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PubMed2003

Lithium action on adrenomedullary and adrenocortical functions and serum ionic balance in different age-groups of albino rats.

The aim of the current study was to investigate lithium action on adrenomedullary and adrenocortical functions and on serum ionic balance in rats. Three age-groups of male rats (juvenile: 30 days, adult: 100 days and aged: 3 years) were used. Each age-group of animal was exposed to short- (10 days) and long-term (25 days) treatments with lithium. Each age-group of rat received lithium at a dose 2mEq/kg body weight daily for 10 and 25 days. Each daily dose (2mEq) was divided equally into half (1 mEq) and each half was injected intraperitoneally twice (at 9 am and 9 pm) for both the durations of experiments. Control animals received physiological saline for similar duration of experiments. Thirty animals were used for each age-group and they were divided equally into 6 groups with 5 each. After termination of all the experiments rats were sacrificed and, adrenal glands were quickly dissected out and processed for epinephrine, norepinephrine and corticosterone estimations and, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSDH) activity of the adrenal gland. Blood was drawn from the heart of each rat and, serum was collected and stored at -20 degrees C until assayed for lithium, calcium, sodium, potassium and corticosterone concentrations. The findings revealed that lithium in both short- and long-term treatments was maintained well within the therapeutic range (0.3-0.8 mEq/l) in all the age-groups of rats. This alkali metal caused depletions of both epinephrine and norepinephrine concentrations from adrenal glands, and elevations of corticosterone in both adrenal and blood serum of each age-group of rat (juvenile, adult and aged). Additionally adrenal 3beta-HSDH activity was also increased in all the age-groups of rats irrespective of duration of the treatments. Short-term treatment of lithium elevated only serum K+ level in juvenile and adult rats and, Ca+ level only in adult animals. Significant elevations of serum K+ and Ca+ levels were observed following long-term treatments of lithium in all the age group of rats. No significant change in serum Na+ level was recorded after lithium treatment, irrespective of duration of treatments, in any age-group of rats. The findings suggest that lithium action, in respect of adrenomedullary and adrenocortical functions and, serum ionic balance, may not be largely related to the age-group of rats and that, lithium acts on adrenomedullary activity probably by stimulating the release mechanism of epinephrine and norepinephrine from the adrenal gland of rats, but stimulates adrenocortical activity by stimulating both synthesis (including 3 beta-HSDH activity) and release of corticorterone. Simultaneously, lithium disturbs normal ionic balance by elevating K+ and Ca+ levels in all the age-group of rats. Thus, the antimanic drug certainly disturbs both adrenomedullary and adrenocortical functions and, serum ionic balance in all the age-group of rats.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Lithium: occurrence, dietary intakes, nutritional essentiality.

Lithium is found in variable amounts in foods; primary food sources are grains and vegetables; in some areas, the drinking water also provides significant amounts of the element. Human dietary lithium intakes depend on location and the type of foods consumed and vary over a wide range. Traces of lithium were detected in human organs and fetal tissues already in the late 19th century, leading to early suggestions as to possible specific functions in the organism. However, it took another century until evidence for the essentiality of lithium became available. In studies conducted from the 1970s to the 1990s, rats and goats maintained on low-lithium rations were shown to exhibit higher mortalities as well as reproductive and behavioral abnormalities. In humans defined lithium deficiency diseases have not been characterized, but low lithium intakes from water supplies were associated with increased rates of suicides, homicides and the arrest rates for drug use and other crimes. Lithium appears to play an especially important role during the early fetal development as evidenced by the high lithium contents of the embryo during the early gestational period. The biochemical mechanisms of action of lithium appear to be multifactorial and are intercorrelated with the functions of several enzymes, hormones and vitamins, as well as with growth and transforming factors. The available experimental evidence now appears to be sufficient to accept lithium as essential; a provisional RDA for a 70 kg adult of 1,000 microg/day is suggested.

Animals↗
PubMed2000

Lithium: thyroid effects and altered renal handling.

BACKGROUND: Lithium is frequently used in the treatment of bipolar affective disorder, and is widely known to affect thyroid function, most commonly resulting in hypothyroidism and goiter. Less well-known is the association between lithium therapy and hyperthyroidism and the potential for lithium to moderate the effects of thyroxine at a cellular level. Lithium excretion relates principally to glomerular filtration rate and proximal tubule function. Thyroxine, through its effects on tubular function, alters lithium clearance such that thyroid disease may cause retention of lithium and subsequent toxicity. CASE REPORTS: We report 2 cases with lithium toxicity, both of whom were later found to be hyperthyroid. One patient developed thyroid storm following dialysis to remove lithium. The other received antithyroid medication early. Both suffered a protracted multifactorial delirium requiring intensive inpatient care. CONCLUSION: In addition to altering thyroid function, lithium therapy may mask the signs of hyperthyroidism by inducing cellular unresponsiveness. In some lithium-treated patients with biochemical hyperthyroidism, early antithyroid treatment may be appropriate. Altered renal tubular function induced by hyperthyroidism may result in retention of lithium and systemic toxicity. We propose induction of the proximal tubule sodium hydrogen antiporter as the relevant mechanism.

Adult↗
PubMed1978

Effects of bicarbonate on lithium transport in human red cells.

Lithium influx into human erythrocytes increased 12-fold, when chloride was replaced with bicarbonate in a 150 mM lithium medium (38 degrees C. pH 7.4). The increase was linearly related to both lithium- and bicarbonate concentration, and was completely eliminated by the amino reagent 4, 4'- diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). DIDS binds to an integral membrane protein (mol wt approximately 10(5) dalton) involved in anion exchange. Inhibition of both anion exchange and of bicarbonate-stimulated lithium influx was linearly related to DIDS binding. 1.1 X 10(6) DIDS molecules per cell caused complete inhibition of both processes. Both Cl- and Li+ can apparently be transported by the anion transport mechanism. The results support our previous proposal that bicarbonate-induced lithium permeability is due to transport of lithium-carbonate ion pairs (LiCO-3). DIDS-sensitive lithium influx had a high activation energy (24 kcal/mol), compatible with transport by the anion exchange mechanism. We have examined how variations of passive lithium permeability, induced by bicarbonate, affect the sodium-driven lithium counter-transport in human erythrocytes. The ability of the counter-transport system to establish a lithium gradient across the membrane decrease linearly with bicarbonate concentration in the medium. The counter-transport system was unaffected by DIDS treatement. At a plasma bicarbonate concentration of 24 mM, two-thirds of the lithium influx is mediated by the bicarbonate-stimulated pathway, and the fraction will increase significantly in metabolic alkalosis.

Bicarbonates↗
PubMed2006

A one-year open-label trial of risperidone augmentation in lithium nonresponder youth with preschool-onset bipolar disorder.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of risperidone augmentation of lithium in preschool-onset bipolar disorder (BD) among youth who insufficiently respond to lithium monotherapy. METHOD: Thirty-eight subjects between the ages of 4 and 17 years (mean age = 11.37 +/- 3.8 years) with onset of BD in preschool years (manic or mixed episode) entered this 12-month trial. All subjects received lithium monotherapy. Patients who failed to adequately respond to lithium monotherapy after 8 weeks and those who relapsed after an initial response were given risperidone augmentation for up to 11 months. The Young Mania Rating Scale (YMRS) was the primary outcome measure. Response was defined as a > or =50% decrease from baseline. Additional data were collected on diagnostic comorbidity, family history, number of hospitalizations, perinatal risk factors, history of physical or sexual abuse, Child Depression Rating Scale-Revised (CDRS-R), Clinical Global Impression (CGI) scale for BD (CGI-BP), Children's Global Assessment Scale (C-GAS), and adverse medication effects. RESULTS: Of the 38 subjects treated with lithium monotherapy, 17 responded, whereas 21 required augmentation with risperidone. Response rate in the youths treated with lithium + risperidone was 85.7% (n = 18/21). Significant predictors of inadequate response to lithium monotherapy requiring augmentation were: (1) attention-deficit/hyperactivity disorder (ADHD), (2) severity at baseline, (3) history of sexual or physical abuse, and (4) preschool age. Combination treatment of lithium and risperidone was found to be safe and well tolerated. CONCLUSIONS: A substantial proportion of youth with a history of preschool-onset BD treated with lithium were either nonresponders or partial responders. Subsequent augmentation of lithium with risperidone in these cases was well tolerated and efficacious. Potential predictors of lithium nonresponse identified in this study may guide the choice of medications earlier in the treatment process.

Adolescent↗
PubMedDate not supplied

Urinary lithium: distribution shape, reference values, and evaluation of exposure by inductively coupled plasma argon-emission spectrometry.

Inductively coupled plasma argon-emission spectrometry (ICPAES) was used to evaluate the lithium content of undiluted urine samples. The method can be performed with 1 mL of urine in a single tube using a routine ICPAES analysis for rapid and convenient assessment of lithium exposure in humans. Urine samples obtained from male workers (n = 86) who had not been exposed to lithium were used for the determination of this element by ICPAES. The obtained concentrations were corrected using a specific gravity of 1.024. The particular frequency distribution resulted in a log-normal distribution diagram for anatomical spread. Geometric mean value for urinary lithium in the nonexposed male workers was 23.5 microg/L, and the confidence interval from a log-normal distribution was 11.0 to 50.5 microg/L. Taking into consideration a short biological half-life and the massive urine excretion of lithium, urinary lithium was considered to be a useful index for monitoring of exposure. Calibration curves obtained for lithium standards had good sensitivity and linearity. Good reproducibility was assessed by lithium addition to urine samples. It was concluded that the obtained lithium reference values would be useful for the early diagnosis of lithium intoxication or in the assessment of the degree of exposure to lithium in subjects at risk.

Adult↗
PubMed1996

Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction.

The potential interaction between lithium and angiotensin-converting enzyme (ACE) inhibitors was investigated in a retrospective, longitudinal, case-control study of 20 hypertensive patients previously stabilized on lithium therapy. The objective of the study was to determine the impact of ACE inhibition on steady-state lithium concentrations and to evaluate the potential association of altered lithium clearance with age, renal function, and electrolyte balance. After initiation of the ACE inhibitor, steady-state lithium concentrations increased by 36.1%, lithium clearance was reduced by 25.5% (p < 0.0001), and four patients presented with symptoms suggestive of lithium toxicity. Significant bivariate correlations were observed for lithium clearance change and age (r = -0.45; p < 0.05) and for lithium clearance change and serum creatinine (r = -0.52; p < 0.02). Multiple regression analysis indicated that 25% of the change in lithium clearance was associated with a change in serum creatinine. This percentage was increased to 35% by the inclusion of age in the regression model. None of the other variables (age, height, weight, or change in serum sodium/potassium) made a significant contribution to this model. The authors concluded that a clinically important increase in lithium concentrations can occur in patients started on ACE inhibitor therapy. As elderly patients may be uniquely predisposed to this interaction, avoidance of this medication combination in older populations should be considered.

Aging↗
PubMed1997

Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression.

Recently, the therapeutic benefit of lithium augmentation in old age has come into question. These data, in light of the documented high incidence of side effects after lithium use in elderly patients, resulted in the design of a prospective, placebo-controlled lithium augmentation withdrawal study in elderly patients with unipolar depression. Twelve eligible geriatric patients (10 women and 2 men; mean [+/-SD] age, 76.2 +/- 5.7 years) with DSM-III-R unipolar depression receiving adjunct lithium therapy were randomized to receive continued lithium augmentation or matching placebo (withdrawal rate 150 mg/day/wk). At each clinic visit, patients were assessed for depression (Montgomery-Asberg Depression Rating Scale and Geriatric Depression Rating Scale) and lithium-induced toxicities (a 21-item side-effect checklist, renal and thyroid biochemistry). Over the 2-year observation period, the placebo group reported a decrease in composite 21-item side-effect score and specific lithium toxicities (e.g., urinary urgency, hand tremor, and renal/thyroid abnormalities). Two patients in the lithium maintenance group had a recurrence of depression at 61 and 96 weeks, respectively, immediately after a stressful life event (cerebrovascular accident [CVA] or death of spouse), and two patients had a recurrence in the placebo group at 7 and 92 weeks, respectively, without any apparent changes in life stresses. No other prognostic risk factors for recurrence were identified. Depression that recurred in patients who were receiving placebo was relatively resistant to reinstitution of lithium augmentation therapy. In otherwise stable geriatric patients with unipolar depression, the documented benefits of reduced side effects should be weighed against the risk of recurrence and subsequent lithium resistance before withdrawal of lithium augmentation.

Aged↗
PubMed1976

Lithium and the antidiuretic hormone.

The effect of lithium on the urine concentrating response to antidiuretic hormone (ADH) and the excretion of ADH has been studied in rats and man. The maximum urine osmolarity following 18 h dehydration and Pitressin (5 u) was decreased in three out of four patients during lithium treatment compared to their response to the same test in the absence of lithium. In a fifth patient, tested only during lithium treatment, the urine remained hypotonic to plasma throughout this test. Lithium increased the excretion of ADH in non-polyuric patients from 9-22 mu/24 h in the absence of lithium to 36-202 mu/24 - during lithium treatment. In four patients with lithium-induced polyuria, a diuretic acting on the distal tubules, clorexolone, reduced the polyuria. Lithium increased urine volume and the excretion of ADH in four rats receiving lithium in their diet. The response to exogenous ADH was decreased during lithium administration.

Animals↗
PubMed1995

Tenidap sodium decreases renal clearance and increases steady-state concentrations of lithium in healthy volunteers.

1. An open-label, randomised placebo-controlled study was conducted to determine the effects of tenidap sodium, a novel, cytokine-modulating anti-rheumatic drug, on the steady-state concentrations and renal clearance of lithium carbonate. 2. Eighteen healthy male volunteers received 450 mg lithium carbonate twice daily for 15 days and once on day 16. On days 9-16 subjects also received either placebo or 120 mg day-1 tenidap 2 h prior to the morning dose of lithium. 3. Following a single dose of tenidap, the renal clearance of lithium decreased significantly by 0.36 l h-1 (-23%) compared with the clearance in the placebo group, which increased by 0.18 l h-1 (+14%). Steady-state serum lithium levels increased after a single dose of tenidap by 0.069 mEq l-1 (+13%), and in the placebo group levels increased by 0.003 mEq l-1 (+0.5%); this difference was not significant. 4. After 7 days' continuous administration of tenidap, the renal clearance of lithium had decreased by 0.38 l h-1 (-25%), compared with the placebo group in which clearance had increased by 0.16 l h-1 (+12%). The steady-state serum concentration of lithium increased by 0.208 mEq l-1 (+39%) in the tenidap group and by 0.063 mEq l-1 (+10%) in the placebo group. Both of these differences were significant. 5. Two subjects who received lithium plus tenidap experienced gastrointestinal side effects, compared with none of those who were administered lithium plus placebo. 6. It is recommended that serum lithium levels be monitored when tenidap and lithium are administered concomitantly.

Adult↗
PubMed2004

Implication of serum concentration monitoring in patients with lithium intoxication.

The aim of the present study was to determine the relationships between serum lithium level, duration of lithium intoxication, severity of symptoms, and the outcome of the disease. Subjects with a serum lithium level of >/=1.2 mEq/L were included in the study. Seventy-eight patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. The demographic characteristics, clinical manifestations, and concomitant medications were recorded. Most patients with acute lithium intoxication had mild symptoms, independent of the serum lithium levels. In patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in those with acute intoxication. None of the 78 intoxicated patients in the present survey died or suffered from persistent neurological sequelae. Patients with concomitant medications, older age, and existing neurological illness may have an increased susceptibility to lithium toxicity. Regular monitoring of serum lithium level is essential for lithium-treated patients. Clinicians should pay attention to patients with pre-existing neurological illness, older age, or receiving medications that may interact with lithium.

Acute Disease↗
PubMed1997

Renal tubular lithium reabsorption in potassium-depleted rats.

1. In order to identify the tubular sites responsible for the reduced fractional excretion of lithium (FELi) during potassium depletion, free-flow micropuncture was performed in anaesthetized rats that had been fed a low potassium (low-K+) diet or a control diet for 5-6 days. FELi in low-K+ rats was 0.09 +/- 0.02, compared with 0.25 +/- 0.01 in control animals. 2. Fractional water reabsorption in proximal convoluted tubules was enhanced in potassium-depleted rats. However, fractional lithium reabsorption was not. Consequently, the tubular fluid-to-plasma lithium concentration ratio at the late proximal convoluted tubule was raised in the low-K+ animals (1.50 +/- 0.03 vs. 1.18 +/- 0.02; P < 0.001). 3. Fractional lithium delivery to the early distal tubule in low-K+ rats (0.31 +/- 0.01) was similar to that in control animals (0.30 +/- 0.02). However, whereas in control rats there was no significant difference between early and late distal tubular deliveries of lithium, late distal fractional lithium delivery in the low-K+ group was reduced markedly (to 0.10 +/- 0.01). 4. Treatment of potassium-depleted rats with amiloride had no effect on lithium reabsorption in the proximal convoluted tubule or loop of Henle. However, fractional lithium delivery to the end of the distal tubule was increased slightly (to 0.15 +/- 0.02; P < 0.05) and FELi was increased substantially (to 0.22 +/- 0.01; P < 0.001). 5. It is concluded that two factors contribute to the reduced FELi seen in potassium-depleted rats: lithium reabsorption in the superficial distal tubules and amiloride-sensitive lithium reabsorption in the collecting ducts. The data also suggest heterogeneity with respect to lithium handling between superficial and deep nephrons during potassium depletion.

Amiloride↗
PubMed1987

Changes in serum thyroxine (T4) and serum thyroid stimulating hormone (TSH) during prolonged lithium treatment.

We determined serum T4 and serum TSH serially in a cohort of patients given lithium treatment for up to 6 years; the total lithium exposure time was 409 years and the average serum lithium concentration 0.69 mmol/l. T4 showed a small and not significant fall at 6 months and returned to the pre-lithium level at 12 months. Hereafter, T4 rose gradually and after 6 years of lithium treatment T4 was 53% higher than the pre-lithium value. TSH was significantly increased at 6 and 12 months and then returned to the pre-lithium level. Eight patients required thyroxine treatment for lithium-induced hypothyroidism, i.e. 2 per 100 years of lithium exposure time. Single deviant values of T4 and TSH could be seen, followed by normal values. We suggest that TSH is determined at intervals during lithium treatment. It may be prudent to subject lithium-treated patients with abnormal thyroid values to re-examination and to abstain from starting thyroxine treatment on the basis of a single deviant value.

Follow-Up Studies↗
PubMed1989

Factors associated with discontinuation of long-term lithium treatment.

Sixty-four outpatients with major affective disorder according to DSM-III and on continuous lithium treatment for an average duration of 7.8 years were first investigated in 1980 and then followed for 7 years. The predictive value of patients' attitudes to their lithium, the prognostic influence of psychiatric status, side effects, and anamnestic and laboratory data including lithium parameters were studied. At the end of the 7-year follow-up, 61% of the patients were still on lithium maintenance treatment, 25% had discontinued lithium for clinical reasons, and 14% of the patients had died. Side effects of lithium were the major clinical reason for discontinuing treatment, while attitudes towards medication were of minor importance. Approximately one fourth of the patients who discontinued lithium were differentiated from those who continued treatment by showing a high frequency of the neurologic side effects incoordination, paresthesia, and disturbed sensibility in addition to having more severe tremor. In yet another fourth of those who discontinued for clinical reasons, lithium was stopped by the treating psychiatrist as maximal urine osmolality values were considered to be too low. These patients did not show any signs of clinically significant impairment of renal functions. Their psychiatric status was excellent in terms of extremely low CPRS scores. The patients who died during the follow-up period were differentiated from those who continued treatment by a much higher frequency of alcohol and drug abuse prior to the initiation of lithium therapy. The total number of side effects and the number of severe side effects were significantly larger than in continuers on lithium. The most common causes of death were cardiovascular disease and suicide. In no case was the cause of death attributed to lithium therapy.

Adult↗
PubMed1978

Myocardial pharmacokinetics of lithium in vitro.

The myocardial pharmacokinetics of ionised lithium were investigated in isolated, intact rabbit hearts, which were retrogradely perfused with a modified Krebs-Henseleit solution containing lithium in a concentration of 5 mM. The rate of myocardial accumulation of lithium as a function of time was indirectly followed at constant coronary flow by means of determination of the lithium content of fractional samples of the coronary output of perfusate collected during the lithium perfusion period. The disposition rate of lithium from the myocardium was similarly determined with respect to the time lapse after the perfusion had been switched over to a lithium-free liquid. The accumulation and disposition processes were found to fit bi-exponential functions, as an expression of the myocardium behaving as a two-compartment system obeying apparently first order, linear kinetics with respect to ionised lithium. A pronounced decrease of the uncomposite elimination rate constants k10 and especially k21 was observed after continuous perfusion with 5 mM lithium perfusion liquid for about 30 min. During this perfusion period at steady state, an absolute increase of myocardial lithium accumulation obviously took place. A possible correlation of these findings to the cardiac effects of lithium is discussed.

Animals↗
PubMed1980

Dissociation by lithium of hormone-induced formation of cyclic AMP and release of glycerol in isolated rat fat cells.

It has been suggested that lithium exerts some of its pharmacological actions by inhibition of the membrane-bound enzyme adenylate cyclase. However, the relationship between the lithium inhibition of adenylate cyclase and the corresponding physiological parameters, e.g. lipolysis, has not been investigated. In the present study it was found that lithium inhibited both the norepinephrine-induced accumulation of cAMP and release of glycerol in isolated rat fat cells, but only in the lower dose range of norepinephrine. At maximally effective concentrations of norepinephrine, where in the presence of 40 mM of lithium the formation of cAMP was reduced by approximally 40%, lipolysis remained unaffected. The basal content of cAMP and the basal release of glycerol were not inhibited by lithium. In addition to the inhibitory effect of lithium, lithium was found to stimulate the release of glycerol. This stimulatory effect of lithium may be explained by a prevention by lithium of the feedback inhibition by free fatty acids of adenylate cyclase and/or triglyceride lipase, since it could be avoided by increasing the concentration of bovine serum albumin in the incubation medium. It is concluded that lithium by inhibition of hormone-stimulated adenylate cyclase activity inhibits lipolysis only at submaximal hormone concentrations. This dissociation by lithium of cAMP accumulation and glycerol release may suggest that at least at high concentrations of norepinephrine cAMP-independent factors are involved in lipolysis.

Adipose Tissue↗
PubMed1998

Determination of trace lithium in human erythrocytes by electrothermal atomic-absorption spectrometry with pyrocoated graphite tubes and integrated platform.

Electrothermal graphite-furnace atomic-absorption spectroscopy with pyrocoated graphite tubes, integrated platform and matrix modification was used to determine submicromolar concentrations of trace lithium in human red blood cells. Matrix-matched samples were used to establish calibration curves for concentrations up to 0.58 microM (addition-calibration method) with satisfactory linearity (r2 > 0.99) and intra- and inter-day variability (CV < 11.4%). The median concentration of trace lithium in the cells of 40 healthy Caucasian volunteers devoid of medical or psychiatric history was 0.23 microM (inter-quartile range 0.20-0.30). The levels of trace lithium in the red blood cells correlated (r2 = 0.83) with plasma concentrations (median 0.13 microM, inter-quartile range 0.11-0.19) measured in the same blood sample. Dietary factors (e.g. consumption of lithium-containing mineral water) affected both levels. The red blood cell/plasma lithium ratio had a median value of 1.57 (inter-quartile range 1.16-2.07), implying that trace lithium is accumulated in erythrocytes. This contrasts with most reports of red blood cell/plasma ratio, measured during therapeutic treatment with lithium, for which the average value is 0.5-0.8, albeit for much higher concentrations of lithium (approx. 500-800 microM). The proposed analytical method has the required sensitivity and accuracy for determination of trace lithium in red blood cells and makes it possible to perform epidemiological studies to assess human exposure to environmental lithium in diet and beverages, and inter-individual variations in trans-membrane and renal lithium kinetics at the submicromolar level.

Bipolar Disorder↗
PubMed2004

Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria.

The use of LiCl in clinical psychiatry is routinely complicated by overt nephrogenic diabetes insipidus (NDI), the mechanism of which is incompletely understood. In vitro studies indicate that lithium can induce renal medullary interstitial cell cyclooxygenase 2 (COX2) protein expression via inhibition of glycogen synthase kinase-3beta (GSK-3beta). Both COX1 and COX2 are expressed in the kidney. Renal prostaglandins have been suggested to play an important role in lithium-induced polyuria. The present studies examined whether induction of the COX2 isoform contributes to LiCl-induced polyuria. Four days after initiation of lithium treatment in C57 BL/6J mice, urine volume increased in LiCl-treated mice by fourfold compared with controls (P < 0.0001) and was accompanied by decreased urine osmolality. This was temporally associated with increased renal COX2 protein expression and increased urinary PGE(2) excretion, whereas COX1 levels remained unchanged. COX2 inhibition significantly blunted lithium-induced polyuria (P < 0.0001) and reduced urinary PGE(2) levels. Lithium-associated polyuria was also seen in COX1-/- mice and was associated with increased urinary PGE(2). COX2 inhibition completely prevented polyuria and PGE(2) excretion in COX1-/- mice, suggesting that COX2, but not COX1, plays a critical role in lithium-induced polyuria. Lithium also induced renal medullary COX2 protein expression in congenitally polyuric antidiuretic hormone (AHD)-deficient rats, demonstrating that lithium-induced COX2 protein expression is not secondary to altered ADH levels or polyuria. Lithium also decreased renal medullary GSK-3beta activity, and this was temporally related to increased COX2 expression in the kidney from lithium-treated mice, consistent with a tonic in vivo suppression of COX2 expression by GSK-3 activity. In conclusion, these findings temporally link decreased GSK-3 activity to enhanced renal COX2 expression and COX2-derived urine PGE(2) excretion. Suppression of COX2-derived PGE(2) blunts lithium-associated polyuria.

Adjuvants, Immunologic↗