[Neutrophils' contribution to ischaemia and reperfusion injury in liver]. / Udzial neutrofili w uszkodzeniu watroby na skutek niedokrwienia i reperfuzji.

Neutrophils are cells which induce liver injury due to ischaemia and reperfusion. They are active especially in the later phase of reperfusion (> 6 hrs) since they gather in the liver and release mediators damaging hepatocytes directly. Inflow ofneutrophils into the liver is possible due to chemotaxia which involves, among others, chemokines CXC (interleukin-8 and its counterparts). Neutrophils' ability to induce chemotaxia is determined by their specific glycoprotein receptors in cell membranes. Neutrophils contribute to ischaemia/reperfusion liver injury because they adhere to vessel endothelium, cross the wall of hepatic microcirculation vessels and adhere to hepatocytes. Selectins play a crucial role in neutrophils' contact with endothelial cells, and ICAM-1, predominantly in their adhesion to hepatocytes. Also beta2-integrin and Mac-1 play essential role. Neutrophils damage hepatocytes by realising proteases, free radicals, TNF-alpha, TGF-beta and leucotrien. Neutrophils together with endothelial cells also disturb the hepatic microcirculation.

Trimetazidine increases [3H]glucose uptake in rat brain.

Trimetazidine, a clinically effective antianginal agent with no negative inotropic or vascular properties, acts by optimizing cardiac energy metabolism through inhibition of free fatty acid oxidation, shifting substrate utilization from fatty acids to glucose. Up to now there has been no study associating trimetazidine's effect on metabolic processes with glucose utilization in the mammalian brain. The objective of the present study was to determine if trimetazidine altered [(3)H]glucose uptake in rat brain. Adult male Wistar rats were administered trimetazidine (Metazydyna, Polfa) either as a single dose (10.0 mg/kg po) or for 14 consecutive days (5.0 mg/kg po per day) or vehicle saline (2.0 ml/kg po). Sixty minutes after the single dose or 14th dose of trimetazidine, and 15 min before experiment termination and brain dissection, 6-[(3)H]D-glucose (500 Ci/kg ip; Amersham) was administered. Using liquid scintillation counting, trimetazidine, either in a single or multiple dose regimen, was found to increase [(3)H]glucose uptake (DPM/100 mg of wet tissue) in all dissected regions of the brain (i.e., striatum, hippocampus, frontal cortex, thalamus with hypothalamus, pons with medulla oblongata, and cerebellum). Therefore, central effects need to be taken into consideration as possibly adding to known beneficial cardiac effects of trimetazidine.

[Apoptosis and necrosis--two different ways leading to the same target]. / Apoptoza i martwica--dwie drogi do jednego celu.

Both apoptosis and necrosis lead to the same target, i.e. the death of the cell. However their mechanisms are different although they are evoked by similar factors. The differences between apoptosis and necrosis concern not only morphological features but also biochemical changes taking place in the cell. In the case of apoptotic death of cell, its intracellular content is not released and that is why inflammatory reaction, which is present in necrosis, is absent. In necrosis, defined as a passive death, majority of enzymes as well as metabolic tracts are lost and the released lysosome enzymes digest cellular components. Apoptosis, on the other hand, is an active process which requires supply of adenosine triphosphate (ATP) and which is controlled by many genes. There are many factors that determine the kind of cell death. The most important of them seems to be the level of intracellular ATP connected with caspase activation. This is the reason why mitochondria are considered to be the main cell organelles, which determine the type of cell death. Disturbances in the flow of ions connected with the activation of specific ion channels as well as free oxygen radicals are of importance here, too.

Proteinous amino acids in muscle cytosol of rats' heart, after their treatment with propranolol, pentylenetetrazol or reserpine.

Tissue levels of nineteen amino acids and total free amino acids, were assayed by gas-liquid chromatography in cytosols of rat atrial and ventricular muscle cardiomyocytes. The tissues were assayed after the rats had been administered IP with the three cardioactive drugs, exerting a significant effect on their heart action: propranolol, pentylenetetrazol and reserpine. It was demonstrated that while in the atrial and ventricular cardiac muscle cytosols of control rats, arginine, glutamine and cysteine were detected in high levels (35.1% and 17.6%; 14.8% and 51.6%; 9.9% and 0.25% of the total free amino acids, respectively), all three drugs significantly reduced the total amounts of cytosolic free amino acids in both atrial and ventricular heart muscles. All three drugs (with reserpine in particular) modified the levels of arginine, cysteine, phenylalanine, tryptophan, isoleucine and tyrosine. The role of these amino acids in the heart muscle cytosol, and their involvement in the mechanism of action of these three cardioactive drugs, is discussed.

Proteinous amino acids in hearts' muscle cytosol of rats pretreated with digoxin, caffeine or isoproterenol.

Levels of the 19 proteinous amino acids and total free amino acids were assayed by gas-liquid chromatography in cytosols of rat atrial and ventricular muscle cardiomyocytes. The tissues were assayed after the rats had been exposed to the cardioactive drugs digoxin, caffeine, and isoproterenol, each having different mechanisms of action. We demonstrated that, in the atrial and ventricular cardiac muscle cytosol of control (untreated) rats, arginine, glutamine, and cysteine existed in their highest levels: 35.1% and 17.6%; 14.8% and 51.6%; 9.9% and 0.25% of the total free amino acids, respectively. The levels of the other amino acids in the atrial and ventricular cardiac muscle cytosols ranged between 0.1% and 10.0% of the total free amino acids. Digoxin, caffeine, and isoproterenol significantly reduced the total amount of cytosolic free amino acids in the atrial heart muscle cytosol to 7.6%, 9.0%, and 9.2% of the control value (100%), and in the ventricular heart muscle cytosol to 31.1%, 43.2%, and 28.3% of the control. The three drugs tested changed the cytosols' levels of arginine, cysteine, tryptophane, asparagine, and tyrosine in atrial and ventricular heart muscle cytosol, as compared to the control groups (calculated as a percent of the total free amino acids in the experimental groups). The role of proteinous amino acids in the function of the heart muscle and in the mechanism of action of these drugs on the mammalian heart is discussed.

[Effect of ischemia and reperfusion on liver circulation changes]. / Wplyw niedokrwienia i reperfuzji na zmiany w krazeniu watrobowym.

Liver transplantation is becoming more and more common treatment method of liver diseases. The occurring complications may result from ischemia and reperfusion. However, the precise mechanism of these changes is not fully known. Microcirculation disturbances leading to ischemic damage of cells or their death are among those factors which cause liver damage under the influence of ischemia and reperfusion. These disturbances are intensified by increase of liver ischemia time and correlate with the number of wasted away hepatocytes. Endothelial cells, Browicz-Kupffer cells, neutrophils and thrombocytes are thought to play an essential role in liver microcirculation disturbances. Disturbed balance between local vasodilators and vasoconstrictors is also an important factor as it increases the lesions caused by reperfusion due to improper blood circulation. Nitrogen oxide (NO) is the most important local vasodilator. Inhibition of its synthesis in the period of early liver damage due to reperfusion causes a decrease of blood flow and increase of the occurring changes. Such strong vasoconstrictors as endothelin-1 and thromboxane play an important role. Reperfusion by damaging endothelial cells of sinusoid vessels affects the loss of endothelial barrier by the liver sinusoid vessels.

Proteinous amino acids in muscle cytosol of rats' heart after exercise and hypoxia.

Levels of 19 proteinous amino acids and of total free amino acids were assayed by gas-liquid chromatography in cytosols of rat atrial and ventricular heart muscle cardiomyocytes. These amino acids were assayed after the rats had been exposed to either exercise (swimming) or hypoxia (hypobaric pressure of 686 hectoPascals). Out of the total free amino acids levels of arginine, glutamine and cysteine in atrial and ventricular cardiac muscle cytosols of control rats were the highest of all amino acids assayed. The control levels of all other amino acids assayed in atrial or ventricular cardiac muscles ranged from 0.1% to 10.6% of the total free amino acids in the control rats. Physical stress (exercise and hypoxia) significantly reduced the total amount of cytosolic free amino acids in both heart muscles. While hypoxia decreased the levels of arginine in both heart muscles, exercise abolished the level of cysteine in the atrial heart muscle. Decrease in arginine levels, and elimination of cysteine from the heart's atrial muscle after physical stress, may be attributed to its utilization of nitric oxide and to its synthesis of atriopeptin and/or endothelin during stress. No change was recorded in either experimental group in the level of glutamine in heart muscle cytosol. Exercise and hypoxia affect, in different modes, the levels of all other amino acids assayed, except for tryptophan, tyrosine, and histidine, which are precursors of endogenous neurotransmitters. The impact of proteinous amino acids on some bodily functions is discussed.

RNA and protein synthesis in different organs of rat offspring after chronic cadmium exposure during pregnancy.

Despite binding by placental metallothionein, cadmium (Cd) relatively easily enters fetal circulation and may be harmful to tissues and organs of offspring. Although Cd toxicology is relatively well described in the literature there are only few studies on Cd toxicity exerted during fetal life. We examined the influence of cadmium exposure during pregnancy on RNA and protein synthesis in different organs of the rat offspring. Their dams were fed diet containing cadmium chloride-treated drinking water during the whole pregnancy period at 50 ppm dose level. The offspring, 6-weeks-old male Wistars rats, weighing 105 + 10 g were subjected to examination. Synthesis of RNA and proteins was quantitated by scintillation technique, which measured incorporation of tritiated uridine and alanine, respectively. A set of 17 organs and tissues was examined. RNA synthesis increased significantly in buccal mucosa, tongue, parotid gland, cardiac muscle, brain and bone marrow. A strong induction of RNA synthesis in all four studied brain regions attracts special attention. The activation of RNA metabolism may be partly explained by the increased expression of genes involved in detoxication and adaptation (e.g., metallothionein, stress response proteins, etc.). A profile of protein synthesis was much more heterogenous with elevated H3-alanine uptake in 12 organs of experimental animals, however without any statistical significance. Since the study of protein synthesis did not demonstrate any significant changes in Cd-treated animals, the profile of RNA synthesis cannot be simply extrapolated on protein synthesis, probably because of complex post-transcriptional and post-translational genetic modifications.

[Ammonia and GABA-ergic neurotransmission in pathogenesis of hepatic encephalopathy]. / Amoniak i neurotransmisja GABA-ergiczna w patogenezie encefalopatii watrobowej.

Pathogenesis of hepatic encephalopathy has not been fully revealed and there are many factors which may affect its development. Ammonia and changes in GABA-ergic neurotransmission seem to be the most essential of these factors. Hepatic encephalopathy is frequently, though not always, accompanied by elevated blood ammonia level. Due to the changes in permeability of blood-brain barrier the ammonia level in the brain also increases which results in both stimulating and inhibitory neurotransmission disturbances. Ammonia also affects abnormal interaction of metabolic neurones and astrocytes as well as glutamine-serotonin balance. Another essential factor affecting hepatic encephalopathy development are disturbances in GABA-ergic neurotransmission connected with GABAA receptor complex. When the liver is damaged GABA-ergic neurotransmission increases due to a higher GABA level, natural benzodiazepine receptor agonists as well as neurosteroids synthesised in astrocytes. Many studies point to the fact that ammonia and GABA-ergic neurotransmission disturbances interrelate with each other. There is a concept saying that both these factors cause hepatic encephalopathy. Ammonia may indirectly increase GABA-ergic neurotransmission and also inhibit the function of the central nervous system by synergistic activity with benzodiazepine receptor ligands. So far it is not known whether GABA-ergic neurotransmission is affected by ammonia only or by other factors as well.

[Therapeutic management of hepatic encephalopathy]. / Postepowanie terapeutyczne w encefalopatii watrobowej.

Therapeutic management in hepatic encephalopathy depends on its etiology as well as progression degree. Both in acute and chronic encephalopathy one should tend to establish probable causes and try to eliminate them. Cutting down on proteins in diet is one of the most important suggestions in chronic hepatic encephalopathy. In order to reduce intestinal production of ammonia, non-absorbable disaccharides (lactulose), antibiotics (neomycin) and sodium benzoate are the most commonly used. Branched chain amino acids administered orally or parenterally may be useful in improving patient's condition and restoring the balance of blood amino acids. The GABA-benzodiazepine receptor theory led to application of its antagonists, such as flumazenil, in the management of hepatic encephalopathy. However, providing a proper treatment is not easy due to unstable and often not very characteristic course of hepatic encephalopathy. What is more, clinical trials of some drugs used in the treatment of hepatic encephalopathy do not confirm their effectiveness.