Effect of lithium preparations on the toxic effects of adrenaline

Experiments on rats have shown that intravenous injection of adrenaline in a dose of 0.3-0.4 mg/kg causes cardiac arrhythmia. In this case the primary arrhythmia developing immediately after adrenaline injection is followed by the recovery of sinusal rhythm which was replaced by the secondary arrhythmia. Apart from arrhythmias, there developed pulmonary edema. The animals died 2--3 minutes after adrenaline injections. Lithium chloride and lithium hydroxybutyrate removed the secondary arrhythmia and pulmonary edema. Lithium hydroxybutyrate has proved to be more effective.     

Effects of lithium hydroxybutyrate on circadian rhythm of rest-activity and sleep structure in experimental animals]

Lithium hydroxybutyrate (10 mg/kg, 10 days) influences circadian temperature and activity rhythms of rats in "open field" and sleep structure according to the time of preparation of the injection (8.30 or 19.30). It was stated that lithium hydroxybutyrate modified circadian rhythms and sleep structure less after morning injections into the rats, while evening administration destabilized circadian rhythms, increased slow-sleep and decreased REM sleep duration.     

Effect of lithium preparations on cardiac arrhythmias resulting from ligation of the common carotid arteries

In experiments on cats with dissected vagus and aortal nerves under chloralose-urethane anesthesia, ventricular disorders of the cardiac rhythm were induced by ligation of the common carotid arteries. Appearance of arrhythmias was preceded by an increase in the sympathetic activity (recorded from the inferior cardiac or renal nerve) accompanied by a rise of the arterial blood pressure and of the heart rate. Intravenous injection of lithium chloride or hydroxybutyrate resulted in lowering of the sympathetic activity, arterial blood pressure, and heart rate, and led to the recovery of the sinus rhythm.     

Dynamics of carrageenin-induced inflammation after use of lithium oxybutyrate

Lithium hydroxybutyrate (200 mg/kg) has been shown to depress the development of carrageenan inflammation. Subcutaneous drug injection in chronic inflammation of the mucous membrane in the hamster cheek pouch restored the blood flow, checked dilatation of the blood vessels, decreased their permeability and prevented necrosis of the mucous membranes. Subcutaneous drug injection depressed all the signs of both phases of acute inflammatory reaction in the rat hind foot and promoted preservation of the hind foot function. Therefore, lithium hydroxybutyrate may be an effective preparation for the treatment of inflammation.     

Effect of lithium salts on neuropathological syndromes of spinal origin

Experiments on noninbred rats were made to study the influence of lithium hydroxybutyrate on two patterns of spinal cord pathology: the generalized myoclonus and painful syndrome of spinal origin. The syndromes were induced by generators of pathologically enhanced excitation in the ventral and dorsal horns of the spinal cord. The effects of lithium chloride and sodium hydroxybutyrate were examined to compare the influence of lithium (cation) and hydroxybutyrate (anion) components to elucidate the role of each of the components. Lithium hydroxybutyrate appeared more effective, since it inhibited the generator of pathologically enhanced excitation in the appropriate structures, provoking the anticonvulsant effect in myoclonus and suppressing the painful syndrome.     

Protective effect of lithium oxybutyrate on the ischemic myocardium

In the experiments on different animal species (mice, cats, dogs) lithium hydroxybutyrate has been shown to have antihypoxic and anti-ischemic effects. Lithium hydroxybutyrate improved the functional state of the ischemic myocardium, stimulated the accumulation of macroergic phosphates (ATP) in the heart, protected the ischemic myocardium and delayed the progression of the reversible ischemic damage into the irreversible one. The improvement of the collateral coronary circulation plays an important role in the anti-ischemic action of the drug.     

Effects of lithium salts on experimental neurogenic lesions of the stomach and heart

It has been demonstrated in experiments on noninbred rats that lithium chloride and lithium hydroxybutyrate exert a prophylactic therapeutic effect in respect to neurogenic gastric lesions and reduction in the content of creatine phosphate in gastric and cardiac tissues, induced by stressful exposures (3-hour immobilization and electric stimulation of hungry animals). The effects of lithium hydroxybutyrate were more demonstrable than those of lithium chloride.     

Comparative study of several preparations in different models of cerebral hypoxia

The antihypoxic effects of gutimine, piracetam, sodium hydroxybutyrate and lithium hydroxybityrate were studied on different models of brain hypoxia. All the drugs under study produced a remarkable antihypoxic effect in experimental asphyxic hypoxia, increasing brain resistance to oxygen deficiency and rapidly restituting brain function. Drug pretreatment of the animals with carotid artery occlusion raised the number of animals which survived 24 h after the operation. GABA salts appeared the most effective. Sodium hydroxybutyrate increased the lifespan of rats under histotoxic hypoxia.     

Prophylactic effects of sodium oxybutyrate and lithium oxybutyrate on stress-induced depression of the activity of normal killers in mice

The possible use of sodium hydroxybutyrate and lithium hydroxybutyrate for the prevention of the decrease in splenic natural killer activity has been studied in CBA mice upon 6-hour immobilization stress. Both agents proved to be effective in preventing stress-induced depression of NK activity. However, a protective effect of lithium hydroxybutyrate was observed at a dose 4 times lower than that of sodium hydroxybutyrate.     

Electrocardiogram abnormalities in captive chimpanzees (Pan troglodytes)

Although cardiovascular disease is the leading cause of death in the captive chimpanzee population, little is known about the prevalence and etiology of heart disease in this species. We reviewed the physical exam records of 265 common chimpanzees (Pan troglodytes) for electrocardiogram abnormalities. During the 24-mo period reviewed (August 2003 through August 2005), 34 animals were diagnosed with cardiac arrhythmias consisting of ventricular arrhythmias, supraventricular arrhythmias, conduction disturbances, mixed arrhythmias, and bradycardia. The incidence of cardiac arrhythmia was significantly higher in male animals, chimpanzees 20 to 39 y old, and those with structural heart disease. Incidence of cardiac arrhythmia was not significantly higher in animals with hypertension, hyperlipidemia, or chronic viral infections. During the retrospective period, 7 animals with cardiac arrhythmias died or were euthanized. Mortality was significantly higher in animals with ventricular arrhythmias compared with those without ventricular arrhythmias. We conclude that in the common chimpanzee, age, male gender, and structural heart disease are risk factors for developing cardiac arrhythmias and that ventricular arrhythmias are risk factors for mortality.     

Lithium and Valproate Protect Hippocampal Slices Against ATP-induced Cell Death

Lithium and valproate (VPA) are the most commonly prescribed mood-stabilizing drugs. Recently, several studies have reported their neuroprotective properties in several models of neural toxicity and, in some pathological conditions, large amounts of intracellular ATP can be released from damaged cells. In the present study, we investigate the potential neuroprotective effect of lithium and VPA against ATP-induced cell death in hippocampal slices of adult rats. Acute (in vitro) and chronic (in vivo) treatment at therapeutic doses with lithium or VPA significantly prevent the ATP-induced cell death. Lithium and VPA also exerted a synergic effect in the prevention of ATP-induced cell death. Moreover, hippocampal slices prepared from rats chronically treated with lithium or VPA presented a significant reduction in cell death in the presence of cytotoxic extracellular ATP. Although further investigations are necessary, our results show the neuroprotective effect of lithium and VPA against neuronal death induced by extracellular ATP, probably through a different pathway, and suggest novel uses of these drugs in neurogenerative diseases. L. C. Wilot and A. Bernardi equally contributed by this work.     

Study of the mechanism of the anti-hypoxic action of lithium oxybutyrate using cerebral ischemia as a model

A study was made of energy metabolism and concentration of malonic dialdehyde (MDA) in cerebral tissue of mice given sodium hydroxybutyrate and lithium hydroxybutyrate 30 and 60 s after decapitation. Administration of lithium hydroxybutyrate brought about a more economic consumption of the glycogen pool as compared with "hypoxic" control. The differences were revealed in the action of both salts on ATP. The concentration of MDA declined after their administration, lithium hydroxybutyrate being more efficacious. The possible mechanisms of the action of lithium hydroxybutyrate are discussed.     

Cocaine-enhanced arrhythmogenesis: neural and nonneural mechanisms.

Cocaine abuse increases the susceptibility to cardiovascular complications and sudden cardiac death in man. We used programmed electrical stimulation of the heart to examine the arrhythmogenic influence of cocaine. Twenty-three pentobarbital-anesthetized adult dogs underwent programmed electrical stimulation using one to four extrastimuli before and during cocaine infusion. Autonomic decentralization was performed prior to the protocol in eight dogs. Induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia, and ventricular fibrillation. Intravenous cocaine, and subsequent adrenergic and muscarinic receptor blockade, or calcium channel blockade were evaluated for their influence on arrhythmogenesis. The incidence of induced ventricular arrhythmias was significantly elevated following cocaine and was reduced following propranolol and atropine. Verapamil, however, did not reduce the incidence of induced arrhythmias. In addition, cocaine significantly increased arrhythmia induction in decentralized animals, but propranolol, atropine, and phentolamine failed to reduce the proarrhythmic effects of cocaine in these animals. Thus, cocaine has a proarrhythmic effect on the heart with multiple mechanisms. The adrenergic mechanism appears to be a result of neurotransmitter uptake blockade, whereas the likely ionic mechanism is a neurally independent, direct effect on the heart.     

Redistribution of myocardial blood flow in chronic ischemia under the effects of pharmacological agents

In the experiments with anesthetized dogs under chronic myocardial ischemia the effect of propranolol, diltiazem, lithium and sodium hydroxybutyrate on the myocardial blood flow redistribution was studied with the help of ultrasonic method. The redistribution was estimated by the ratio change of blood flows in veins which drain blood directly from the focus of myocardial ischemia and total myocardial of left ventricular (v cardiac magna). It was established that propranolol increases the ratio and diltiazem decreases it. Some differences in the effect of antihypoxic drugs were revealed. Sodium hydroxybutyrate redistributed the blood flow in favour of the focus of myocardial ischemia and lithium hydroxybutyrate increased the blood flow both in the focus of myocardial ischemia and in the conditionally-intact region of myocardium of left ventricular.     

Lithium's effects on rat liver glucose metabolism in vivo

Oral administration of lithium carbonate to fed-healthy rats strongly decreased liver glycogen content, despite the simultaneous activation of glycogen synthase and the inactivation of glycogen phosphorylase. The effect seemed to be related to a decrease in glucose 6-phosphate concentration and to a decrease in glucokinase activity. Moreover, in these animals lithium markedly decreased liver fructose 2,6-bisphosphate, which could be a consequence of the fall in glucose 6-phosphate and of the inactivation of 6-phosphofructo-2-kinase. Liver pyruvate kinase activity and blood insulin also decreased after lithium administration. Lower doses of lithium carbonate had less intense effects. Lithium administration to starved-healthy and fed-streptozotocin-diabetic rats caused a slight increase in blood insulin, which was simultaneous with increases in liver glycogen, glucose 6-phosphate, and fructose 2, 6-phosphate. Glucokinase, 6-phosphofructo-2-kinase, and pyruvate kinase activities also increased after lithium administration in starved-healthy and fed-diabetic rats. Lithium treatment activated glycogen synthase and inactivated glycogen phosphorylase in a manner similar to that observed in fed-healthy rats. Glycemia was not modified in any group of animals. These results indicate that lithium acts on liver glycogen metabolism in vivo in at least two different ways: one related to changes in insulinemia, and the other related to the direct action of lithium on the activity of some key enzymes of liver glucose metabolism.     

Inhibition of heart formation by lithium is an indirect result of the disruption of tissue organization within the embryo

Lithium is a commonly used drug for the treatment of bipolar disorder. At high doses, lithium becomes teratogenic, which is a property that has allowed this agent to serve as a useful tool for dissecting molecular pathways that regulate embryogenesis. This study was designed to examine the impact of lithium on heart formation in the developing frog for insights into the molecular regulation of cardiac specification. Embryos were exposed to lithium at the beginning of gastrulation, which produced severe malformations of the anterior end of the embryo. Although previous reports characterized this deformity as a posteriorized phenotype, histological analysis revealed that the defects were more comprehensive, with disfigurement and disorganization of all interior tissues along the anterior-posterior axis. Emerging tissues were poorly segregated and cavity formation was decreased within the embryo. Lithium exposure also completely ablated formation of the heart and prevented myocardial cell differentiation. Despite the complete absence of cardiac tissue in lithium treated embryos, exposure to lithium did not prevent myocardial differentiation of precardiac dorsal marginal zone explants. Moreover, precardiac tissue freed from the embryo subsequent to lithium treatment at gastrulation gave rise to cardiac tissue, as demonstrated by upregulation of cardiac gene expression, display of sarcomeric proteins, and formation of a contractile phenotype. Together these data indicate that lithium's effect on the developing heart was not due to direct regulation of cardiac differentiation, but an indirect consequence of disrupted tissue organization within the embryo.     

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.     

Lithium inhibits growth of intracellular Mycobacterium kansasii through enhancement of macrophage apoptosis

Mycobacterium kansasii (Mk) is an emerging pathogen that causes a pulmonary disease similar to tuberculosis. Macrophage apoptosis contributes to innate host defense against mycobacterial infection. Recent studies have suggested that lithium significantly enhances the cytotoxic activity of death stimuli in many cell types. We examined the effect of lithium on the viability of host cells and intracellular Mk in infected macrophages. Lithium treatment resulted in a substantial reduction in the viability of intracellular Mk in macrophages. Macrophage cell death was significantly enhanced after adding lithium to Mk-infected cells but not after adding to uninfected macrophages. Lithium-enhanced cell death was due to an apoptotic response, as evidenced by augmented DNA fragmentation and caspase activation. Reactive oxygen species were essential for lithium-induced apoptosis. Intracellular scavenging by N-acetylcysteine abrogated the lithium-mediated decrease in intracellular Mk growth as well as apoptosis. These data suggest that lithium is associated with control of intracellular Mk growth through modulation of the apoptotic response in infected macrophages.     

Efficacy of lithium hydroxybutyrate in reserpine depression

Long-term administration of lithium hydroxybutyrate (10 mg/kg, for 7 days) prevents the depression of avoidance behavior in rats and EEG alterations in the cortex and subcortical structures of rabbit brain induced by a single injection of 0.125 mg/kg reserpine.     

Indices of acute inflammation against a background of lithium oxybutyrate action

The experiments on rats have shown that intraperitoneal administration of silver nitrate solution induces peritonitis while subplantar histamine, serotonin and prostaglandin E2 administration leads to an acute paw edema. Preliminary subcutaneous injection of lithium hydroxybutyrate prevents the development of inflammation.