Alterations of lithium clearance in rats by different modes of lithium administration

This study examines the effects of acute versus dietary lithium administration on proximal tubular fluid output (Vprox) and sodium clearance in 6 groups of unrestrained, conscious rats. Vprox was estimated on the basis of the renal lithium clearance. The aim was to find the mode of lithium administration which least influences the proximal and distal reabsorption of sodium. The lithium doses used resulted in serum lithium concentrations between 0.2 and 0.3 mmol/l with no difference between the groups. Acute intravenous lithium administration increased lithium clearance by 40% and sodium clearance by 109%. Administration by gastric tube increased lithium clearance by 22% and sodium clearance by 78% in comparison to dietary administration of lithium. Potassium excretion did not change by acute lithium administration. The data presented indicate that prior to measurements of lithium clearance, lithium should be administered in the diet for 2 days, since acute lithium administration, intravenously or by gastric tube, causes great changes in renal tubular reabsorption.     

Molecular effects of lithium

Bipolar affective disorder is a common, severe, chronic, and often life-threatening illness, associated with other medical and psychiatric conditions (i.e., co-morbidity). The treatment of this devastating disorder was revolutionized by the discovery of lithium's antimanic effects over fifty years ago. Recent molecular and cellular biological studies have identified a number of unexpected targets for this monovalent cation, notably glycogen synthase kinase-3 and neurotrophic signaling cascades. These findings are leading to a reconceptualization of the biological underpinnings of bipolar disorder and are resulting in considerable interest in utilizing lithium for the treatment of certain neurodegenerative disorders. We review recent insights into lithium's actions including its direct inhibitory actions on inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphosphatase, bisphosphate nucleotidase, and phosphoglucomutase enzymes. We also discuss lithium's intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium's actions may lead to the strategic development of improved therapeutics for the treatment of bipolar disorder.     

Sensitivity of yeasts to lithium

A wide range of tolerance to Li⁺ has been found among 12 different yeasts. Concentrations that do not allow long-term growth also arrest growth of an actively growing culture within 2–5 h. At the same concentrations protein and RNA synthesis are inhibited with little or no lag period (<50 min) but respiration is not affected at these concentrations. Lower concentrations that do not inhibit growth, may impair sporulation. For given extracellular conditions, intracellular Li⁺ concentrations are lower in the more tolerant yeast strains.     

Monitoring of lithium levels in human serum after therapy with lithium preparations by capillary isotachophoresis

An isotachophoretic method for the evaluation of the level of lithium salts in serum samples was optimized. Use of operating systems containing polyethylene glycol permitted the separation of cationically migrating components from Li (i.e., Na, K and Ca). The pretreatment of serum samples involves only appropriate dilution with demineralized water depending on the concentration of the major components such as sodium. The lithium levels were studied both in model samples and serum from patients treated with lithium preparations.     

Dorsalization of mesoderm induction by lithium

Lithium dorsalizes the body plan of Xenopus embryos when administered at the 32-cell stage (K.R. Kao and R.P. Elinson, 1988, Dev. Biol. 127, 64-77). In this paper, we have attempted to determine the effects of lithium on mesoderm induction, in order to localize the target of action of lithium. In the 32-cell embryo, the vegetal-most tier 4 cells are able to induce dorsal development in the overlying, equatorial tier 3 cells (R.L. Gimlich and J.C. Gerhart, 1984, Dev. Biol. 104, 117-130). Our experiments show that microinjection of lithium into either tier 3 or tier 4 cells of ultraviolet-irradiated, dorsoanterior-deficient embryos rescues normal development. Lineage tracer studies show that only tier 3-injected cells contribute progeny to dorsal axial structures while tier 4-injected cells contribute progeny to endoderm. Sandwich explants between animal caps and ventral vegetal cells cause induction of large amounts of muscle in the explants if either caps or vegetal cells are pretreated with lithium. Similarly, fibroblast growth factor-mediated mesoderm induction is also modified by lithium so that muscle is induced instead of ventral mesoderm. We conclude that lithium dorsalizes the response of animal cells to mesoderm induction signals, while not acting directly as a mesoderm inducer itself. The target of action of lithium is likely the third tier of cells of the 32-cell embryo.     

Perturbations of iodine metabolism by lithium

A kinetic study of the effects of lithium on iodine metabolism in hyperthyroidism is reviewed. The analysis, carried out in collaboration with Mones Berman, disclosed several unexpected findings. In addition to the inhibition of thyroid iodine release predicted by animal studies, an apparent decrease in extrathyroidal iodine disappearance was observed. This was confirmed by a direct study of the metabolic clearance of labeled thyroxine in hyperthyroid subjects. In euthyroid subjects, lithium did not alter thyroxine disappearance. Also unexpectedly, the lithium-induced perturbations did not promptly return to the control state after the serum lithium level had become undetectable. This suggested a delayed release of lithium from extravascular pools, a phenomenon later described in bone. These findings demonstrated the power of kinetic modeling when used as an analytical tool.     

Binding of lithium diiodosalicylate to glycophorin

Glycophorin was purified from human erythrocyte ghosts by the lithium diiodosalicylate -phenol procedure utilizing 125I-labeled lithium diiodosalicylate. The glycophorin preparation was found to contain 8.9 +/- 2.1 mol lithium diiodosalicylate per mol glycophorin. This bound lithium diiodosalicylate cannot be removed by extensive washings with a variety of polar organic solvents nor by treatment with the detergent, sodium deoxycholate. Further, the hydrophobic peptide produced from glycophorin by trypsin digestion contained 3.4 mol lithium diiodosalicylate per mol peptide.