Li-treated Rats Research Articles

Tissue-specific protective properties of lithium: comparison of rat kidney, erythrocytes and brain.

Lithium (Li) represents a first choice mood stabilizer for bipolar disorder (BD). Despite extensive clinical use, questions regarding its mechanism of action and pathological mechanism of renal function impairment by Li remain open. The present study aimed to improve our knowledge in this area paying special attention to the relationship between the length of Li action, lipid peroxidation (LP), and Na+/K+-ATPase properties. The effects of therapeutic Li doses, administered daily to male Wistar rats for 1 (acute), 7 (short term) and 28 days (chronic), were studied. For this purpose, Na+/K+-ATPase activity measurements, [3H]ouabain binding and immunoblot analysis of α-Na+/K+-ATPase were performed. Li-induced LP was evaluated by determining the malondialdehyde concentration by HPLC. Sleep deprivation (SD) was used as an experimental approach to model the manic phase of BD. Results obtained from the kidney were compared to those obtained from erythrocytes and different brain regions in the same tested animals. Whereas treatment with therapeutic Li concentration did not bring any LP damage nor significant changes of Na+/K+-ATPase expression and [3H]ouabain binding in the kidney, it conferred strong protection against this type of damage in the forebrain cortex. Importantly, the observed changes in erythrocytes indicated changes in forebrain cortices. Thus, different resistance to SD-induced changes of LP and Na+/K+-ATPase was detected in the kidney, erythrocytes and the brain of Li-treated rats. Our study revealed the tissue-specific protective properties of Li against LP and Na+/K+-ATPase regulation.

Effects of Chronic and Acute Lithium Treatment on the Long-term Potentiation and Spatial Memory in Adult Rats.

ObjectiveAlthough, accumulating evidence is delineating a neuroprotective and neurotrophic role for lithium (Li), inconsistent findings have also been reported in human studies especially. Moreover, the effects of Li infusion into the hippocampus are still unknown. The aims of this work were (a) to assess whether basal synaptic activity and long-term potentiation (LTP) in the hippocampus are different in regard to intrahippocampal Li infusion; (b) to assess spatial learning and memory in rats chronically treated with LiCO3 in the Morris water maze.MethodsField potentials were recorded form the dentate gyrus, stimulating perforant pathways, in rats chronically (20 mg/kg for 40 days) or acutely treated with LiCO3 and their corresponding control rats. In addition, performance of rats in a Morris water maze was measured to link behaviour of rats to electrophysiological findings.ResultsLiCO3 infusion into the hippocampus resulted in enhanced LTP, especially in the late phases, but attenuated LTP was observed in rats chronically treated with Li as compared to controls. Li-treated rats equally performed a spatial learning task, but did spend less time in target quadrant than saline-treated rats in Morris water maze.ConclusionDespite most data suggest that Li always yields neuroprotective effects against neuropathological conditions; we concluded that a 40-day treatment of Li disrupts hippocampal synaptic plasticity underlying memory processes, and that these effects of prolonged treatment are not associated with its direct chemical effect, but are likely to be associated with the molecular actions of Li at genetic levels, because its short-term effect preserves synaptic plasticity.

The investigation of the possible protective influence of selenium on antioxidant barrier in heart of rats exposed to lithium.

Selenium is an essential element possessing antioxidant properties and the treatment with it has displayed protective effects against toxicity of different substances occurring in the environment and food as well as against the side effects of some drugs. Lithium is used in medicine although numerous side effects can occur during therapy, including disturbances of the heart. For these reasons studies to find protective adjuvants have been performed. In the current study the possibility of selenium (as sodium selenite) application as a protective adjuvant in lithium treatment was studied. Male Wistar rats were treated: control - with saline; Li-group - with Li2CO3 (2.7 mg Li/kg b.w.); Se-group - with Na2SeO3 (0.5 mg Se/kg b.w.); Li+Se-group simultaneously with Li2CO3 and Na2SeO3 (2.7 mg Li/kg b.w. and 0.5 mg Se/kg b.w., respectively) by a stomach tube for a period of three weeks, once a day. In heart homogenate activities of antioxidant enzymes - catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), concentrations of low-molecular-weight antioxidants - ascorbic acid (AA) and reduced glutathione (GSH) as well as total antioxidant status (TAS) values were determined. GPx/SOD and CAT/SOD ratios were evaluated. In comparison with control selenium caused no significant changes of the studied parameters except for GPx, whereas lithium slightly disturbed TAS and markedly GPx, CAT and CAT/SOD ratio. In Li-treated rats co-administration of selenium displayed tendency towards restoring the impaired parameters. The results suggest that research on selenium application as an adjuvant in lithium therapy is worthy to be continued.

Effect of sodium selenite on chosen anti- and pro-oxidative parameters in rats treated with lithium: A pilot study

BackgroundSelenium is an essential element of antioxidant properties. Lithium is widely used in medicine but its administration can cause numerous side effects including oxidative stress. The present study aimed at evaluating if sodium selenite could influence chosen anti- and pro-oxidant parameters in rats treated with lithium. MethodsThe experiment was performed on four groups of Wistar rats: I (control) – treated with saline; II (Li) – treated with lithium (2.7mgLi/kg b.w. as Li2CO3), III (Se) – treated with selenium (0.5mgSe/kg b.w. as Na2SeO3), IV (Li+Se) – treated with Li2CO3 and Na2SeO3 together at the same doses as in group II and III, respectively. All treatments were performed by stomach tube for three weeks in form of water solutions. The following anti- and pro-oxidant parameters: total antioxidant status (TAS) value, catalase (CAT) activity, concentrations of ascorbic acid (AA) and malonyldialdehyde (MDA) in plasma as well as whole blood superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured. ResultsSelenium given alone markedly enhanced whole blood GPx and diminished plasma CAT vs. control. Lithium significantly decreased plasma CAT and slightly increased AA vs. control. Selenium co-administration restored these parameters to the values observed in control animals. Furthermore, selenium co-administration significantly increased GPx in Li-treated rats. All other parameters (TAS, SOD and MDA) were not affected by lithium and/or selenium. ConclusionFurther research seems to be warranted to decide if application of selenium as an adjuvant in lithium therapy is worth considering.

Lithium treatment induces a marked proliferation of primarily principal cells in rat kidney inner medullary collecting duct

Lithium (Li) treatment for 4 wk has previously been shown to increase the fraction of intercalated cells in parallel with a decrease in the fraction of principal cells in the kidney collecting duct (Christensen BM, Marples D, Kim YH, Wang W, Frøkiaer J, and Nielsen S. Am J Physiol Cell Physiol 286: C952-C964, 2004; Kim YH, Kwon TH, Christensen BM, Nielsen J, Wall SM, Madsen KM, Frøkiaer J, and Nielsen S. Am J Physiol Renal Physiol 285: F1244-F1257, 2003). To study how early this fractional change starts, the origin of the cells and the possible mechanism behind the changes, we did time course studies in rats subjected to different durations of Li treatment (i.e., for 4, 10, and 15 days). Increased urine output was already observed at day 4 of Li treatment with decreased AQP2 levels although not statistically significant. At days 10 and 15, both a significant polyuria and downregulation in AQP2 expression were observed. At day 10, the density of H+-ATPase-positive cells was increased in the IMCD of Li-treated rats and this was further pronounced at day 15. Some of the H+-ATPase-positive cells did not costain with Cl-/HCO3- exchanger AE1, indicating that they were not fully differentiated to type A IC. By double labeling for either H+-ATPase and proliferating-cell nuclear antigen (PCNA) or for AQP4 and PCNA, we found that proliferation mainly occurred in proximal IMCD cells at day 4 and it increased toward the middle part of the IMCD in response to prolonged Li treatment. Most cells expressing PCNA were stained with AQP4 but not with H+-ATPase. Triple-labeling for H+-ATPase, AQP4, and PCNA showed a subset of cells negative for all three proteins or only positive for PCNA. In contrast, a 4-wk recovery period after 4 wk of Li treatment reversed the enhanced proliferative rate to the control levels. In conclusion, the Li-induced increase in the density of intercalated cells is associated with a high proliferative rate of principal cells in the IM-1 and IM-2 rather than a selective proliferation of intercalated cells as expected. This is likely to contribute to the remodeling of the collecting duct after Li treatment.

Lithium-induced renal toxicity in rats: Protection by a novel antioxidant caffeic acid phenethyl ester

Lithium carbonate used in the long-term treatment of manic-depressive illness has been reported to lead to progressive renal impairment in rats and humans. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygene species mediated oxidative stress in ischemia-reperfusion and toxic injuries. The beneficial effect CAPE on lithium-induced nephrotoxicity has not been reported yet. The purpose of this study was to examine a possible renoprotective effect of CAPE against lithium-induced nephrotoxicity in a rat model. Twenty-two adult male rats were randomly divided into three experimental groups, as follows: control group, lithium-treated group (Li), and lithium plus CAPE-treated group (Li+CAPE). Li were treated intraperitoneally (i.p.) with 25 mg/kg Li2CO3 solution in 0.9% NaCl twice daily for 4 weeks. CAPE was co-administered i.p. with a dose of 10 microM/kg/day for 4 weeks. Serum Li, blood urea nitrogen and plasma creatinine, urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury), and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in Li-treated rats. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Serum Li levels were found high in the Li and Li+CAPE groups. In Li-administrated rats, urinary NAG and renal MDA levels were increased according to control and Li+CAPE groups (p < 0.05). CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD, CAT and GSH-Px activities were decreased in Li-administrated animals; CAPE caused a significant increase in the activities of these antioxidant enzymes. In conclusion, CAPE treatment has a protective effect against Li-induced renal tubular damage and oxidative stress in a rat model.

Activation of hypothalamic neuronal nitric oxide synthase in lithium-induced diabetes insipidus rats.

The expression of the neuronal nitric oxide synthase (nNOS) gene in the paraventricular (PVN) and supraoptic nuclei (SON) in rats with lithium (Li)-induced polyuria was examined by using in situ hybridization histochemistry. The state of the thyroid axis in these rats was also examined by in situ hybridization histochemistry for thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) mRNAs and radioimmunoassay for circulating thyroid hormones. Adult male Wistar rats consuming a diet that contained LiCl (60 mmol/kg) for 4 weeks developed remarkable polyuria. The urine in the Li-treated rats was hypotonic and had a large volume and low ionic concentration. The nNOS mRNA in the PVN and SON was significantly increased in the Li-treated rats in comparison with that in control. The increased levels of the nNOS mRNA in the PVN and SON were confirmed by NADPH-diaphorase histochemical staining. There were no differences of TRH mRNA in the PVN, TSH mRNA in the anterior pituitary and plasma concentrations of free T3 and free T4 between Li-treated rats and control rats. These results suggest that Li-induced diabetes insipidus may activate nNOS in the PVN and SON without change of the thyroid axis.

Altered expression of renal AQPs and Na(+) transporters in rats with lithium-induced NDI.

Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H exchanger (NHE3), type 2 Na-Pi cotransporter (NaPi-2), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), and thiazide-sensitive Na-Cl cotransporter (TSC) were examined in rats treated with Li orally for 4 wk: protocol 1, high doses of Li (high Na(+) intake), and protocol 2, low doses of Li (identical food and normal Na(+) intake in Li-treated and control rats). Both protocols resulted in severe polyuria. Semiquantitative immunoblotting revealed that whole kidney abundance of AQP2 was dramatically reduced to 6% (protocol 1) and 27% (protocol 2) of control levels. In contrast, the abundance of AQP1 was not decreased. Immunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked increase in urinary Na(+) excretion in both protocols. However, the expression of several major Na(+) transporters in the proximal tubule, loop of Henle, and distal convoluted tubule was unchanged in protocol 2, whereas in protocol 1 significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 expression was associated with chronic Li treatment. In conclusion, severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria. In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na(+) transporters do not participate in the development of Li-induced polyuria.

Glomerular structure in lithium-induced chronic renal failure in rats.

The effects of long-term lithium administration on glomerular structure and intervention with angiotensin converting enzyme inhibitor (ACEI) were studied in rats. Male Wistar rats were fed a lithium-containing diet (Li) or control diet (C) for 16 weeks postnatally. Li-treated rats developed renal failure, hypertension and proteinuria. During the subsequent 24 weeks, subgroups were treated with ACEI. The kidneys were fixed by perfusion, and tissue blocks were serially cut for estimation of glomerular volume and glomerular characteristics by light microscopy. Mesangial and mesangial matrix volume fractions, surface density of capillary walls, basement membrane thickness and foot process width (FPW) were measured by electron microscopy. Glomerular volume was decreased in Li-rats, with increased intra-individual variation. In all Li-rats, some glomeruli (mean 27%) were abnormal, with severe changes in only three rats. Ultrastructural parameters obtained by systematic sampling of three glomeruli in each rat showed no differences among groups. Among Li-treated animals there was a significant correlation between FPW and albumin excretion per unit filtration surface, and between filtration surface per glomerulus and inulin clearance. In conclusion, long-term lithium administration to newborn rats caused marked changes in glomerular volume which were not associated with measurable changes in structural parameters. No effect of ACEI-treatment was detectable.

Upregulation of the expression of vasopressin gene in the paraventricular and supraoptic nuclei of the lithium-induced diabetes insipidus rat

The expression of arginine vasopressin (AVP) gene in the paraventricular (PVN) and supraoptic nuclei (SON) was investigated in rats with lithium (Li)-induced polyuria, using in situ hybridization histochemistry and radioimmunoassay. The male Wistar rats consuming a diet that contained LiCl (60 mmol/kg) for 4 weeks developed marked polyuria. The Li-treated rats produced a large volume of hypotonic urine with low ionic concentrations. Plasma sodium concentrations were found to be slightly increased in the Li-treated rats compared with those in controls. Plasma concentration of AVP and transcripts of AVP gene in the PVN and SON were significantly increased in the Li-treated rats compared with controls. These results suggest that dehydration and/or the activation of visceral afferent inputs may contribute to the elevation of plasma AVP and the upregulation of AVP gene expression in the PVN and the SON of the Li-induced diabetes insipidus rat.

Mechanism of lithium-induced polyuria in the rat

While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in the isolated rat papillary collecting duct have suggested that the defect may be due to a circulating factor that inhibits the action of arginine vasopressin (AVP). Since Li-treatment can produce a form of hyperparathyroidism and parathyroid hormone (PTH) can act as a partial agonist to AVP, in vivo and in vitro studies were performed on rats made polyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-treatment for three weeks produced an increase in PTH (194 +/- 20 compared with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an increase in the plasma calcium concentration (2.38 +/- 0.05 compared with 2.25 +/- 0.04 mmol/liter; P < 0.05). Clearance studies were performed on water loaded Li-treated and control rats, and the defect in urine concentration was only observed with a low physiological concentration of AVP (10 mU/kg body wt over 5 min). Maximal urine osmolality was 328 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. There was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papillary solute concentrations were unchanged. When Li-treated rats had been parathyroidectomized (PTX), a significant difference in urine concentration with the low AVP concentration could not be demonstrated when compared to non-PTX control rats. In the isolated papillary collecting duct preparation a medium was used that contained fresh plasma from Li-treated or control rats, both intact and PTX. Experiments using plasma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 microU/ml) compared to 52.6 +/- 9.0% in control rats (P < 0.01). However, when plasma from Li-treated PTX rats was used, the AVP induced increase in water permeability (54.7 +/- 11.2%) was not significantly different from that observed in PTX control rats. These studies show that the NDI-like defect in Li-treatment is small and easily overcome by higher concentrations of AVP and suggests that the concentration defect is at least in part due to increased circulating levels of PTH acting as a partial agonist to AVP and thereby inhibiting its hydroosmotic action.

Behavioral evidence for the existence of two pools of cellular inositol

Lithium reduces brain inositol levels by inhibiting inositol monophosphatase. In a previous study it was found that administration of pilocarpine to Li-treated rats causes limbic seizure behavior which can be reversed by i.c.v. myo-inositol but not chiro-inositol, suggesting that this behavior is related to inositol depletion in the PI cycle. Hyponatremia can lower brain inositol and hypernatremia can raise brain inositol. We now report that induction of low brain inositol by hyponatremia followed by pilocarpine did not cause limbic seizures. Induction of high brain inositol using hypernatremia followed by Li-pilocarpine administration did not reverse limbic seizures. These data support the concept that inositol available for Pl synthesis and inositol for osmotic function are sequestered in different cellular pools.

Effects of acute and chronic lithium treatment on amphetamine-induced dopamine increase in the nucleus accumbens and prefrontal cortex in rats as studied by microdialysis.

The effects of acute and chronic administration of lithium (Li) on the basal levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA), and the amphetamine-induced DA increase were assessed in the Nucleus Accumbens (NAC) and Prefrontal Cortex (PFC) by brain dialysis in freely-moving rats. Acute Li (2 meq/L) was locally administered by reverse dialysis. Chronic Li (2 meq/kg) was intragastrically administered for 14 days. No effect was observed after acute Li administration. However, after chronic Li administration, the basal levels of DOPAC and the amphetamine-induced DA increase in the NAC were significantly higher in the Li-treated rats than in the saline-treated controls. In the PFC, while the amphetamine-induced DA increase was not affected by chronic Li, the basal levels of DA and DOPAC were significantly decreased after Li administration. The effects of chronic Li in the NAC could be due to increased synthesis and/or decreased release of DA, whereas in the PFC the effects could be due to a decreased synthesis of DA. The absence of effects of acute Li administration is in agreement with the therapeutic inefficacy of the acute use of the cation. The changes observed after chronic treatment in the NAC and the PFC could be related to the effects of Li on mood disorders and cognitive functions, respectively.

Blood-brain barrier transfer of l-Trp and α-MTrp in Li-treated rats

Blood-brain barrier (BBB) transport for l-Trp and α-methyl- l-tryptophan was evaluated in Li-treated rats. Five different brain areas as well as left to right differences were examined. No left to right difference in the PS product was observed. Lithium treatment had a significant effect on the plasma concentration of Val, Leu and Ile but no effect on plasma total or free Trp. The ratio of plasma Trp to the sum of Leu, Val, Ile, Phe, Met and Tyr is increased in the Li-treated rats but not significantly. However, the ratio of Trp/(Val + Leu + Ile) is significantly increased in the Li-treated rats. The K m apparent ( K m app) for the BBB Trp transport is significantly decreased (affinity of the carrier for Trp is increased) in the Li-treated rats. A decrease in the K m app is one of the possible factors responsible for an increase in the brain Trp concentration and subsequent increase in the brain serotonin synthesis in Li-treated rats.

Influence of chronic lithium treatment on urinary amount of furosemide in rats.

The present study was undertaken to examine whether the urinary amount of furosemide is influenced by chronic lithium treatment. LiCl at 2 mEq/kg/day in 1 ml vehicle (5% glucose solution) or 1 ml of vehicle alone was injected intraperitoneally for 8 days into Wistar rats. On day 8, 30 mg/kg of furosemide in 3% body weight of 1% NaCl was given orally, and urine was collected for 6 hr after dosage. The urinary amount of furosemide in the Li-treated rats was significantly lower than that in the control animals [Li group (n = 12): 514 +/- 75 (mean +/- S.E.) vs. control group (n = 12): 916 +/- 85 micrograms/kg/6 hr, P less than 0.01]. This finding indicates that pharmacokinetic alterations of furosemide might occur during chronic treatment with lithium.

Influence of repeated administration of lithium on urinary excretion of prostaglandins in rats.

The present study was undertaken to examine whether urinary excretions of prostaglandins increase by repeated administration of a non-toxic dose of lithium. Our previous study demonstrated that 2 mEq/kg/day of lithium chloride (LiCl) is not a toxic dose; and therefore, this dose of LiCl in 1 ml vehicle (5% glucose solution) or 1 ml of vehicle alone was injected intraperitoneally for 7 days into Wistar rats. On day 7, 3% body weight of 1% NaCl solution was given orally; and urine for the determination of PGE2 and 6-keto-PGF1 alpha, a metabolite of PGI2, was collected for 6 hr after dosage. Thereafter, blood samples for measuring plasma renin activity (PRA) were obtained. The urinary amounts of PGE2 and 6-keto-PGF1 alpha in the Li-treated rats were significantly greater than those in the control animals. The values of PRA did not significantly differ between the two groups of rats. These findings indicate that the production of prostaglandins, including those of PGE2 and PGI2, are enhanced during repeated administration of a non-toxic dose of lithium. The enhanced production of prostaglandins might not be mediated through the activated renin-angiotensin system.

Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain

Rats were given chronically i.p. imipramine (20 mg/kg), LiCl (1 mg/kg) or both drugs to examine the effects of lithium (Li) on the alterations of imipramine pharmcokinetics in the whole brain and on the imipramine-related changes of norepinephrine (NE) and serotonin (5-HT) levels in the brain. When rats were given Li for 3 days, followed by a single injection of imipramine, the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat, although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats. In rats receiving both drugs for 10 days, the steady state levels of imipramine and desipramine in the brain were the same as those in the vehicle-treated rats but the steady state level of desipramine was reached earlier with Li treatments presumably because of the enhanced demethylation of imipramine. Consequently, the desipramine-dependent alterations of NE and 3-methoxy-4-hydroxyphenylglycol levels in the brain appeared to be induced earlier and more markedly when Li was given simultaneously. As the 5-hydroxyindole acetic acid (5-HIAA) levels were elevated in the brains of Li-treated rats and reduced in brains of imipramine-treated rats as compared with the level in vehicle-treated rats, the 5-HIAA level in rats receiving both drugs was equivalent to that in vehicle-treated rats.

Effects of chronic dietary lithium on phosphatidylinositol pathway in heart and arteries of DOCA-salt hypertensive rats.

The sensitivity of the phosphatidylinositol (PI) pathway was evaluated in slices of atria (A), ventricles (V), and mesenteric artery (MA) in normotensive (NT) and DOCA-salt hypertensive (DOCA-HT) rats. During norepinephrine (NE) activation, the PI reactivity was two to three times greater in A, V, and MA of HT rats compared to NT rats. The long-term (2 weeks) administration of dietary lithium (Li) reduced the activation of PI by NE in left A and right V but caused no changes in MA of HT rats. The Li-treated hypertensive rats were also characterized by a lower systolic blood pressure and a lower ratio of ventricular weight/body weight. Plasma epinephrine (E) levels that were higher in HT rats were normalized in DOCA-HT + Li-treated rats, while the NE levels remained elevated in the DOCA-HT + Li group.

Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7 +/- 0.09 mM (mean +/- SEM; n = 36). Li-treated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex--43%; medulla--64%; papilla--74%). Plasma urea was significantly (P less than 0.001) lower in Li-treated rats (5.4 +/- 0.2 mM) compared with controls (6.8 +/- 0.3 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (delta = -60%) reduced. Also, the cAMP accumulation in MCT and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Li-treated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (delta approximately equal to -30%) reduced, while the activity of cAMP phosphodiesterase (cAMP-PDIE) in the same segment showed no significant difference from the controls. Also, the content of ATP in MCT microdissected from Li-treated rats and incubated in vitro did not differ from controls. The rate of [14C]succinate oxidation to 14CO2 in MAL was inhibited (-77%) by 1 mM furosemide, which indicates that this metabolic process is coupled with NaCl cotransport in MAL. The rate of (14)CO(2) production from [14C]succinate in MAL was not significantly different between control and Li-treated rats. In MCT of control rats, the rate of [14C]succinate oxidation was approximately 3 times lower than in MAL. The rate of (14)CO(2) production from [(14)C]succinate in MCT of Li-treated rats was significantly (delta +33%) higher than in MCT dissected from control rats. Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules. On the other hand, NaCI reabsorption in MAL is apparently not affected by chronic Li treatment.

Effects of Indomethacin on Renal Concentrating Capacity in Lithium-Treated Rats

An investigation was carried out to determine whether or not the administration of indomethacin to Li-treated rats would raise PLi2, and whether or not there would be any change in the type or severity of Li-induced renal functional abnormalities. It was found that indomethacin increased PLi, apparently by decreasing CLi. Umax, already reduced by Li, was further impaired by the additional administration of indomethacin. The Li-induced impairment of TcH2O was not worsened by added indomethacin, but a wide variance of the data might have masked any effect. Significant inverse correlations were found between Umax and PLi and between maximum TcH2O and PLi, suggesting that the indomethacin-induced impairment in renal concentrating capacity is attributable to the increased PLi.