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PubMed1976

Inhibition of thyroglobulin biosynthesis and degradation by excess iodide. Synergism with lithium.

Lithium and excess iodide inhibit the release of thyroid hormone from preformed stores. We thus tested the hypothesis that this was due to an inhibition of thyroglobulin breakdown. Rats were pre-treated with propyl-thiouracil (PTU) for 3 weeks in order to deplete their thyroids of thyroglobulin. While the PTU was continued, lithium chloride (0.25 mEq./100 g weight) or potassium iodide (3 mg per rat) were injected every 12 h for d days. Thereafter the thyroglobulin content in thyroid gland homogenates was measured. PTU pre-treatment lowered the thyroglobulin content from 4.21 to 0.22 mg/100 mg gland. Lithium caused a marked re-accumulation of thyroglobulin to 0.60 mg/100 mg within 3 days. While iodide alone had only a borderline effect, it markedly potentiated the action of lithium and a combination of the two drugs increased the thyroglobulin content to 1.04 mg/100 mg. Thyroxine was injected into similarly pre-treated animals to suppress secretion of thyrotrophic hormone. This markedly inhibited the proteolysis of thyroglobulin and 1.3 mg/100 mg gland accumulated after 3 days. Excess iodide, given in addition to thyroxine, decreased the amount of thyroglobulin accumulated to 0.75 mg/100 mg gland. To study whether this could be explained by an inhibitory action of iodide on thyroglobulin biosynthesis, thyroid glands from animals treated with excess iodide were incubated in vitro in the presence of 0.2 mM iodide for 3 h. Iodide decreased the incorporation of radioactive leucine into total thyroidal protein and into thyroglobulin by 25 and 35% respectively. Iodide did not inhibit protein synthesis in the kidney, liver or muscle tissue. Thus, large doses of iodide selectively inhibit thyroglobulin biosynthesis.

Animals↗

PubMed1964

INFLUENCE OF LITHIUM IONS ON THE TRANSMEMBRANE POTENTIAL AND CATION CONTENT OF CARDIAC CELLS.

The effect of lithium ions on cardiac cells was investigated by recording the changes in transmembrane potential and by following the movement of Li, Na, and K across the cell membrane. Isolated preparations of calf Purkinje fibers and cat ventricular muscles were used. Potentials were measured by intracellular microelectrodes; ion transport was estimated by flame photometric analysis and by using the radioactive isotopes of Na and K. It was shown (a) that Li ions can replace Na ions in the mechanism generating the cardiac action potential but that they also cause a marked depolarization and pronounced changes in action potential configuration; (b) that the resting permeability to Li ions is high and that these ions accumulate in the cell interior as if they were not actively pumped outwards. In Li-Tyrode [K](i) decreases markedly while the K permeability seems to be increased. In a kinetic study of net K and Na fluxes, the outward movement of each ion was found to be proportional to the second power of its intracellular concentration. The effect on the transmembrane potential is explained in terms of changes in ion movement and intracellular ion concentration.

Animals↗

PubMed2006

D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation.

Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates.

Animals↗

PubMed1985

Polyphosphoinositide metabolism in adrenal glomerulosa cells.

We examined the effect of angiotensin II, a calcium-mobilizing hormone on polyphosphoinositide metabolism in isolated rat adrenal glomerulosa cells. In cells preloaded with [32P]phosphate or with [3H]inositol, stimulation with angiotensin resulted in an approx. 40% reduction in the radioactivity of triphosphoinositide (PtdIns4,5P2) within 15 s. Only a slight increase in radioactivity was observed in the subsequent 30 min. Changes in labelling of diphosphoinositide (PtdIns4P) showed similar kinetics. Incorporation studies also showed a reduction in the pool size of [32P]PtdIns4P and [32P]PtdIns4,5P2 in response to angiotensin. Production of inositol phosphates in the absence or presence of lithium, a cation-inhibiting myo-inositol-1-phosphatase, was examined in cells preloaded with [3H]inositol. The results indicate that the production rate of inositol tris- and bisphosphate shows a manifold increase in the first seconds of stimulation and remains enhanced for at least several minutes. The present data suggest that the rate of resynthesis of polyphosphoinositides also increases shortly after the activation of PtdIns4,5P2 phosphodiesterase. Corticotropin, a hormone acting via cyclic AMP, neither affected polyphosphoinositide metabolism nor modified the action of angiotensin II.

Adrenal Glands↗

PubMed1985

Receptor-mediated inositide hydrolysis is a neuronal response: comparison of primary neuronal and glial cultures.

Cholinergic and adrenergic receptor-stimulated inositide hydrolysis was studied in neuronal and glial cells cultured from brains of 1-day-old Wistar-Kyoto rats. Incubation of the cells with [3H]inositol led to the incorporation of radioactivity specifically into inositol phospholipids. Labeling of the membrane lipids reached a maximum in 2-3 days. Receptor-stimulated breakdown of inositides was determined by following the accumulation of inositol phosphates after incubation of the labeled cells for 60 min with carbachol or norepinephrine in the presence of 10 mM lithium. Carbachol (1 mM) stimulated inositol phosphate production in neurons 30 times higher than that seen in glia. The response stimulated by norepinephrine (75 microM) was 6 times higher in neurons than glia. The response to carbachol was blocked by atropine, and the norepinephrine-induced response was inhibited by prazosin suggesting that the receptors mediating the responses were muscarinic and alpha 1-adrenergic, respectively. These results suggest that muscarinic cholinergic and alpha 1-adrenergic stimulated inositide hydrolysis is primarily a neuronal response and that this biochemical event may be important for transmembrane signaling which occurs during neurotransmission.

Animals↗

PubMed1996

The rate of transbilayer movement of erythrocyte membrane cholesterol is correlated with sodium-lithium countertransport.

Hypertension is associated with some abnormalities in cell membrane structure, including an impaired distribution of cholesterol into the monolayers of erythrocyte membrane. Transbilayer movement of membrane cholesterol modulates the formation of these structural cholesterol domains. We tested whether the rate of cholesterol movement may influence on the erythrocyte Na(+)-Li+ countertransport, that is a marker of human essential hypertension. In single regression analysis, the half-time for the decrease in specific radioactivity of cholestenone (inverse of membrane cholesterol transbilayer movement) was negatively related to the erythrocyte cation flux mediated by Na(+)-Li+ countertransport (r = -0.8983, P < 0.0001 for control subjects; r = -0.8191, P < 0.005 for normocholesterolaemic hypertensive patients; r = -0.7664, P < 0.005 for hypercholesterolaemic hypertensive patients). These data suggest that changes in the transbilayer movement of membrane cholesterol interfere with the main cation transport system which is implicated in the pathophysiology of essential hypertension. This also provides a new link between kinetic cholesterol pools and cell membrane functions.

Antiporters↗

PubMed1989

[Therapy of hyperthyroidism: indications, advantages and disadvantages of treatment of the adult and the elderly].

Hyperthyroid syndromes can be approached in three different ways: medical, surgical and radiant. The medical therapy concerning the treatment of Basedow's disease is based on the extended use of thionamide drugs, which inhibits thyroid hormone biosynthesis and allows progressive recovery to normal glandular function. Agranulocytosis has been reported as the most serious side-effect. Inorganic iodide, lithium salts, beta-adrenergic receptor blocking agents and glucocorticoids have been employed as therapeutic alternatives, though of not common clinical use. Thyroidectomy is preferentially indicated in the treatment of toxic adenoma in fertile age groups and hyperfunctional bulky goiters. The postoperative complications connected with thyroidectomy are the main disadvantages. The use of radioactive iodine is currently the therapy chosen for toxic adenoma after forty years of age and particularly for hyperthyroid syndromes of elderly people, in whom scanty compliance with therapeutic suggestions and the increased postoperative risk make it preferable to other therapies, though incidental development of hypothyroidism after radioactive iodine treatment is not an unusual consequence.

Adult↗

PubMed1976

[Effects of lithium chloride on norepinephrine and dopamine metabolism in the rat brain].

Lithium chloride (LiCl) was injected acutely (2.4 mEq/kg and 1.2mEq/kg X 2 for 3 hr, i.p.) or subacutely (2.5 mEq/kg X 2/day for 4.5 days, i.p.) in rats, and behavioral effects, steady state levels of norepinephrine (NE), dopamine (DA) and serotonin (5HT) and the metabolism of intraventricularly administered 14C-NE and 14C-DA in the brain were investigated. Acute and subacute administratin of LiCl suppressed the spontaneous motor activity, but had no effect on the levels of NE, DA and 5HT in the brain. Acute administration of LiCl did not influence the total radioactivity and the levels of NE and its metabolites in NE metabolism, while subacute administration of LiCl increased the deaminated metabolites. In DA metabolism, the deaminated metabolites were decreased by acute administration of LiCl and the O-methylated deaminated metabolites were increased by subacute administration. From these results, it is suggested that LiCl stimulates the monoamine oxidase pathway in NE and DA metabolism and the behavioral sedative effects of LiCl are attributed to the reduced functional activity of brain NE and DA neurons.

Animals↗

PubMed1973

The excess radioactivity of trypsin mixtures.

The radioactivities of mixtures of trypsin and HB(3)O(3) or LiCl have been measured and compared with the radioactivity of the constituents. No evidence was found for the production of heavy particles, as had been previously reported, neither were the excess counting rates of the mixtures over that of its constituents as large. The residual excess radioactivity was about four orders of magnitude smaller than that published, yet was still statistically significant, consisting mainly of electrons having a maximum energy less than about 400 keV. The excess radioactivity of a mixture of trypsin and LiCl had a probable half-life between 5 and 46 days. Possible mechanisms for these excesses are discussed.

Absorption↗

PubMed1985

Evidence for the formation of inositol 4-monophosphate in stimulated human platelets.

Human platelets were prelabeled with [3H] inositol and exposed to thrombin or vasopressin. The radioactive inositol monophosphates were separated by high-performance liquid chromatography and identified by cochromatography with unlabeled standard substances. Radioactive inositol 1-monophosphate (Ins 1-P) and inositol 4-monophosphate (Ins 4-P) were detected in unstimulated platelets and accumulated in response to thrombin or vasopressin. Ins 4-P as well as Ins 1-P increased after the formation of inositol 1,4-bisphosphate (Ins 1,4-P2) and inositol 1,4,5-trisphosphate (Ins 1,4,5-P3). Lithium augmented the accumulation of Ins 1-P and Ins 1,4-P2 in stimulated platelets, and also of Ins 4-P in platelets stimulated by vasopressin, but not by thrombin. The results indicate that Ins 1,4-P2 formed in stimulated platelets is partly degraded to Ins 4-P. The significance of Ins 4-P as a marker molecule for the study of inositol phosphate metabolism in stimulated cells is discussed.

Blood Platelets↗

PubMed1987

Inositol-phosphate response to oxytocin stimulation in dispersed bovine mammary cells.

The effect of oxytocin on the breakdown of phosphoinositides in dispersed bovine mammary cells was studied. In the presence of 10 mM LiCl, addition of oxytocin to dispersed bovine mammary cells in which phosphatidylinositol was pre-labelled caused a time and dose-dependent increase in radioactive inositol monophosphate incorporation. These results suggested that the breakdown of phosphoinositides may be the linkage between the oxytocin receptor and contraction of mammary myoepithelial cells.

Animals↗

PubMed1987

Cancer risk from inorganics.

Inorganic metals and minerals for which there is evidence of carcinogenicity are identified. The risk of cancer from contact with them in the work place, the general environment, and under conditions of clinical (medical) exposure is discussed. The evidence indicates that minerals and metals most often influence cancer development through their action as cocarcinogens. The relationship between the physical form of mineral fibers, smoking and carcinogenic risk is emphasized. Metals are categorized as established (As, Be, Cr, Ni), suspected (Cd, Pb) and possible carcinogens (Table 6), based on the existing in vitro, animal experimental and human epidemiological data. Cancer risk and possible modes of action of elements in each class are discussed. Views on mechanisms that may be responsible for the carcinogenicity of metals are updated and analysed. Some specific examples of cancer risks associated with the clinical use of potentially carcinogenic metals and from radioactive pharmaceuticals used in therapy and diagnosis are presented. Questions are raised as to the effectiveness of conventional dosimetry in accurately measuring risk from radiopharmaceuticals.

Animals↗

PubMed2004

Synthesis of 11C-labelled N,N'-diphenylurea and ethyl phenylcarbamate by a rhodium-promoted carbonylation via [11C]isocyanatobenzene using phenyl azide and [11C]carbon monoxide.

The reaction with phenyl azide and [11C]carbon monoxide to give N,N'-diphenyl[11C]urea and ethyl phenyl[11C]carbamate has been studied with the aim of development of a new methodology for carbonylation using [11C]carbon monoxide with high specific radioactivity. The synthesis of 11C-labelled N,N'-diphenylurea from phenyl azide and [11C]carbon monoxide, with 1,2-bis(diphenylphosphino)ethane-bound Rh(I) complex at 120 degrees C at a pressure of 35 MPa in the presence of aniline was accomplished in 82% trapping efficiency and 82% conversion yield. This approach was also useful for the synthesis of ethyl phenyl[11C]carbamate with lithium ethoxide as a nucleophilic reagent giving 90% trapping efficiency and 76% conversion yield. These reactions can be considered to proceed via a [11C]isocyanate or a [11C]isocyanate-coordinated Rh complex to give the corresponding 11C-products. This protocol provides the chemical basis for the synthesis of [11C]urea and [11C]carbamate derived from [11C]isocyanates.

Journal Article↗

PubMed1991

[The effect of combined therapy with the use of thymalin and piracetam on the level of middle-molecule peptides in the blood and on the lipid peroxidation activity in patients with diffuse toxic goiter].

The content of medium-weight molecular peptides (MMP), lipid peroxidation (LPO) activity, the profile of blood thyroid hormones, and radioactive iodine absorption by the thyroid were determined in 104 patients with light, moderate and grave diffuse toxic goiter (DTG). The content of MMP in the blood correlated with the gravity of DTG and thus may serve an additional test for its determination. Depending on the treatment 66 patients with DTG of medium gravity were distributed into 5 groups: group I included patients given mercazolyl, group II patients on lithium carbonate, group III patients who received mercazolyl and thymalin, group IV patients on mercazolyl and piracetam, and group V included patients given mercazolyl, thymalin and piracetam. A study was made of the blood content of MMP and LPO activity before therapy and after euthyroidism attainment. The treatment with the use of mercazolyl, thymalin and piracetam was found to produce a beneficial effect on the parameters under study and the clinical course of DTG.

Adjuvants, Immunologic↗

PubMed1977

Sodium efflux from voltage clamped squid giant axons.

1. The efflux of radioactive sodium was measured from squid axons during simultaneous voltage clamp experiments such that it was possible to determine the efflux of sodium associated with a measured voltage clamp current. 2. The extra efflux of sodium associated with voltage clamp pulses increased linearly with the magnitude of the depolarization above 40 mV. A 100 mV pulse of sufficient duration to produce all of the sodium current increased the rate constant of efflux by about 10(-6). 3. Application of 100 nM tetrodotoxin eliminated the sodium current and the extra efflux of radioactive sodium. 4. Cooling the axon increased the extra efflux/voltage clamp pulse slightly with a Q10 of 1/1-1. On the same axons cooling increased the integral of the sodium current with a Q10 of 1/1-4. 5. Replacing external sodium with Tris, dextrose or Mg-mannitol reduced the extra efflux of sodium by about 50%. The inward sodium current was replaced with an outward current as expected. 6. Replacing external sodium with lithium also reduced the extra efflux by about 50% but the currents seen in lithium were slightly larger than those in sodium. 7. The effect of replacing external sodium was not voltage dependent. Cooling reduced the effect so that there was less reduction of efflux on switching to Tris ASW in the cold than in the warm. 8. The extra efflux of sodium into sodium-free ASW is approximately the same as the integral of the sodium current. Adding external sodium produces a deviation from the independence principle such that there is more exchange of sodium than predicted. Such a deviation from prediction was noted by Hodgkin & Huxley (1952c). 9. Using the equations of Hodgkin & Huxley (1952c) modified to include the deviation from independence reported in this paper and its temperature dependence, one can predict the temperature dependence of the sodium efflux associated with action potentials and obtain much better agreement than is possibly without these phenomena. 10. This deviation from independence in the sodium fluxes is the type expected from some kind of mixing and binding of sodium within the membrane phase.

Animals↗

PubMed1982

The extraction, characterization and in vitro translation of RNA from adult Schistosoma mansoni.

We have extracted RNA from Schistosoma mansoni using the lithium chloride-urea method which gives good yields of undegraded RNA. The results of agarose gel electrophoresis of RNA extracted by this procedure suggest that S. mansoni has an in vivo nick in the large rRNA sub-unit. Translation of the RNA in a rabbit reticulocyte lysate gave significant incorporation of [35S]methionine into synthesized proteins. Immunoprecipitation of these translation products using a hyperimmune monkey serum sedimented between 5 and 8% of the radioactivity, which appeared to be present in approximately 13 proteins of molecular weights 18, 20, 21, 22, 23, 35, 40, 54, 60, 70, 74, 78 and 105 K Daltons.

Animals↗

PubMed1982

Calcium-independent release of GABA from isolated horizontal cells of the toad retina.

1. When toad retinae were incubated first with veratrine, then with antibodies that reacted with the outer segments of photoreceptors, and finally with complement, horizontal cells survived and most other neurones died. This preparation of 'isolated' horizontal cells accumulated radioactive GABA from the incubation medium. The subsequent release of radioactive GABA could then be measured. 2. The efflux of GABA was increased by exposure to an elevated potassium concentration or added glutamate. Both procedures are known to depolarize horizontal cells. 3. GABA in the external medium also increased the efflux of GABA. 4. The increase in GABA efflux produced by an elevated potassium concentration was unaffected with calcium in the external medium was replaced with cobalt and when sodium was replaced with choline or lithium. 5. The increase in GABA efflux produced by glutamate was unaffected when calcium was replaced with cobalt and when sodium was replaced with lithium, but was inhibited when sodium was replaced with choline. 6. The increase in GABA efflux produced by external GABA was unaffected when calcium was replaced with cobalt but required sodium. Neither choline nor lithium would substitute for sodium. 7. An increase in GABA efflux was accompanied by an increase in sodium efflux. 8. After a high concentration of GABA (2-20 mM) had produced a maximal increase in GABA efflux, the addition of glutamate produced no further effect. Conversely, after a high concentration of glutamate (2-20 mM) had produced a maximal increase in efflux, the addition of external GABA produced only a small further increase. These and the preceding results could occur if GABA release were mediated by a carrier system which could be activated by either depolarization or homoexchange.

Animals↗

PubMed1992

Lithium treatment of affective disorders: effects of lithium on the inositol phospholipid and cyclic AMP signalling pathways.

The effects of lithium (Li+) on the adenylyl cyclase and inositol phospholipid receptor signalling pathways were compared directly in noradrenergic and carbachol stimulated rat brain cortical tissue slices. Li+ was a comparatively weak inhibitor of noradrenaline-stimulated cyclic AMP accumulation with an IC50 of approx. 20 mM. By contrast, half-maximal effects of Li+ on inositol monophosphate (InsP) accumulation in [3H]inositol labelled tissue slices occurred at about 1 mM. A similar IC50 for Li+ of about 1 mM was also obtained for noradrenaline-stimulated accumulation of CMP-phosphatidate (CMPPA), a sensitive indicator of intracellular inositol depletion, in tissue slices that had been prelabelled with [3H]cytidine. The effect of myo-inositol (inositol) depletion on the prolonged activity of phosphoinositidase C (PIC) was examined in carbachol-stimulated cortical slices using a novel mass assay for InsP. Exposure to a maximal dose of carbachol for 30 min in the presence of 5 mM Li+ caused a 10-fold increase in the level of radioactivity associated with the InsP fraction, but only a 2-fold increase in InsP mass. During prolonged incubations in the presence of both carbachol and Li+ the accumulation of InsP mass was enhanced if 30 mM inositol was included in the medium. The results are compatible with the inositol depletion hypothesis of Li+ action but do not support the concept that adenylyl cyclase or guanine nucleotide dependent proteins represent therapeutically relevant targets of this drug.

Animals↗