Sodium pump and Na+/H+ antiport restoration in erythrocytes from cancer patients in remission.

We previously showed that in erythrocytes from cancer patients, the sodium pump is decreased and the optimal intracellular pH for Na+/H+ antiport activity is shifted toward an acidic value. We now have studied these sodium transporters in erythrocytes from patients in remission. Moreover, we intended to explain why the transporters were impaired in erythrocytes, which have no apparent bearing on cancer tissues.

A non ouabain-like inhibitor of the sodium pump in uremic plasma ultrafiltrates and urine from healthy subjects.

A non ouabain-like inhibitor of the sodium pump was separated from uremic plasma ultrafiltrates and normal urine. Under the same chromatographic conditions (C18 column and a gradient of acetonitrile as eluant), ouabain was eluted in a fraction different from the inhibitor. Affinity chromatography based on the formation of a complex between Na,K-ATPase and the inhibitor achieved the differentiation ouabain.

Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation.

Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore.

1. Trimetazidine is an anti-ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug.

Calcium channel blockers correct in vitro mitochondrial toxicity of cellulose acetate.

We studied the action of rinse solutions from cellulose acetate hemodialyzers on isolated mitochondria. We showed that concentrates from the rinses impaired the adenosine 5'-triphosphate (ATP) synthesis as reflected by the decrease in respiration during state 3 and in P/O ratio. This impairment results from a calcium release from mitochondria that is induced by rinse solution concentrates.

In vitro mitochondrial test to assess haemodialyser biocompatibility.

Background: This paper describes an in vitro mitochondrial test to assess the biocompatibility of haemodialysers.

Methods: We tested on isolated liver mitochondria the effect of solutions obtained by an aqueous rinse of different haemodialysers (cuprophane, cellulose acetate, Hemophan, polyacrylonitrile, polymethylmethacrylate, polysulphone, polyamide). Moreover, to determine the penetration into the cell and the cytotoxicity of these solutions from haemodialysers, we examined the effect of rinse solutions on HT29-D4 cells.

Differential effects of zidovudine and zidovudine triphosphate on mitochondrial permeability transition and oxidative phosphorylation.

1. The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. 2.

[Clinical pilot study on repeated use of heparin, vancomycin, colimycine locked flush solution for central intravenous implanted catheter in oncology].

With an anti-infectious and an antithrombotic prophylaxis aims, a locked flush solution including heparin and vancomycin, was used systematically for implantable venous access system for each patient, from january to april 1995. Since the 6th of april 1995, in order to widen the antibiotic spectrum on Gram negative bacteriae, we added colimycin at the flush solution. In 1995, 342 hospitalised patients held this type of venous access and received chemotherapy and/or radiochemotherapy for cancer.

Sodium pump and Na+/H+ activities in uremic erythrocytes. A microcalorimetric and pH-metric study.

The sodium pump and Na+/H+ antiport activities in red blood cells from uremic hemodialyzed patients were measured concomitantly. The patients selected (n = 35) were normotensive and free of intercurrent illness known to affect Na transport. The Na pump activity of intact red blood cells in suspension in their own plasma was measured by flow microcalorimetry.

Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific.

Comparison of the effects of cyclosporine A and trimetazidine on Ca(2+)-dependent mitochondrial swelling.

Cyclosporine A (CsA) is a known potent inhibitor of pro-oxidant-induced mitochondrial swelling. In the present study we show that CsA's effect is only transient when the liver mitochondrial swelling in induced by Ca2+ plus tert-butylhydroperoxide (t-BH). After an initial inhibition, swelling is worsened by CsA as evidenced by an extent of mitochondrial swelling that exceeds that of the control.

A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis.

In a one-year parallel group double-blind placebo-controlled study of dextromethorphan (1.5 mg/kg) in amyotrophic lateral sclerosis, no significant differences were observed in the rate of progression (Norris scale) in comparing 24 patients randomly assigned to the dextromethorphan group and 25 patients randomly assigned to the placebo group. Of the 24 patients in the dextromethorphan group, 17 had limb onset and 7 had bulbar onset disease; average duration of disease was 12.

Trimetazidine reverses calcium accumulation and impairment of phosphorylation induced by cyclosporine A in isolated rat liver mitochondria.

When applied to rat liver mitochondria in contact with Ca++, cyclosporine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomena in a dose-dependent manner. These two effects were demonstrated in separate experiments.

Impairment of sodium pump and Na+/H+ antiport in erythrocytes isolated from cancer patients.

We sought to determine whether the impairment of sodium pump activity and Na+/H+ exchange reported in tumorigenic cells was specific to these cells or more general. Sodium pump activity and Na+/H+ exchange were measured in erythrocytes from 49 cancer patients and 51 healthy subjects. Cancer patients with a newly detected cancer or in relapse and without associated pathologies known to modify these sodium transporters were included in this study.

[Pharmacological modulation of mitochondrial oxidative phosphorylation: inhibition by cyclosporine A, restoration by trimetazidine].

When applied to a suspension of isolated mitochondria extracted from rat hepatocytes, cyclosporine A decreases ATP synthesis and induces Ca2+ accumulation. Both effects are considered as possible determinants, even partly, of renal toxicity observed with this drug. Trimetazidine antagonizes both effects at concentrations easily reached in man with therapeutic dosages.

Lack of pharmacodynamic interaction between trimetazidine and cyclosporin A in human lymphoproliferative and mouse delayed hypersensitivity response models.

The hypothesis of an interaction between trimetazidine and the immunosuppressive effect of cyclosporin A was investigated in two models: a) ex vivo, the lymphoproliferative response of normal human lymphocytes to phytohemagglutinin and a murine monoclonal antibody against the CD3 T-lymphocyte membrane complex; b) in vivo, the delayed hypersensitivity response model in mouse. The uptake of methyl-3H-thymidine was measured in both models. For the lymphoproliferative response, statistical analysis showed that there was a significant inhibitory effect of cyclosporin A on cell proliferation (P < 0.

Opposite effects of urea on hemoglobin-oxygen affinity in anemia of chronic renal failure.

We studied the action of urea on the spin-spin relaxation rate of 2,3-diphosphoglycerate (2,3-DPG) phosphorus atoms in normal and uremic erythrocytes. At concentrations from 10 to 60 mM, urea increased the relaxation rates of 2,3-DPG P-3 phosphorus atoms. This evidenced a stronger binding of 2,3-DPG to hemoglobin (Hb), suggesting that the deoxyform of Hb was stabilized.

Is the beneficial effect of calcium channel blockers against cyclosporine A toxicity related to a restoration of ATP synthesis?

ATP synthesis inhibited by Cyclosporine A is restored by calcium channel blockers: nifedipine, verapamil, bepridil, diltiazem. ATP synthesis was estimated using liver mitochondria by measuring the rate of respiration during state 3 and a measure of the yield of ATP synthesis, the P/O ratio. The study of calcium fluxes through mitochondrial membrane indicates that calcium channel blockers counteract the mitochondrial calcium storage induced by cyclosporine A.

Modulation defect of sodium pump evidenced in diabetic patients by a microcalorimetric study.

Sodium pump activity of intact erythrocytes in their own plasma was measured by microcalorimetry in 41 healthy subjects and 35 insulin-dependent diabetic patients. Results show that modulation of the sodium pump is altered in diabetic patients. Addition of insulin increases functioning of the Na(+)-K+ pump in controls but has no effect in diabetic patients.

Ascorbic acid-2-0-beta-glucuronide, a new metabolite of vitamin C identified in human urine and uremic plasma.

A new metabolite of ascorbic acid has been isolated by a multi-step chromatographic procedure both from normal human urine and uremic plasma. Nuclear Magnetic Resonance studies, and chemical and enzymic analyses indicated that the compound is a conjugated structure consisting of equimolar ascorbic and beta-D-glucuronic acids. We determined the pKa value of the ascorbic acid moiety of the compound on the basis of variations of ultraviolet absorbances as a function of pH.

Calcium anti-ionophoretic effect of some calcium channel blockers in rat liver mitochondria.

Beyond their classical action on calcium channels, some calcium channel blockers also exhibit a calcium anti-ionophoretic effect. We studied this effect on respiratory control and Ca2+ fluxes in a mitochondrial model to compare calcium antagonists chosen among three clinical classes: vascular, cardiac, and mixed effects. Synthetic calcium ionophore A23187 decreases respiratory control and modifies Ca2+ fluxes.

Effect of recombinant human erythropoietin treatment in uremic patients on oxygen affinity of hemoglobin.

Anemia of chronic renal failure is associated with a reduced affinity of hemoglobin for oxygen (Hb-O2 affinity). It has been reported that the correction of renal anemia by recombinant human erythropoietin (rhuEPO) treatment could be associated paradoxically with a further decrease in Hb-O2 affinity. We investigated changes in the compensatory mechanisms of chronic renal anemia during 25 weeks of rhuEPO treatment, in 19 chronic hemodialyzed (HD) patients.

Protective effect of some calcium antagonists against mitochondrial calcium injury.

Ischaemia induces an increase in calcium cytosolic concentration, leading to a mitochondrial Ca2+ overload. As Ca2+ uptake and storage into mitochondria are the alternative route to oxidative phosphorylation, the Ca2+ overload induces a decrease in ATP synthesis. We have tested in vitro the ability of certain calcium antagonists to restore the ATP synthesis inhibited by mitochondrial calcium overload.

Chloride dependent intracellular pH increase induced by bepridil in human red blood cells: a possible involvement in correction of ischemic acidosis.

Inhibitors of Na+/H+ exchanger are reported to exert an anti-ischemic effect. Some calcium antagonists and particularly bepridil are commonly used as anti-ischemic agents. Therefore, in this study, we test the hypothesis that protective effect against ischemia may occur at least in part through an action on Na+/H+ exchanger.