivative, calmidazolium, the beta-adrenergic agonist, propranolol, compound 48/80, as well as by the hydrophilic cations neomycin and poly-L-lysine. On the other hand, a pure stimulatory effect was observed with the amphiphilic polypeptide mastoparan and the polycationic compound spermidine, whereas ACTH1-39 and ACTH1-24 (peptides structurally related to mastoparan) revealed a slight inhibitory effect. We conclude that all the cations tested including Mg2+, stimulate PI kinase activity rather unspecifically by binding of the positively charged groups to a membrane component, probably the PI kinase itself. This site is different from that mediating the specific inhibition by calcium (Husebye ES and Flatmark T, Biochim Biophys Acta 968: 261-265, 1988). The inhibitory effect of cationic amphiphiles is correlated to their lipid solubility, and represents a perturbation of the membrane structure, but not a solubilization of enzyme or phosphoinositide from the membrane. The inhibitory effect of hydrophilic cations is due to complexation of ATP.

1-Phosphatidylinositol 4-Kinase↗
PubMed1995

Neurotensin increases the cationic conductance of rat substantia nigra dopaminergic neurons through the inositol 1,4,5-trisphosphate-calcium pathway.

Whole-cell patch-clamp recordings were used to investigate electrophysiological effects of neurotensin on acutely isolated dopaminergic (DA) neurons of the rat substantia nigra pars compacta (SNC). During current-clamp recordings, neurotensin depolarized DA neurons and triggered action potentials. Under voltage-clamp recordings, neurotensin evoked an inward current at a holding potential of -50 mV. Neurotensin-induced inward currents reversed the direction at -5 mV and became smaller as the membrane potential was hyperpolarized from -75 mV. With potassium-free recording solutions, neurotensin evoked voltage-insensitive cationic currents. With sodium-free external solution, neurotensin also caused inward currents by reducing the inwardly rectifying potassium conductance. Neurotensin-induced inward currents mainly resulted from an increase in a non-selective cationic conductance. Neurotensin-evoked cationic currents were inhibited by the intracellular perfusion of 1 mM guanosine-5'-O-(2-thiodiphosphate). In DA neurons internally perfused with 0.5 mM guanosine-5'-O-(3-thiotriphosphate), the cationic current produced by neurotensin became irreversible. Pretreating DA neurons with 500 ng/ml pertussis toxin (PTX) did not significantly affect the ability of neurotensin to evoke cationic currents. Internal perfusion of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist, and buffering intracellular calcium with the Ca(2+)-chelator BAPTA (10 mM) suppressed neurotensin-induced cationic currents. Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), failed to prevent neurotensin from evoking cationic currents. It is concluded that PTX-insensitive G-proteins mediate neurotensin-induced enhancement of the cationic conductance of SNC DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Anions modulate cation-induced responses of single units of the frog glossopharyngeal nerve.

Fibers of the frog glossopharyngeal nerve that are sensitive to water stimulation also respond to Ca, Mg and Na salts. During stimulation with a salt, the cation and the anion are applied together and the anion could influence the response to the cation. We examined this interaction using single unit recordings at the level of fungiform papilla. Nerve impulses of large amplitude were recorded in response to the stimulation of adjacent papillae with increasing concentrations of various Ca, Mg and Na salts. For a given cation, the elicited spike frequency depended on the anion. For example, the responses of single fibers to Ca2+ concentrations above 0.1 mM were maximal with CaSO4 and minimal with Ca(SCN)2. The rank order of efficiency was CaSO4 > CaCl2 = CaBr2 = Ca(NO3)2 > Ca(SCN)2 for Ca2+ ions at 5 mM. The effects of these anions were reversed for Mg and Na salts, the rank orders being Mg(SCN)2 > Mg(NO3)2 > MgBr2 = MgCl2 > MgSO4, for Mg2+ ions at 200 mM, and NaSCN > NaI > NaNO3 > NaBr > NaCl >> NaF = Na2SO4, for Na+ ions at 500 mM. All these sequences correspond to the lyotropic rank order of the anions. In stimulation by a mixture of Ca and Na salts, which have different rank orders with respect to anions, either the response to Ca2+ ions or the response to Na+ ions could be eliminated as a result of mutual antagonism between Ca2+ and Na+ ions. In this case, the rank order of anions was dependent only on the cation that was able to exert a stimulatory effect in the mixture. Threshold concentrations for Ca, Mg and Na salts are influenced by cationic properties, but not by anionic properties. We hypothesize that anions can modulate the efficacy of cation transduction by binding to a membrane element that interacts with each of the three distinct receptors for Ca2+, Mg2+ and Na+ ions without altering the affinities of these receptors for the respective cations. The present results cannot be interpreted in terms of permeability of the apical membrane to anions and changes in surface potential on the apical membrane. The possibility is discussed that an anion-selective paracellular pathway between taste cells is responsible for the effect of anions on the cation-induced response.

Animals↗
PubMed1989

Deposition of immune complexes containing cationized antibodies in myocardial small blood vessels of mice.

Small myocardial blood vessels constitute a site for preferential deposition of preformed cationic immune complexes. This preferential deposition was demonstrated with a limited dose (100 micrograms) of cationized rabbit antibodies to human serum albumin, injected into C57B1/6J mice either alone or in the form of preformed immune complexes. Heart, kidney, liver, intestine, and skeletal muscle were examined for immune deposits by immunofluorescence microscopy. Highly cationized antibodies injected alone showed deposition in glomeruli and in the liver along the sinusoids but not in other tissues. Immune complexes containing native rabbit antibodies deposited only in liver in a Kupffer cell pattern. Moderate and highly cationized antibodies in immune complexes deposited in myocardial small blood vessels, liver, and glomeruli, but not in intestine or skeletal muscle. These complexes deposited via electrostatic interactions since unrelated polycationic molecules, protamine sulfate or cationized rabbit serum albumin, injected 1 min prior to cationic antibodies in immune complexes blocked deposition in myocardial small vessels, glomeruli, and liver. Administration of protamine or cationized rabbit serum albumin 1 min after deposition of cationized immune complexes resulted in displacement of the immune deposits in heart, kidney, and liver, but not when the injection was given 1 hr later. The presented data indicate that with passage of time the immune deposits rearrange and forces other than charge-charge interactions retain them in myocardial vessels.

Animals↗
PubMed1996

Human immunodeficiency virus type-1 (HIV-1) infection increases the sensitivity of macrophages and THP-1 cells to cytotoxicity by cationic liposomes.

Cationic liposomes may be valuable for the delivery of anti-sense oligonucleotides, ribozymes, and therapeutic genes into human immunodeficiency virus type 1 (HIV-1)-infected and uninfected cells. We evaluated the toxicity of three cationic liposomal preparations, Lipofectamine, Lipofectin, and 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE) reagent, to HIV-infected and uninfected cells. Monocyte/macrophages were infected with HIV-1BaL and treated with liposomes in medium containing 20% fetal bovine serum (FBS) for 4 h or 24 h at 37 degree C. Uninfected monocytic THP-1 cells and chronically infected THP-1/HIV-1IIIB cells were treated with phorbol 12-myristate 13-acetate (PMA) and exposed to liposomes in the presence of 10% FBS. Toxicity was evaluated by the Alamar Blue assay and viral p24 production. The toxic effect of cationic liposomes was very limited with uninfected cells, although concentrations of liposomes that were not toxic within a few days of treatment could cause toxicity at later times. In HIV-1BaL-infected macrophages, Lipofectamine (up to 8 microM) and Lipofectin (up to 40 microM) were not toxic after a 4-h treatment, while DMRIE reagent at 40 microM was toxic. While a 4-h treatment of THP-1/HIV-1IIIB cells with the cationic liposomes was not toxic, even up to 14 days post-treatment, all three cationic liposomes were toxic to cells at the highest concentration tested after a 24-h treatment. Similar results were obtained with the Alamar Blue assay, Trypan Blue exclusion and a method that enumerates nuclei. Infected cells with relatively high overall viability could be impaired in their ability to produce virions, indicating that virus production appears to be more sensitive to treatment with the cationic liposomes than cell viability. Our results indicate that HIV-infected cells are more susceptible than uninfected cells to killing by cationic liposomes. The molecular basis of this differential effect is unknown; it is proposed that alterations in cellular membranes during virus budding cause enhanced interactions between cationic liposomes and cellular membranes.

Animals↗
PubMed2006

Kinetic studies of reactions of iron(IV)-oxo porphyrin radical cations with organic reductants.

Iron(IV)-oxo porphyrin radical cations are observed intermediates in peroxidase and catalase enzymes, where they are known as Compound I species, and the putative oxidizing species in cytochrome P450 enzymes. In this work, we report kinetic studies of reactions of iron(IV)-oxo porphyrin radical cations that can be compared to reactions of other metal-oxo species. The iron(IV)-oxo radical cations studied were those produced from 5,10,15,20-tetramesitylporphryinato-iron(III) perchlorate (1), 5,10,15,20-tetramesitylporphryinato-iron(III) chloride (2), both in CH(3)CN solvent, and that from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato-iron(III) perchlorate (3) in CH(2)Cl(2) solvent. The substrates studied were alkenes and activated hydrocarbons diphenylmethane and ethylbenzene. For a given organic reductant, various iron(IV)-oxo porphyrin radical cations react in a relatively narrow kinetic range; typically the second-order rate constants vary by less than 1 order of magnitude for the oxidants studied here and the related oxidant 5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato-iron(IV)-oxo porphyrin radical cation in CH(3)CN solvent. Charge transfer in the transition states for epoxidation reactions of substituted styrenes by oxidants 1 and 2, rho(+) values of -1.9 and -0.9, respectively, mirrors results found previously for related species. Competition kinetic reactions with a catalytic amount of porphyrin iron(III) species and a terminal oxidant give relative rate constants for oxidations of competing substrates that are somewhat smaller than the ratios of absolute rate constants. Water in CH(3)CN solutions has an apparent modest stabilizing effect on oxidant 1 as indicated in slightly reduced rate constants for oxidation reactions. The iron(IV)-oxo porphyrin radical cations are orders of magnitude less reactive than porphyrin-manganese(V)-oxo cations and a corrole-iron(V)-oxo species. The small environment effects found here suggest that high energy demanding hydrocarbon oxidation reactions catalyzed by cytochrome P450 enzymes might require highly reactive iron(V)-oxo transients as oxidants instead of the more stable, isomeric iron(IV)-oxo porphyrin radical cations.

Cations↗
PubMed2006

Evaluation of novel cationic (99m)Tc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups.

This report describes the evaluation of a series of novel cationic (99m)Tc-nitrido complexes, [(99m)TcN(DTC)(PNP)]+ (DTC = crown ether-containing dithiocarbamates; PNP = bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic (99m)Tc-nitrido complexes was accomplished in two steps according to literature methods. Biodistribution studies were performed in rats. Planar images of Sprague-Dawley rats administered with 15+/-2 MBq of cationic (99m)Tc radiotracer were obtained using a PhoGama large field-of-view Anger camera. Samples from both urine and feces were analyzed by a reversed-phase radio-HPLC method. Results from biodistribution studies showed that most of the cationic (99m)Tc-nitrido complexes have a high initial heart uptake with a long myocardial retention. They also show a rapid clearance from the liver and lungs. Cationic complexes [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of (99m)Tc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of (99m)TcN-DBODC5 within the experimental error. These findings have been confirmed by the results from imaging studies. Radio-HPLC analysis of urine and feces samples indicated that there was very little metabolism of cationic (99m)Tc-nitrido complexes in rats under anesthesia. The key finding of this study is that lipophilicity remains the most important factor affecting both heart uptake and target-to-background (T/B) ratios. Crown ethers are very useful functional groups to improve the liver clearance of cationic (99m)Tc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic (99m)Tc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.

Animals↗