Dietary potassium effects on lithium concentration and toxicity in hamsters

Dietary Potassium Effects on Lithium Concentration and Toxicity in Hamsters Harry Klemfuss

Lithium can be toxic in rodents and human patients at concentrations within the therapeutic range for treatment of affective disorders. Diet containing supplemental potassium reduced lithium-induced weight loss in hamsters following daily injections of 3 mmol LiCl/kg for 7-10 days. Potassium supplementation also decreased lithium concentrations in peripheral tissues, but not in brain, after repeated lithium administration. Repeated lithium injection lowered the concentration of potassium in peripheral tissues, but tissue potassium was not restored by dietary potassium supplementation. Toxic effects of single injections of l - l Ommol LiCl/kg were unaffected by dietary potassium. Lithium concentrations in plasma, brain, or peripheral tissues 6-hr after injection of 5 mmol LiCbrkg were also not altered by potassium diet. These data suggest that interactions between lithium and potassium diet differ in peripheral tissues compared to the central nervous system, and after acute versus chronic lithium administration.

Key Words: Lithium, potassium, toxicity, weight, side effects Introduction Lithium concentrations in the therapeutic range (0.6 to 1.2 mmol Li/L plasma) often produce polyuria and thirst, fine tremor, and gastrointestinal disturbances in patients undergoing treatment for affective disorders (Jefferson et al 1987). With plasma concentrations exceeding 2 mmol/L, neurological signs such as coarse tremor, lethargy, and seizures may progress to coma and death (Jefferson et a11987; Schou 1958). Comparable toxic effects are seen in rodents at the same lithium concentrations (Klemfuss and Kripke 1987,1989; Klemfuss et al 1992). Animal studies have shown that the toxic effects of chronic lithium treatment can be ameliorated by adding potassium to the diet (Olesen et al 1975; Klemfuss and Kripke 1987,1989). Furthermore, a central nervous system Fromthe VeteransAffairsMedical Center, San Diego, and Departmentof Psychiatry, Universityof California, San Diego, CA. Address reprint requests to: Harry Klemfuss,PhD, Research Service-151, Veterans AffairsMedical Center, 3350 La Jolla Village Drive, San Diego, CA 92161. Received January 26, 1994; revised May 13, 1994.

© 1995 Society of Biological Psychiatry

action of lithium, delay of circadian rhythmicity, was unaffected by dietary potassium treatment sufficient to prevent toxic effects in rats and hamsters (Klemfuss and Kripke 1987,1989). In human patients treated with lithium for bipolar affective disorder, addition of only 16 to 40 mmol potassium to the customary daily intake reduced tremor and edema (Cummings et al 1988), polyuria and thirst (Tripuraneni 1990), and cardiac repolarization delay (Kast 1991). No change in renal lithium clearance was found in normal subjects given dietary potassium in the normal intake range of 40-160 mmol/day (Hla-Yee-Yee et al 1990), and potassium supplementation apparently did not alter plasma lithium concentration or lithium's therapeutic action (Kast 1991; Cummings et a11988). Based on these reports, dietary potassium augmentation has been proposed as a potential treatment for patients experiencing undesirable side effects of chronic lithium therapy (Klemfuss 1992; Jefferson 1992; Martin 1993). It is not known how dietary potassium prevents lithium toxicity without interfering with central actions. A simple 0006-3223/95/$09.50 SSDI 0006-3223(94)0015 I-R

Lithium-Potassium Interaction

hypothesis, originally proposed in 1957, suggested that potassium and lithium cations compete for occupancy within cells (Coats et al 1957). The present study tests an extension of that hypothesis, proposing that dietary potassium supplementation lowers lithium concentration in peripheral tissues without affecting lithium in the brain. Coats and colleagues reported several instances in which oral or intravenous potassium loading apparently reversed lithium toxicity, and proposed that potassium could be a specific treatment for acute lithium intoxication (Coats et al 1957). Although this proposal has never been fully tested (Jefferson 1992), potassium is not currently used in the treatment of acute lithium intoxication except to treat concurrent hypokalemia. The demonstrated protective effect of dietary potassium in chronic lithium therapy leads us to reexamine the possibility that supplementary potassium might reduce acute lithium toxicity as well.

Methods and Materials Adult Syrian golden hamsters (Sasco, Omaha, NE) weighing 100-130 g were housed singly in plastic cages, with lights on from 6 AM to 8 PM, and were randomly assigned to one of two diets: either a control rodent diet containing 171 mmol potassium and 80 mmol sodium per kilogram of diet (diet TD86299 from Teklad, Madison, WI) or a high-potassium diet containing 1104 mmol potassium/kg of diet (TD85191), as previously described (Klemfuss and Kripke 1989). Food and tap water were available ad libitum throughout each experiment.

Toxicity Experiment Six male and 6 female hamsters were randomly assigned to each diet for at least 2 weeks before injections. Between 7 and 8 AM, each hamster was weighed and injected intraperitoneally (IP) with 1 ml/kg of LiC1 (1, 3 or 5 mmol/ml) or NaC1 (3 mmol/ml) dissolved in deionized water, using a 25 p~l Hamilton syringe. Appearance, body weight, and cumulative water intake of each hamster were recorded 1, 3, and 7 days after the injection. Allowing at least 2 weeks between injections for full recovery of body weight and water balance, each hamster was injected with each of the four treatments (0, 1, 3, and 5 mmol LiC1/kg) in a sequence selected randomly before the first injection. Because dietary potassium treatment did not alter the effects of single lithium injections, the same hamsters were used for repeated lithium injections to reduce the number of animals required. Each hamster was injected once daily with 3 mmol LiC1/kg every morning between 7 and 8 AM for 1 week. During repeated injections, body weight and cumulative water intake were measured daily before the injection. Finally, each hamster was injected IP with 2 ml/kg of 5 mmol/ml LiC1 in deionized

BIOLPSYCHIATRY 1995;37:42-47

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water (10 mrnol/kg), and appearance, weight and water intake were recorded on days 1,3, and 7 after injection.

Lithium and Potassium Concentration Experiment Two groups of 12 male golden hamsters were given the high-potassium diet for 3 weeks, and two groups were given control diet, under the same lighting and housing protocol as the first experiment. Twelve hamsters from each diet treatment received one injection of 1 ml/kg of 5 mmol/ml LiC11P using a Hamilton syringe between 7 and 8 AM on the 21st day of experimental diet. The remaining 12 hamsters from each diet treatment group were injected IP with 1 ml/kg of 3 mmol/ml LiC1 daily, between 7 and 8 AM, on days 11 to 21 of experimental diet. These lithium doses were chosen from preliminary studies to produce similar cumulative weight loss without mortality. On the 21st day of experimental diet, between 6 and 7 hr after the last LiC1 injection, each hamster was overdosed with 100 mg/kg sodium pentobarbital IP. During deep anesthesia 3 ml of blood was withdrawn from the inferior vena cava using a heparinized syringe, and was then centrifuged. Peripheral tissue samples weighing about 100 mg were cut from the anterior pole of the right kidney, liver, and duodenum. Hypothalamus (about 25 mg) and samples of striatum, cortex, and cerebellum each weighing about 100 mg were dissected from 2-mm thick brain slices. All tissue samples were rinsed with deionized water, blotted with filter paper, and placed in tared microcentrifuge tubes containing 0.4 ml of 0.4 N perchioric acid. Tubes were weighed, then samples were homogenized by ultrasonication, diluted to 1 ml with deionized water, and centrifuged. For potassium determinations, plasma and tissue supematant were diluted 1:50 with 0.4 N perchloric acid for analysis. Plasma was diluted 1:10, and tissue supernatant was not diluted for lithium analysis. Both ions were measured from each tissue sample using an Atomic Absorption Spectrophotometer (Varian Techron, Springvale, Australia, Model 1475). Results

Toxicity Experiment Repeated daily injections of 3 mmol/kg LiC1 for 7 days caused cumulative weight loss in hamsters fed the control potassium diet. Hamsters fed the high-potassium diet lost weight at the same rate for the first few days, but then began to regain weight despite continued dosing with lithium at 3 mmol/kg/day (Figure 1). This interaction between time and potassium treatment was significant (F6.~ = 3.7, p < 0.005) by repeated measures analysis of variance. After seven daily lithium injections, animals receiving high-potassium diet lost significantly less weight than controls (p < 0.01, unpaired t-tes0.

44

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BIOL PSYCHIATRY 1995 ;37:42-47

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Days of lithium injection Figure 1. Dietary potassium reverses weight loss during repeated lithium administration. Hamsters were fed either control diet (171 mmol K/kg diet; empty circles) or potassium supplemented diet (1104 mmol K/kg diet; filled circles) for at least 3 weeks, then were injected for 7 days with 3 mmol LiCl/kg body weight. Data are presented as mean (--+ SEM) change from body weight before the first injection on Day 0. Transient hyperactivity and abdominal stretching lasted 30-60 sec after IP injection of 3 mmol/kg NaC1 or 1-5 rnmol/kg LiC1, but animals appeared normal 6 and 24 hr after injection. Growth rate was depressed by acute LiC1 injections in a dose-related manner (Figure 2). Dietary potassium supplementation may have slightly increased weight gain in hamsters injected with NaC1 or 3 mmol/kg LiC1, but had no significant effect on body weight after any single injection. One day after injection of 10 mmol LiC1/kg all hamsters were alive, but appeared lethargic, ataxic, and rigid. Between the second and fifth day after injection, hamsters from both diet groups displayed coarse tremors and clonic seizures. Six of 12 hamsters fed the high-potassium diet died between 1 and 3 days after injection of 10 mmol Li/kg; 6 of 12 hamsters fed control diet died between 2 and 5 days after injection. Thus, long-term potassium supplementation did not prevent mortality after the acute 10 mmol/kg dose of lithium. Water intake was transiently decreased during the first few days after injection of 3-10 mmol LiC1/kg, but after every single injection cumulative water intake had returned to normal levels by the end of the week. Potassium diet did

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Days after lithium injection Figure 2. Body weight after acute lithium injection is unaffected by dietary potassium supplementation. Hamsters fed control (171 rnmol K/kg diet; empty symbols) or potassium supplemented diet (1104 mmol K/kg; filled symbols) were injected IP on Day 0 with 0 mmol Li/kg (control injection of 3 mmol NaCl/kg), or 1, 3, 5, or 10 mmol LiCl/kg body weight. Weight change 1, 3 and 7 days after the injection is presented relative to initial weight on Day 0. The effect of the 1 mmol Li/kg injection was indistinguishable from control, and is not presented. Data from 10 mmol Li/kg experiment includes only hamsters that survived for 1 week after injection. not influence water intake after repeated injection, or any acute lithium dose (p > 0.25). No significant differences were found between male and female hamsters in weight gain, mortality, or water intake.

Lithium and Potassium Concentration Experiments After repeated LiC1 injections, lithium concentrations were significantly lower in the liver and kidney of hamsters fed the high-potassium diet, and nonsignificantly decreased in plasma (p = 0.08) and duodenum (p = 0.13) compared to hamsters fed control diet (Figure 3). Plasma lithium concentration correlated significantly with lithium in liver, kidney, and duodenum (0.63 < r < 0.67; p < 0.001). In hypothalamus, striatum, cerebral cortex, and cerebellum, lithium concentrations were not affected by dietary potassium (p > 0.31) and did not correlate with plasma lithium concentrations (-0.25 < r < 0.19; p > 0.50). Animals fed control diet lost 10.1 _ 2.6 g, whereas potassium-supplemented animals lost only 0.6 --+ 1.5 g (p < 0.005). In contrast, after a single injection of 5 mmol LiC1/kg lithium

Lithium-Potassium Interaction

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1995;37:42-47

45

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Figure 3. Potassium reduces tissue lithium concentration after repeated injection. Hamsters were fed either control (171 mmol/kg K) or potassium-supplemented (1104 mmol K/kg) diet and given daily injections of 3 mmol LiCl/kg for 10 days. Dietary potassium had no effect on hypothalamus (Hypoth.), cortex, cerebellum (Cereb.) or striatal lithium concentrations, but lowered lithium concentrations in liver and kidney 6 hr after the final injection (mean mmol/kg wet weight _ SEM). Effects of diet on lithium in plasma (mmol Li/L) and duodenum (Duod.)just missed statistical significance. (N = 12/group; *p < 0.05 and **p < 0.001 by t-test). concentration was unaltered by potassium diet treatment (Figure 4). Potassium concentrations in kidney, intestine, and liver were significantly lower in hamsters given repeated lithium injections compared to hamsters given a single injection (Table 1), but there were no effects of diet on potassium concentration in plasma (p = 0.44), liver (p = 0.67), intestine (p = 0.28) or kidney (p = 0.64). Potassium concentrations in brain were similar after single or repeated lithium injection. The only significant treatment effect on brain potassium was that the high-potassium diet slightly increased potassium concentration in hypothalamus (123 - 3 versus 136 --6 mmol/kg;p < 0.05, one-tailed t-test).

Discussion Dietary potassium supplementation may have decreased chronic lithium toxicity by reducing the concentration of lithium in peripheral tissues, without affecting brain lithium concentrations. This result would be consistent with previous observations that potassium supplementation sufficient to diminish side effects and toxicity due to lithium does not necessarily decrease lithium's therapeutic actions in patients (Kast 1991; Cummings et al 1988) or chronobiologic actions in rodents (Klemfuss and Kripke 1987,1989). It would be expected that moderate changes in potassium intake should not appreciably alter brain lithium or potas-

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Figure 4. Tissue lithium after acute lithium injection is unaffected by dietary potassium. Six hours after a single injection of 5 mmol Li/kg body weight, lithium concentrations in plasma, peripheral tissue, and brain are unaffectd by potassium pretreatment.

46

BIOLPSYCHIATRY

H. Klemfuss

1995;37:42-47

Table 1. Potassium concentrations in hamsters given a single-lithium injection versus repeated injections Treatment Single

Plasma

Liver"

Duodenums

Kidney~

Hypothal.

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Cereb.

Striatum

High KDiet

6.4+0.3

99+5

77+6

77+6

134+8

78+5

82_+3

75_+2

injection

Control Diet

6.5 _+ 0.2

108 _+ 7

83 _+4

83 _+ 10

122 _+ 5

72 _+ 4

88 _+ 11

73 _ 2

Repeated

High K Diet

6.8-+0.3

57-+9

65_+5

50+4

137_+8

80_+8

84+9

68+10

Lithium injection

ControlDiet

6.2_+0.3

53_+7

69_+6

51+6

124_+4

72_+6

70_+10

68+9

Lithium

Potassium concentrations(mean mmol K/kg wet weight _+ SEM). Difference between single and repeated lithium injection: a FI,~ = 50.9 p < 0.001; b F~,,7-- 5.0, p < 0.05; c FI.~ = 18.3,p < 0.001.

sium content, as homeostatic mechanisms at the bloodbrai~n interface or choroid plexus maintain relatively constant brain potassium concentrations even with large changes in plasma potassium concentration (Bradbury and Kleeman 1967). One potential exception is the inferior hypothalamus, where increased potassium uptake has been reported after potassium loading in rabbits (Bradbury and Kleeman 1967). The mechanism by which potassium treatment lowers peripheral lithium concentration is not known, but probably does not require changes in renal lithium clearance. Lithium clearance increases slightly when rats are given diets containing very low levels of potassium or sodium, but no change in lithium clearance has been reported in rats given diets containing 100 mrnol K/kg or more (Thomsen and Olesen 1986; Thomsen et al 1993). This lack of effect of normal or high potassium intakes on renal lithium clearance is supported by the current observation that brain lithium was unaltered by changes in dietary potassium, and by previous studies in which supplementary dietary potassium blocked lithium toxicity in rats and hamsters without lowering plasma lithium (Klemfuss and Kripke 1987,1989). The nonsignificant decrease in plasma lithium in the present study may have been secondary to decreased retention of lithium by peripheral tissues, such that a higher percentage of injected lithium would be available for renal elimination. Peripheral tissue lithium concentrations would be lowered by either decreased influx or increased efflux of lithium. In nonneural tissue, the primary routes for lithium uptake are via the sodium-potassium pump, bicarbonate pathway, or passive leak (Collard 1986). If potassium supplementation decreased lithium uptake by peripheral tissues, high-potassium diet should reduce intracellular lithium concentrations following acute injection of lithium. This does not seem to be the case, because the high-potassium diet had no effect on weight loss, mortality, or on tissue lithium concentrations after a single lithium injection. Since the effects of potassium supplementation on lithium concentration and toxicity only became apparent after repeated lithium dosing, it seems likely that potassium supplementa-

tion prevented accumulation of lithium by enhancing the efflux of lithium from peripheral tissues. The main route of lithium efflux from peripheral cells is the sodium-lithium countertransport pathway, a ouabain-insensitive system that exchanges one sodium for one lithium ion. Low serum potassium has been associated with elevated sodium-lithium countertransport in human erythrocytes (McDonald et al 1988; Siebers and Maling 1990), but there is as yet no evidence that elevated potassium intake has any effect on sodium-lithium countertransport. Repeated lithium injection significantly decreased potassium content in the three peripheral tissues, but not in brain or plasma. This observation would seem to suggest that lithium's toxic effects on gut and kidney might be related to loss of intracellular potassium. High-potassium diet did not affect peripheral potassium concentration in either lithium treatment group, however, so it does not appear that dietary potassium exerts its beneficial effects on growth and polyuria by restoring normal potassium concentration in peripheral tissues. The hypothesis that dietary potassium supplementation would decrease acute lithium toxicity was clearly not supported in the present study. Acute lithium overdose, compared to chronic intoxication, is associated with higher plasma lithium concentrations, smaller tissue/plasma lithium ratios, and more central nervous system and neurological dysfunction (Jefferson et al 1987; E1-Mallakh 1990). These results suggest that dietary potassium supplementation reduces side effects by decreasing accumulation of lithium in peripheral tissue, but can do little to treat acute lithium overdose or intoxication involving the central nervous system. Whether these interactions between lithium and dietary potassium in rodents also occur in human patients remains to be tested clinically.

This material is based on work supportedby the Officeof Researchand Development,MedicalResearchService,DepartmentofVeteransAffairs.

Lithium-Potassium Interaction

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