Role of the kidneys in the pathogenesis of lithium poisoning]

Lithium intoxication was induced in rats by intraperitoneal administration of lithium chloride in a daily dose of 200 mg/kg (0.22 LD50) for 6 days. Polyuria connected with pathological changes in the epithelium of the convoluted tubules and depression of the antidiuretic hormone--acid mucopolysaccharides system in the area of the straight kidney tubules was observed on the 6th day of the experiments. Oligouria and death of some of the animals on the 7th experimental day was caused by severe lesions the kidney structure. Further observation (30 days) demonstrated that, along with the regeneration processes, there developed a marked sclerosing ofthe kidney tissue. A conclusion was drawn that severe lithium intoxication was associated with the development of acute renal insufficiency. Functional reserves of the kidneys after the cessation of lithium chloride administration remained lowered for a long period.     

Potassium chloride: absorption and excretion

The absorption of potassium chloride in liquid form has been studied, using urinary excretion as an index of absorption. The excretion of potassium chloride was observed after inducing a water diuresis and administering a single dose in liquid form. There is evidence that potassium chloride in liquid form is absorbed rapidly, probably from the stomach, and hence there is a good rationale for its use where rapid absorption is needed, as in digitalis intoxication.     

Sexual specificity of change of pancreatic alpha-amylase activity in rats in cadmium intoxication

It was shown that the activity of alpha-amylase in the pancreas tissue, intestine content and blood, as well as kinetic characteristics in different substratum concentration changed in males and females after unitary oral administration of chloride cadmium in the dose 5 mg/kg. It was revealed that, after a single administration of chloride cadmium, growth of the pancreas weight, contents of protein and activity of alpha-amylase in the pancreatic tissue increased with parallel reduction of activity of enzyme in the small intestine. In acute cadmium intoxication, functional reorganizations in the pancreas are identical to initial stages of carcinogenic shifts. Such shifts are more expressed in females in comparison with males, especially after the cadmium intoxication.     

Enzymatic activity of hydrolases in the spinal cord of rat after an acute and subacute calomel introxication.

Studies have been performed on changes in the activity of hydrolytic enzymes in spinal cord following a toxic action of calomel. With the use of a gastric cannule, the rats were being administered mercurous chloride. The first group were given Hg2Cl2 in a 0-05 g. dose for four days whereas the second experimental group received a 0-012 g. for ten days. As a result of the studies, both in an acute and subacute calomel intoxication, an increase in TTP-ase and NsE activity in spinal cord as well as a decrease in ATP-ase, AChE and AcP activity were found. It was also shown that mercurous chloride intoxication exerts of influence on AIP and BuTJ activity. In the discussion an attempt was made to explain some of the observed phenomena.     

Effects of modulators of cytokine levels on mice and rats survival under combined radiation/thermal injuries

The influence of LPS-induced increasing of proinflammatory cytokine production inhibitors (pentoxifylline--POF, glycine--G), Kupffer cells elimination (gadolinium chloride--GC) and monoclonal anti-IL-6 antibodies on 30-days survival, mean survival time and probability of mortality within animals under combined radiation/thermal injury were evaluated. Experiments were carrying out on mice (whole body gamma-irradiation at the dose of 7 Gy + 10% body surface full-thickness thermal burn) and rats (gamma-irradiation at the dose of 7.5 Gy + 15% body surface burn). It was established that POF, G and GC didn't modify survival. Mouse anti-IL-6 monoclonal antibodies administration 1 h prior and 1, 2, 3 days after combined injury increased 30-days animal survival up to 60% in each group and up to 90% while antibodies were injected in 6, 7, 8 days after combined injuries; 100% lethality was registered in untreated mice. Possible anti-inflammatory inactivity reasons of modulators of cytokine levels under combined injury conditions are discussed.     

Morphological changes in spleen, bone marrow and blood of rats after continuous gamma irradiation and indomethacin treatment.

A possibility of modifying the radiation damage of haematopoiesis by indomethacin administered during continuous irradiation was followed. Indomethacin was given in drinking water (average dose of 740.7 micrograms/kg per day) within 7-days continuous irradiation with gamma rays (a daily dose rate of 2.055 Gy, total accumulated dose of 14.385 Gy). Under the given conditions no marked protective effect of indomethacin on haematopoiesis was found with the exception of mild stimulation of myelopoiesis and an increased release of developmentally younger cells of myeloid and erythroid series to the peripheral blood as well.     

Resistance of KP and CBA mice to cadmium chloride assessed on the basis of the bone marrow stromal cell growth in vitro

Using a culture of bone marrow stromal cells, resistance of two inbred mice strains, KP and CBA, to cadmium chloride was assessed. Mice were administered with a single dose of CdCl2 (12 mumoles (kg b. wt) and bone marrow cells were examined after 7 days of culture. In KP strain, a decrease in the number of fibroblasts and proliferation of adipocytes was observed, as compared with control animals. In CBA strain, cadmium did not influence the number of fibroblasts and caused only an insignificant increase in the amount of adipocytes. Red blood cell count, hematocrit and Fe2+ level were unchanged both strains after cadmium administration. The observed differences in populations of cultured stromal cells confirmed the sensitivity of the KP mice to cadmium and indicated that the stromal cells can be regarded as useful indicator of cadmium intoxication.     

Acute toxicity and hematological and serum changes caused by various cobalt salts in rats

The acute toxicities of chloride, acetate, cobalt nitrate and cobalt sulphate (II) were investigated in rats. The values obtained for the LD50 (7 days) were 133, 194, 198 and 279 mg of Co/kg respectively, when the salts were given orally. The values for intraperitoneal administration were 10.6, 8.8, 8.3 and 11.5 mg of Co/kg. The majority of deaths occurred during the first 48 hours. The physical and clinical signs appearing after the intoxication disappeared for the most part after the first 72 hours. Also, the effect produced by chloride and cobalt acetate (II) given orally and intraperitoneally, in some hematological parameters and serum parameters during the first 24 hours after intoxications, has been studied at several doses. A noteworthy increase was observed in the hemoglobin and hematocrit as well as in the plasma proteins. There was significant hyperglycemia and also significant changes in the lipid parameters such as triglycerides and cholesterol. The duration and degree of the change depended on the dose. As a general rule, no significant differences were registered between the results obtained for the two salts.     

Regional Cerebral Glucose Metabolism and Blood Flow During the Silent Phase of Methylmercury Neurotoxicity in Rats

Methylmercuric chloride was given to rats in a neurotoxic dose regimen (six daily doses of 8 mg kg-1 p.o.). During the silent (asymptomatic) phase of intoxication, the rates of cerebral glucose influx and cerebral glucose phosphorylation were measured simultaneously using 2-deoxyglucose. Regional cerebral blood flow was also measured using iodoantipyrine. The unidirectional flux of glucose into brain was not affected by methylmercury, and differences in the rates of glucose phosphorylation from region to region remained coupled to the regional cerebral blood flow. However, the blood flow was reduced throughout the brain, an observation suggesting that the operational level of metabolically regulated blood flow had been reset. Thus, in spite of a generalised reduction in blood flow, there was no indication of impaired cerebral glucose supply or utilization during the silent phase of methylmercury intoxication.     

Alcohol intoxication: ion channels and genetics

Acute in vitro exposure to ethanol and other intoxicant-anesthetics activates gamma-aminobutyric acid (GABA)-stimulated chloride channels and inhibits voltage-dependent calcium and sodium channels of isolated brain membranes. The question of whether these neurochemical actions are responsible for intoxication in vivo has been addressed using animal populations displaying genetic differences in sensitivity to alcohol and benzodiazepine intoxication. These genetic approaches include inbred strains, selected lines, recombinant inbred strains, and heterogeneous stocks. Genetic differences in ion channel function provide strong evidence for a role of the GABA-stimulated chloride channel in ethanol and benzodiazepine intoxication; the role of calcium and sodium channels is less clear.     

Phosphatases and esterases activity in the brain following an acute sublimate intoxication.

Experiment studies were performed on rats that were administered mercury chloride sublimate with a special gastric cannule in a single 6 mg dose for four consecutive days. As a result of the investigations some changes in the phosphates and esterases activity were revealed. The diminution of AcP, AIP, ATP-ase and AChE activity as well as in the increase in TPP-ase activity in the neurocytes, and also the appearance on NsE activity in many oligodendrocytes was observed. The fall in ATP-ase activity was, above all, observable in cerebral and cerebellar capillaries, which is, in the authors opinion, a manifestation of enzymatic damage to the blood-brain barrier due to a toxic action of mercuric chloride. In the discussion attention was drawn to differences in the degree of enzymatic activity between a mercuric chloride intoxication and that with mercurous chloride, as well as attempt was made to explain the pathogenetic mechanism of this phenomenon. Furthermore, notice was brought to the fact that in the course of sublimate encephalopathy no changes are observed in BuTJ activity.     

Ophthalmoscopic observations of ocular fundus in colony-born cynomolgus monkeys aged from 0 day to 90 days

Apparently healthy 242 colony-born cynomolgus monkeys (Macaca fascicularis) aged from 0 day to 90 days were examined for the findings of ocular fundus by using ophthalmoscope. One drop of mixed solution of 0.5% tropicamide and 0.5% phenylephrine hydrochloride was instilled into each eye of the monkey. Then, those monkeys were anesthetized with ketamine-HC1 at the dose level of 10mg/kg B. W. Regular and fluorescein photographs were taken with Kowa RC-II ophthalmoscope-camera by using daylight typed color film. Following findings were obtained in each age class: Retinal color was salmon pink with 0 to 3-days-old neonates, salmon pink and blue to green with 7 days to 14-days-old animals and blue to green with 60-days to 90-days-old monkeys. As regards optic disc, 0- to 14-days-old animals were observed to be light orange in color, and the infant aged more than 28-days showed orange color. Retinal arteries and veins were lightly reddish in color with every age class. Macular color was salmon pink in 0-day-old cases, slightly dark in 3-days-old neonates and very dark after 14-days of age. Lightly retinal reflex was noted in 0- and 7-days-old animals. The reflex was observable in 14-days-old animals without any case of exception. Retinal hemorrhages were recorded in 22 (67%) of 36 neonates born in natural condition and 10 (33%) of 30 neonates born by cesarean section. These findings will be useful as the criteria for ophthalmoscopic observations of the cynomolgus monkeys as laboratory use.     

Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity

Rapid administration of large doses of ammonia leads to death of animals, which is largely prevented by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. The present study focuses on a subunit(s) of NMDA receptor involved in ammonia-induced death by use of NMDA receptor GluRepsilon subunit-deficient (GluRepsilon(-/-)) mice and the selective GluRepsilon2 antagonist CP-101,606. Acute ammonia intoxication was induced in mice (eight per group) by a single intraperitoneal (i.p.) injection of ammonium chloride. Appearance of neurological deteriorations depended on the doses of ammonium chloride injected. While wild-type, GluRepsilon1(-/-), GluRepsilon4(-/-), and GluRepsilon1(-/-)/epsilon4(-/-) mice all died by ammonium chloride at 12 mmol/kg during the first tonic convulsions, two of eight GluRepsilon3(-/-) mice survived. Pretreatment of wild-type mice with CP-101,606 prevented two mice from ammonia-induced death. Pretreatment of GluRepsilon3(-/-) mice with CP-101,606 prevented the death of three mice and prolonged the time of death of non-survivors. Similarly, the neuronal form of nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) as well as the nonselective NOS inhibitor L-NMMA, but not the inducible NOS inhibitor 1400W, partially prevented the death of mice and prolonged the period of death. Furthermore, ammonium chloride prolonged the increase in intracellular free Ca2+ concentration ([Ca2+]i) and subsequent NO production induced by NMDA in the cerebellum. These results suggest that activation of NMDA receptor containing GluRepsilon2 and GluRepsilon3 subunits and following activation of neuronal NOS are involved in acute ammonia intoxication which leads to death of animals.     

Effects of keishi-ka-jutsubu-to (traditional herbal medicine: Gui-zhi-jia-shu-fu-tang) on in vivo insulin action in streptozotocin-induced diabetic rats

This study investigated the effects of the traditional herbal medicine, Keishi-ka-jutsubu-to (KJT) on insulin action in vivo and insulin signaling in skeletal muscle in STZ-induced diabetes. Rats were divided into single and 7-days oral administration groups. Euglycemic clamp (insulin infusion rates: 3 and 30 mU/kg/min) was used in awaked rats and the insulin signaling in skeletal muscle was evaluated. At low-dose insulin infusion, the decreased metabolic clearance rates of glucose (MCR) in diabetic rats were improved by a single and 7-days administration of KJT (800 mg/kg BW, p.o.; acute effect: 6.7 +/- 0.6 vs. 12.3 +/- 1.2, and 7-days effect: 6.3 +/- 0.5 vs. 13.9 +/- 1.0 ml/kg/min, P<0.001, respectively). During high-dose insulin infusion, the MCR was increased in 7-days KJT treated diabetes compared with saline diabetes, but, these changes were not observed after a single KJT treatment. About 90% of the increasing effect in MCR induced by the 7-days KJT treatment was blocked by L-NMMA. However, no further additive effects were seen in KJT + SNP treatment. IRbeta protein increase and decreased IRS-1 protein expression in diabetes were significantly improved by KJT treatment. KJT had no effect on the GLUT4 protein content. The increased tyrosine phosphorylation level of IRbeta, IRS-1, and IRS-1 associated with PI 3-kinase were significantly inhibited in KJT treated diabetes. The present study suggests that the improvement of impaired insulin action in STZ-diabetes by administration of KJT may be due, at least in part, to enhanced insulin signaling, which may be involved with production of nitric oxide (NO).     

Temperature regulation following nickel intoxication in the mouse: effect of ambient temperature

1. The purpose of this study was to examine the interaction between ambient temperature (Ta) and the effects of nickel chloride on the thermoregulatory system of the mouse. 2. Male mice of the BALB/c strain were injected with nickel chloride at dosages of 0, 0.1, 1.0, 2.5, 5.0 and 10.0 mg/kg intraperitoneally and placed in an environmental chamber set at a Ta of either 10, 20, 30 or 35 degrees C for 60 min. Colonic temperature was then measured after one hour of exposure at a given Ta. 3. The thermoregulatory effects of nickel chloride were highly dependent on Ta. Nickel chloride had no effect on body temperature at Ta's of 30 and 35 degrees C. 4. 10 mg/kg dosage of nickel chloride caused a significant reduction in colonic temperature at a Ta of 20 degrees C. At a Ta of 10 degrees C the 5 and 10 mg/kg dosages of nickel chloride caused a significant lowering of body temperature. 5. Using segmented linear regression techniques it was shown that the threshold dose of nickel chloride for causing hypothermia was 9.6 and 3.3 mg/kg at Ta's of 20 and 10 degrees C, respectively. 6. This study has shown that two stressors, low Ta and nickel chloride intoxication, when applied independently have no effect on body temperature; however, when applied simultaneously, they have a significant toxic effect on thermoregulation.     

Heparin exerts anti-apoptotic effects on uterine explants by targeting the endocannabinoid system

Miscarriage caused by Gram-negative bacteria infecting the female genital tract is one of the most common complications of human pregnancy. Intraperitoneal administration of LPS to 7-days pregnant mice induces embryo resorption after 24 h. Here, we show that LPS induced apoptosis on uterine explants from 7-days pregnant mice and that CB1 receptor was involved in this effect. On the other hand, heparin has been widely used for the prevention of pregnancy loss in women with frequent miscarriage with or without thrombophilia. Besides its anticoagulant properties, heparin exerts anti-inflammatory, immunomodulatory and anti-apoptotic effects. Here, we sought to investigate whether the administration of heparin prevented LPS-induced apoptosis in uterine explants from 7-days pregnant mice. We found that heparin enhanced cell survival in LPS-treated uterine explants and that this effect was mediated by increasing uterine FAAH activity. Taken together, our results point towards a novel mechanism involved in the protective effects of heparin.     

Effect of supplemental magnesium on the kidney levels of cadmium, zinc, and copper of mice exposed to toxic levels of cadmium

In this report, we present the results of our investigations on the effect of Mg pretreatment on Cd and bioelements (Cu and Zn) contents in kidney of mice exposed to acute and subacute Cd intoxication. Acute intoxication was performed on male Swiss mice given a single oral dose of 20 mg Cd/kg body weight and mice given the same dose of Cd but pretreated with 40 mg Mg/kg body weight. For subacute intoxication one group of mice was given 10 mg Cd/kg body weight every day, for 2 wk, and the other one received the same dose of Cd after oral Mg intake of 20 mg/kg body weight. Cd, Cu, and Zn content was determined in kidney by atomic absorption spectrophotometry. In acute Cd intoxication, Mg pretreatment resulted in significant decrease of Cd in kidney after 4 and 6 h, compared with animals given only Cd. Under the condition of subacute Cd intoxication, Mg supplementation reduced Cd kidney content after 2 wk for about 30%, compared with animals treated with Cd only. The effect of Mg on Cu and Zn kidney content was also beneficial.     

Effect of anthocyanins on selected biochemical parameters in rats exposed to cadmium

Cadmium is a dangerous occupational and environmental toxin. It accumulates in the human organism mainly in liver and kidneys. Cadmium half-life is about 10 years, so the symptoms of cadmium intoxication may occur several years after the exposure. Until now in treating intoxication with this metal chelating compounds have been used, burdened with numerous undesirable symptoms. In our investigations anthocyanins from Aronia melanocarpa were used to reduce the harmful results caused by cadmium. Administering anthocyanins with cadmium chloride resulted in a statistically significant decrease of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity, concentration of bilirubin and urea in blood serum and decreased cadmium cumulation in liver and kidneys in relation to animals receiving cadmium chloride only.     

Induction of necrosis in cadmium-induced hepatic oxidative stress and its prevention by the prophylactic properties of taurine

The present study has been carried out to investigate the protective role of taurine against cadmium (Cd)-induced oxidative impairment in murine liver. Oral administration of cadmium chloride (CdCl₂) at a dose of 4 mg/kg body weight for 6 days increased the accumulation of the Cd in the liver and diminished the liver weight to body weight ratio. The CdCl₂ altered the levels of intracellular trace elements, cofactors of various metalloenzymes and increased the activities of serum marker enzymes related to liver dysfunction. In addition, Cd intoxication also attenuated intracellular antioxidant power, the activities of antioxidant enzymes as well as the levels of cellular metabolites. Moreover, level of hepatic metallothionein, lipid peroxidation, protein carbonylation, DNA fragmentation, concentration of intracellular reactive oxygen species (ROS) and the activities of cytochrome P450s have been increased due to Cd toxicity. In addition to the oxidative impairments, Cd exposure caused hepatic cell death mainly via the necrotic pathway. Oral administration of taurine at a dose of 100 mg/kg body weight for 5 days prior to CdCl₂ intoxication prevented the alterations of all the toxic-induced hepatic damages. Histological studies also supported the beneficial role of taurine against Cd-induced hepatic damages. Combining all, results suggest that taurine could protect hepatic tissues against Cd-induced oxidative stress probably through its antioxidant activity.     

Chromosomal aberrations in bone-marrow cells of mice given a normal or a calcium-deficient diet supplemented with various heavy metals

Mice kept on a normal (1.1% calcium) or low-calcium (0.03%) diet were exposed for one month to zinc chloride (0.5% Zn), lead acetate (0.5% Pb) or cadmium chloride (0.06% Cd) or to a mixture of these salts at half the above concentrations. These concentrations, given in a poor calcium diet, represent an LD 50/30 days. After the mice were killed bone-marrow cells were assayed for chromosomal aberrations, and serum calcium was determined. Chromosomal aberrations were detected in the mice maintained on a low-calcium diet and exposed to lead, zinc or a mixture of lead, zinc and cadmium. The possible mechanism for the synergistic action on genetic effects of the lack of calcium and intoxication by heavy metals are discussed, and it is recommended that routine attention be given to the state of calcium metabolism in heavy-metal intoxication.