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PubMed1978

Myocardial effects of lithium in vitro.

The myocardial effects of increasing concentrations of ionic lithium were investigated in isolated, spontaneously beating rabbit hearts, which were retrogradely perfused with a modified Krebs-Henseleit solution containing lithium in concentration of 1, 5 or 10 mM. The following functional parameters were continuously recorded: heart rate, amplitude and rate of contraction, coronary flow, myocardial oxygen consumption and ECG. The lowest concentration of 1 mM lithium did not cause any measurable changes in these parameters. A concentration of 5 mM lithium produced a rather slowly developed increase in amplitude and rate of contraction of about 22% without any concomitant increase of oxygen consumption. A delayed increase in the oxygen consumption of about 21%, but accompanied by a significant decrease in contractility however, occurred much later in the experiments, probably as an expression of a decrease in myocardial efficiency. The highest lithium concentration produced similar effects. None of the other parameters measured were markedly influenced by lithium. The positive inotropic effect of lithium on myocardial contractility was very convincingly verified in isolated electrically stimulated rabbit papillary muscles by isometric measurements of the maximum tension produced and the rate of its development. An inhibitory influence of lithium on the positive inotropic effect of increasing frequency of stimulation was observed. Adrenergic beta-receptor blockade did not abolish the positive inotropic effect of lithium. A possible causative influence of lithium on the cellular calcium metabolism is discussed.

Adrenergic beta-Antagonists↗
PubMed1987

Effects of lithium on calmodulin-stimulated adenylate cyclase activity in cortical membranes from rat brain.

The influence of lithium on calmodulin-stimulated adenylate cyclase activity has been studied in vitro and after chronic treatment. Chronic lithium treatment decreased calcium-calmodulin-stimulated adenylate cyclase activity in rat cortical membranes, while no effect was observed on GTP-stimulated activity. Lithium in vitro inhibited adenylate cyclase activity stimulated by isoprenaline, GTP or calcium-calmodulin. Calcium-calmodulin-stimulated activity was more sensitive to lithium (2 mM) than isoprenaline- and GTP-stimulated activities (5 mM) and activities by these agents combined. Lithium had no effect on the unstimulated enzyme activity. The inhibitory effect of lithium in vitro on calcium-calmodulin-stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithium in vitro on the GTP-stimulated adenylate cyclase activity was increased by substituting manganese for magnesium in the assay media. Furthermore, the manganese-stimulated activity was also reduced by lithium. The latter effect was not observed in calmodulin-depleted membranes, but the inhibitory effect of lithium could be restored by addition of exogenous calmodulin. The present results suggest that lithium might influence the interaction of calmodulin with the enzyme and/or interfere with the divalent cation site(s) on the adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1984

Evidence for bicarbonate-dependent lithium reabsorption in dog kidneys.

To examine whether lithium is reabsorbed along a transcellular or a paracellular route, experiments were performed in anesthetized volume-expanded dogs under conditions of constant glomerular filtration rate (GFR). Quabain, in doses inhibiting about 80% of Na, K-ATPase, and ethacrynic acid, another inhibitor of transcellular NaCl reabsorption, did not inhibit lithium or bicarbonate reabsorption. Lithium reabsorption increased in proportion to plasma concentration of lithium (PLi) up to 12 mM, suggesting a passive transport of lithium. During ouabain administration acetazolamide halved bicarbonate reabsorption, the main driving force for paracellular reabsorption, and halved the reabsorption of lithium. The reabsorbate concentration of lithium, calculated from data obtained before and after acetazolamide infusion, was almost equal to PLi. Mannitol, which reduces paracellular osmotic transport without affecting bicarbonate reabsorption, reduced lithium and chloride reabsorption in the same proportion as acetazolamide (r = 0.87). Combined acetazolamide and mannitol administration reduced fractional lithium reabsorption to 0.09 +/- 0.02. These data indicate that lithium is not actively transported but reabsorbed passively along a paracellular route by osmotic forces provided by transcellular NaHCO3 reabsorption.

Acetazolamide↗
PubMed1993

Sinus node dysfunction during long-term lithium treatment.

BACKGROUND AND OBJECTIVE: Lithium has occasionally been reported to cause symptomatic sinus node bradyarrhythmias. The prevalence and mechanism of these arrhythmias during long-term treatment are unknown. The aims of this study were (a) to evaluate the systemic effects of lithium treatment on cardiac conduction in individuals who were free from cardiovascular disorders; (b) to assess the prevalence of lithium treatment in a group of patients with pacemakers; and (c) to evaluate the interaction between the parasympathetic limb of the autonomous nervous system and the sinus node cells during long-term lithium treatment. PATIENTS AND METHODS: 45 patients who had been treated with lithium for > 12 months were investigated in a long-term electrocardiography study. Only patients without cardiovascular disease, or concomitant chronotropic medication, or metabolic disorders known to cause rhythm disturbances were included. An age-stratified population was used as a reference group. 21 patients also underwent analysis of carotid sinus pressure and sinus cycle length before and after atropine to clarify whether neural mechanisms were involved. The prevalence of lithium treated patients was determined in 650 patients with pacemakers. RESULTS: (a) Signs of moderate sinus node dysfunction (sinus arrest > 1.5 s, minimum heart rate < 50 beats/min) were found in 56% and 78% respectively in the lithium-treated group compared with 30% and 30% respectively in the reference group (p < 0.01). Severe sinus node dysfunction was equally common in both groups. (b) The prevalence of chronic lithium treatment in the pacemaker population was 0.46%. (c) Sinus cycle variations were abnormal in the basal state in three (14%) patients and in 11 (52%) patients after atropine despite signs of intact and normal parasympathetic innervation. CONCLUSIONS: Depressed sinus node function was significantly more common in a lithium-treated population than in an age-stratified reference group. Clinically significant dysfunction, however, was uncommon. The effect of lithium on the sinus node seemed to be intrinsic and was not caused by increased parasympathetic tone.

Aged↗
PubMed1998

Stimulatory effect of lithium on glucose transport in rat adipocytes is not mediated by elevation of IP1.

Lithium has been shown to increase glucose uptake in skeletal muscle and adipose tissues. The therapeutic effect of lithium on bipolar disease is thought to be mediated by its inhibitory effect on myo-inositol-1-monophosphatase (IMPase). We tested the hypothesis that the stimulatory effect of lithium on glucose uptake results from inhibition of IMPase and the resultant accumulation of inositol monophosphates (IP1) by comparing the effects of lithium and a selective IMPase inhibitor, L-690,488, on isolated rat adipocytes. Insulin produced a concentration-dependent stimulation of 2-deoxy-D-[14C]glucose (2-DG) transport (10 microU/ml caused half-maximal activation). Acute exposure to lithium stimulated basal glucose transport activity in a concentration-dependent manner, with a threefold stimulation at 30 mM lithium. Lithium also potentiated insulin-stimulated 2-DG transport. Lithium produced a concomitant increase in IP1 accumulation. In contrast, L-690,488 increased IP1 to levels comparable to those of lithium without stimulatory effects on 2-DG transport. These results demonstrate that stimulatory effects of lithium on glucose transport are not mediated by the inhibition of IMPase and subsequent accumulation of IP1 in rat adipocytes.

Adipocytes↗
PubMed1994

Lithium reabsorption in perfused loops of Henle: effects of perfusion rate and bumetanide.

The contribution of the loop segments to lithium reabsorption in sodium-replete, anesthetized Sprague-Dawley rats was examined by perfusing superficial loops of Henle between late proximal convolutions and early distal tubules. Preliminary experiments in which lithium was initially present only inside or outside the perfused loop confirmed substantial permeability of one or more of the loop segments to lithium. In subsequent experiments, in which lithium was infused intravenously and included in the perfusate so that the perfusate-to-plasma lithium concentration ratio was close to that found in late proximal tubules during lithium clearance studies, lithium reabsorption was inversely related to the perfusion rate: values for fractional lithium reabsorption (FRLi) at perfusion rates of 10, 20, and 30 nl/min were 58 +/- 3, 17 +/- 2, and 2 +/- 2%, respectively. Bumetanide (10(-6) M) markedly inhibited FRLi but also reduced water reabsorption, suggesting an effect on the pars recta at this dose; 10(-7) M bumetanide, which was without effect on water reabsorption, had only a small effect on FRLi at a perfusion rate of 10 nl/min but reduced FRLi by approximately 70% at 20 nl/min. We argue that the remarkable flow dependency of lithium reabsorption, together with its bumetanide sensitivity, provides evidence for significant voltage-driven lithium reabsorption in the thick ascending limb of Henle.

Absorption↗
PubMed1978

The role of plasma volume, plasma renin and the sympathetic nervous system in the posture-induced decline in renal lithium clearance in man.

Excretion of lithium in urine was studied in 2 healthy males while recumbent and while upright, either walking or standing quietly. An oral dose of 24.3 mmol of Lit was taken as three lithium carbonate tablets 13 h before clearance tests. Renal lithium clearance decreased and lithium fractional reabsorption increased while upright. Standing immersed to the neck in water, which prevents the fall in plasma volume upon changing posture from recumbent to upright, prevented the fall in renal lithium clearance as well as the rise in lithium fractional reabsorption while upright. Oral doses of guanethidine (total dose of 200 mg) or oxprenolol (total dose of 140 mg) taken to prevent high levels of sympathetic nervous system activity and plasma renin, respectively, failed to prevent the fall in renal lithium clearance or the rise in lithium fractional reabsorption upon changing posture from recumbent to upright. The findings indicate that the fall in renal lithium clearance and the rise in lithium fractional reabsorption upon changing posture from recumbent to upright is related to the fall in plasma volume but not to high levels of sympathetic nervous system activity or plasma renin activity.

Absorption↗
PubMed1989

Electroencephalographic changes and other indices of neurotoxicity with haloperidol-lithium therapy.

This prospective study was undertaken in order to establish indices of possible neurotoxicity due to the combination of lithium with haloperidol and a combination of lithium with other neuroleptics. Twenty-one subjects who were receiving neuroleptic-lithium combination were studied. Of them, 14 had a primary affective disorder-manic phase, and 7 had schizophrenia as judged by Feighner criteria. The subjects were evaluated on clinical, neuropsychological measures and EEG at baseline and 10-14 days after addition of lithium to the neuroleptic regimen. Of 11 subjects receiving the haloperidol-lithium combination, 5 (45.4%) showed abnormal responses on EEG. Of these 5 subjects, 3 showed abnormal photic responses, and 2 showed slowing in posterior alpha activity. These photoparoxysmal and photomyoclonic responses are indicative of cerebral pathophysiology resulting from the interactive effect of the haloperidol-lithium combination. The photic and other associated EEG abnormalities reported may be the earliest indication of neurotoxicity. No significant changes were observed in the EEG in 10 subjects treated with other neuroleptic-lithium combinations. In a statistical comparison the haloperidol-lithium combination had significantly more frequent EEG changes than the combination of lithium with other neuroleptics. This study presents sufficient evidence from reported photic and other associated EEG changes to pursue further investigation of neurotoxicity due to haloperidol-lithium therapy. Such a study should employ a larger number of subjects, random assignment of subjects to treatment and control groups, and blind evaluation of data.

Adult↗
PubMed1985

Inhibitory effect on lithium on p-aminohippurate transport in rat kidney cortex in vitro.

The effect of lithium on p-aminohippurate (PAH) transport was studied using slices and basolateral membrane vesicles prepared from rat kidney cortex. The addition of lithium in concentrations ranging from 0.5 to 5 mM caused a concentration-dependent inhibition of PAH accumulation in the slices. Lithium inhibited PAH accumulation in the slices, not only during the rapid uptake period (after 10 min) but also during the approach to equilibrium (after 30 min). The effect of lithium (2 mM) in the slices was irreversible. The inhibitory effect of lithium was not the result of changes in the water distribution and the concentrations of ATP, sodium and potassium in the slices during incubation. The effect of lithium on the kinetic parameters for PAH accumulation was to decrease Vmax, while apparent Km remained constant. There was no lithium effect on the efflux of PAH from the slices back into the incubation medium, indicating that lithium inhibited PAH influx to the kidney cell. No evidence was obtained to indicate that lithium (1 mM) directly affected PAH uptake by isolated basolateral membrane vesicles. These results suggest that lithium seems to affect metabolism linked to the carriers for PAH transport other than ATP production and sodium gradient and then seems to decrease the mobility of the carriers in the membranes.

Adenosine Triphosphate↗
PubMedDate not supplied

Effects of uninephrectomy and high protein feeding on lithium-induced chronic renal failure in rats.

Rats with lithium-induced nephropathy were subjected to high protein (HP) feeding, uninephrectomy (NX) or a combination of these, in an attempt to induce glomerular hyperfiltration and further progression of renal failure. Newborn female Wistar rats were fed a lithium-containing diet (50 mmol/kg) for 8 weeks and then randomized to normal diet, HP diet (40 vs. 19%), NX or HP+NX for another 8 weeks. Corresponding non-lithium pretreated groups were generated. When comparing all lithium treated versus non-lithium-treated groups, lithium caused a reduction in glomerular filtration rate (GFR) without significant changes in effective renal plasma flow (as determined by a marker secreted into the proximal tubules) or lithium clearance. Consequently, lithium pretreatment caused a fall in filtration fraction and an increase in fractional Li excretion. Lithium also caused proteinuria and systolic hypertension in absence of glomerulosclerosis. HP failed to accentuante progression of renal failure and in fact tended to increase GFR and decrease plasma creatinine levels in lithium pretreated rats. NX caused an additive deterioration in GFR which, however, was ameliorated by HP. NX+HP caused a further rise in blood pressure in Li-pretreated rats. The results indicate that Li-induced nephropathy, even when the GFR is only modestly reduced, is associated with proteinuria and arterial systolic hypertension. In this model of chronic renal failure the decline in GFR is not accompanied by a corresponding fall in effective renal plasma flow, which may be the functional expression of the formation of nonfiltrating atubular glomeruli. The fractional reabsorption of tubular fluid by the proximal tubules is reduced, leaving the distal delivery unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Relationship between plasma, RBC, and CSF lithium concentrations in human subjects.

Simultaneous measurement of plasma, RBC, and plasma lithium concentrations took place with 17 inpatients chronically treated with lithium, at various times after the last lithium dose. RBC lithium levels were significantly higher than CSF lithium levels. Specimens drawn 10 or more hours after the last dose showed higher RBC and CSF lithium and lower plasma lithium than specimens drawn 4 or less hours after the last lithium dose. None of the lithium measurements differentiated manic-depressives from schizophrenics or schizoaffectives. Plasma, RBC, and CSF lithium all intercorrelated highly and equally.

Adult↗
PubMed1998

Lithium discontinuation and subsequent effectiveness.

OBJECTIVE: Several reports have raised concern that the discontinuation of lithium may result in treatment resistance following recurrence of affective disorder. This report explores this possibility. METHOD: The data derive from a large, naturalistic follow-up of patients with major depressive disorder or mania. Twenty-eight of the patients in the study were free of lithium and experiencing an episode of mania or schizoaffective mania diagnosed according to Research Diagnostic Criteria when they entered the study, recovered while taking lithium, later experienced a recurrence while not taking lithium, and then resumed lithium treatment. Survival analyses of time to recovery and, subsequently, time to recurrence, used continued lithium treatment as an additional censoring variable. RESULTS: Patients given lithium recovered no more quickly from their index episode than they did from their first prospectively observed episode. Moreover, lithium prophylaxis appeared no less effective after the first prospectively observed episode than after the index episode. CONCLUSIONS: These findings provide no evidence that lithium discontinuation results in treatment resistance when lithium is resumed.

Adult↗
PubMed2005

Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial.

OBJECTIVE: The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence. METHOD: Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214). RESULTS: Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg). CONCLUSIONS: These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence.

Adult↗
PubMed1996

Increased serum lithium concentration secondary to treatment with tiaprofenic acid and fosinopril.

OBJECTIVE: To describe a patient in whom the administration of tiaprofenic acid and fosinopril was associated with decreased lithium clearance, resulting in increased serum lithium concentrations. CASE SUMMARY: A woman treated with lithium for bipolar affective disorder was concurrently treated with tiaprofenic acid 200 mg tid for shoulder pain. Previously initiated treatment with fosinopril was maintained during this time. The urinary lithium clearance was decreased during this combination therapy, necessitating a reduction in the lithium dosage. DISCUSSION: Lithium is approximately 80% reabsorbed in the proximal tubule, and the addition of tiaprofenic acid may have resulted in enhanced tubular lithium reabsorption. The possible influence of concurrent fosinopril therapy may also have contributed to altered lithium pharmacokinetics in this case. CONCLUSIONS: Serum lithium concentrations should be monitored if patients taking lithium are treated with tiaprofenic acid.

Aged↗
PubMed1997

Lithium blocks cell cycle transitions in the first cell cycles of sea urchin embryos, an effect rescued by myo-inositol.

Lithium is a classical inhibitor of the phosphoinositide pathway and is teratogenic. We report the effects of lithium on the first cell cycles of sea urchin (Lytechinus pictus) embryos. Embryos cultured in 400 mM lithium chloride sea water showed marked delay to the cell cycle and a tendency to arrest prior to nuclear envelope breakdown, at metaphase and at cytokinesis. After removal of lithium, the block was reversed and embryos developed to form normal late blastulae. The lithium-induced block was also reversed by myo- but not epi-inositol, indicating that lithium was acting via the phosphoinositide pathway. Lithium microinjection before fertilization caused arrest prior to nuclear envelope breakdown at much lower concentrations (3-5 mM). Co-injection of myo-inositol prevented the block. Microinjection of 1-2 mM lithium led to block at the cleavage stage. This was also reversed by coinjection of myo-inositol. Embryos blocked by lithium microinjection proceeded rapidly into mitosis after photolysis of caged inositol 1,4,5-trisphosphate. These data demonstrate that a patent phosphoinositide signalling pathway is essential for the proper timing of cell cycle transitions and offer a possible explanation for lithium's teratogenic effects.

Animals↗
PubMed2002

Goiter in a newborn exposed to lithium in utero.

OBJECTIVE: To report a case of neonatal goiter and biological hypothyroidism in a newborn exposed to lithium in utero resulting from therapy given to the mother before and during her pregnancy. CASE SUMMARY: A male neonate, born at 37 weeks' gestation, presented with a goiter without other signs of hypothyroidism. His serum thyroid-stimulating hormone concentration was high and unbound tetrathyroxine concentration was low, indicating that chronic exposure to lithium was present. Oral thyroxine treatment was initiated when the infant was 3 days old and continued for 11 weeks. Treatment was effective in reducing the goiter and hormone concentrations, and allowing normal growth and psychomotor development during the following 3.5 months. Other drugs taken by the mother during pregnancy are not known to induce thyroid abnormalities. DISCUSSION: Lithium is used for prophylaxis and treatment of bipolar disorder. Goiter and hypothyroidism in adults have been described in patients treated with lithium; thyroid disorders are reversible if lithium is discontinued. Few cases of goiter and hypothyroidism have been reported in newborns exposed to lithium in utero. In our patient, congenital hypothyroidism required longer thyroxine treatment than lithium-induced thyroid disorders. The delay before improvement seems to be similar to that observed in adults. The Naranjo probability scale indicated that lithium was the probable cause of hypothyroidism resulting from in utero exposure. CONCLUSIONS: Lithium is a well-known goitrogenic agent. Thus, if lithium treatment needs to be continued during pregnancy in women with bipolar disorder, adequate screening for morphology by ultrasonography and systematic hormonal biological control in newborns are recommended.

Bipolar Disorder↗
PubMed2004

Lithium-mediated phosphorylation of glycogen synthase kinase-3beta involves PI3 kinase-dependent activation of protein kinase C-alpha.

Lithium, a known mood-stabilizer frequently used in treatment of bipolar disorders, is an effective glycogen synthase kinase-3beta (GSK-3beta) inhibitor. This led to the idea that GSK-3beta is an in vivo target directly inhibited by lithium. As lithium is a weak in vitro inhibitor of GSK-3beta (IC50=2 mM), however, we speculated that it inhibits GSK-3beta via an indirect, yet unknown, mechanism. The present studies show that lithium increased the phosphorylation of a key inhibitory site of GSK-3beta, serine-9 (Ser-9), in HEK293 cells and in PC12 cells. This phosphorylation was significantly reduced by protein kinase C (PKC) inhibitors GF109203X and Ro31-8425, as well as GO6976, an effective inhibitor toward conventional PKC isoforms (cPKC). Consistent with these results, lithium increased PKC-alpha activity approximately twofold in both cell lines. Because PI3 kinase is a potential upstream regulator of cPKC, its inhibition by wortmannin or LY294002 also abolished the lithium-induced serine phosphorylation of GSK-3beta in HEK293 and PC12 cells. Moreover, lithium did not activate PKB, and in addition, its activity was not dependent on the presence of medium inositol nor did it affect the autophosphorylation activity of GSK-3beta. Finally, intracerebroventricular injection of lithium increased GSK-3beta Ser-9 phosphorylation and enhanced PKC-alpha activity 1.8-fold in mouse hippocampus, confirming this lithium response in vivo. Our studies propose a new mechanism by which lithium indirectly inhibits GSK-3beta via phosphatidylinositol 3 kinase- dependent activation of PKC-alpha.

Animals↗
PubMed2006

Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity.

In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD(c14) cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.

Adenylyl Cyclases↗