Light and electron microscopy were used to study the effects of a lithium-supplemented diet on renal structure in the rat. At the end of a 7-week experimental period serum lithium levels were 1.14 ± 0.20mM. Lesions consisting of groups of dilated tubules were found in the immediate vicinity of the interlobular arteries in all experimental animals. These tubules were identified as the connecting tubule or the initial portion of the collecting tubule. The epithelium of these tubules was generally flattened but was punctuated by markedly swollen epithelial cells. PAS-positive deposits found in both types of cells were identified as glycogen. Electron microscopy revealed considerable lithium-induced damage in the swollen cells including increased numbers of mitochondria, many of which were swollen or otherwise damaged, dilated cisternae of endoplasmic reticulum and vacuolization of the apical cytoplasm. The flattened cells of these tubules were similar to the dark or intercalated cells of normal collecting tubules. Some detachment of epithelial cells from their basement membrane was evident in these tubules. Damage was less severe in distal convoluted tubules. Lithium-induced changes were not observed in glomeruli, proximal tubules or ascending thick limbs of Henle. In medullary collecting tubules damage was less severe than in cortical collecting tubules, but detachment of epithelial cells was a common finding. The interstitial tissue of the papilla exhibited histochemical and ultrastructural changes consistant with lithium blockade of the action of antidiuretic hormone. The ultrastructural damage to cortical tubules is similar to that found in patients receiving therapeutic lithium for long periods of time. The anatomic sites of lithium-induced pathology correspond to the location of lithium-induced pathophysiology.
Clearance determinations were carried out in three groups of rats: A high lithium group given food to which 70 mmol/kg of lithium were added for 4-6 weeks leading to a mean serum lithium concentration of 0.85 mmol/l, a low lithium group given food to which 15 mmol/kg of lithium were added for two days before the clearance period leading to a mean serum lithium concentration of 0.22 mmol/l, and a group given the same food without lithium. The sodium and potassium contents of the food were kept high in order to avoid lithium-induced development of negative sodium balance and excessive polyuria. The rats were housed in four rooms with 6-hour displaced 24-hour light-dark cycles. The results showed that high doses of lithium led to a significant increase of the lithium clearance and the urine flow. Small amounts of lithium influenced neither the clearance values nor the urine flow. All renal variables were increased by about 50-100% during the dark period. The serum lithium concentration was least influenced by the diurnal rhythm. It is concluded that serum lithium concentrations measured at any time of the day are fairly representative of the 24 hours. A lithium clearance measured during daytime is valid for this period only. Long-term lithium treatment leads to an increase of the renal lithium clearance but does not diminish the normal diurnal rhythm of the kidney function.
Rats were given identical doses of lithium chloride, 4 mmol/kg body weight/day for 8 days, by different routes. Intraperitoneal administration led to a high serum lithium peak and the development of pronounced polyuria-polydipsia. Subcutaneous administration led to a lower serum peak and the development of less pronounced polyuria-polydipsia. Administration by gastric tube led to a nearly constant serum lithium concentration without any peak and the development of moderate polyuria-polydipsia. Our study shows that the route by which lithium is administered affects the lithium concentration pattern and may influence lithium effects.
Ten rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain) were divided into two groups. Five rats were given lithium-containing food and five served as controls. During the first weeks the lithium content of the food was 40 mM/kg dry weight; in order to obtain a serum lithium level comparable to that used in treatment of patients, 0.7-1 mAf, the lithium content of the food had to be raised to 60 mM/kg dry weight. Within a few days with this lithium intake, the rats developed signs of intoxication, loss of weight and decrease of fluid intake. The condition was reversed by giving the rats a free choice between 0.9-percent NaCl and tap water. With this regimen a stable serum lithium concentration of 0.8 mAf was maintained for 2 months without any signs of intoxication. The lithium-treated rats drank more saline than did the controls. This extra sodium intake resulted in a 50-percent higher total fluid intake by the lithium-treated rats than by the controls. Equally large fluid intakes of the two groups were obtained by adding more sodium to the food of the control animals and less to the food of the lithium-treated rats. During the following 2 months, the mean serum lithium concentration was; 1.1 mM and no signs of intoxication occurred. The administration of extra sodium to the lithium-treated rats did not abolish the lithium-induced lowered antidiuretic response to vasopressin. The study shows that by appropriate administration of the lithium and sodium intakes it is possible to maintain rats at a serum lithium level of 0.7-1 mM for long periods of time without signs of intoxication and with the same body weight as control rats. This may be useful for studies of lithium-induced effects. By using Brattleboro rats for the experiments, it is possible to eliminate the difference in urine flow between the lithium-treated rats and the control rats.
In the present study the hypothesis is tested that long‐term lithium administration produces a general lowering of hormone responses that are mediated via the adenyl cyclase‐cyclic AMP systems. Rats were given lithium in the food for more than one month before the experiments, and the serum lithium concentration was maintained at a level of 0.7–0.9 mM. Lithium administration did not lower the response to 33 or 100 U/kg b.wt. of parathyroid hormone as measured by the decrease in the urinary excretion of calcium and by an increase in urinary excretion of phosphate and cyclic AMP; on the contrary, the effects of parathyroid hormone were higher in the lithium than in the control group. Lithium did not lower the response to 200 μg/kg b.wt. glucagon as measured by liver glycogen breakdown. The liver glycogen concentration was equal in the lithium and in the control group before the hormone was administered; one hour after its administration the liver glycogen concentration was reduced by about 40 per cent in both groups. Lithium led to a significant increase in the response to glucagon as measured by the increase in the urinary excretion of cyclic AMP. On the basis of the data obtained the hypothesis under investigation must be rejected.
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