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We undertook this study to evaluate effects of a long-term pretreatment with a new stabilized drug preparation n-3 polyunsaturated fatty acids (PUFAs) in the development of experimental adrenalin-induced necrosis of the myocardium. It was found out that the preliminary administration of PUFAs makes for a significant reduction in the mass of the infarcted area of the myocardium. Severely manifest arrhythmias were less frequently seen in treated animals, with death rates among them being lower than in controls, and what is more, an excess activation of the biomembrane lipid peroxidation and suppression of the function of the system of antioxidant defence, occurring in necrosis of the myocardium in an experimental setting, appeared to be generally preventable. It is suggested that the ability of n-3 PUFAs to modulate the properties of the biological membranes might account for the above effects.

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The effect of lithonite and piracetam on the cardiac rhythm, dynamics of infarction, metabolism, and immunological reactivity of the animals' organism was studied in dogs with experimental myocardial infarction. The pharmacotherapeutic activity of lithonite was found to be higher than that of piracetam.

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The effect of piracetam on the dynamics of the infarction development, free radical lipid peroxidation in the myocardium and the immunological reactivity was studied on dogs with experimental myocardial infarction during the course and prophylactic treatment. The antiarrhythmic, antihypoxic, antioxidant effects of the drug, its positive influence on the parameters of humoral and cellular immunity were revealed. The comparative assessment of piracetam action during cardiogenic stress caused by myocardial infarction showed a higher pharmacological effect in therapeutic use.

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Influence of litonit and piracetam on development of experimental myocardial infarction, free radical lipid oxidation in myocardium and immunological reactivity was studied in dogs. The analysis of pharmacological action of litonit and piracetam in cardiogenic stress proves more positive effect of litonit upon dynamics of myocardial infarction, peroxide lipid oxidation process, humoral and cellular immunity indexes.

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The influence of cyclophosphamide immunodepressants and 6-mercaptopurine on the electrocardiogram shifts, myocardial metabolism and humoral and cellular immunity indices has been studied on the dogs with experimental infarction. The results of the investigation show the incongruity to use cyclophosphamide immunodepressants and 6-mercaptopurine under myocardial infarction as they inhibit immunological reactivity, deteriorate coronary circulation and myocardial metabolism as well as retard reparative processes in the cardiac muscle.

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The effect of oral levorin used for a prolonged period of time on the lipid composition and activity of alkaline phosphatase and invertase of the microvilli membranes of the small intestinal enterocytes of old dogs was studied. Higher ratios of cholesterol/phospholipids in the membranes and inactivation of alkaline phosphatase and invertase were noted in the old dogs as compared to the young ones. Exposure of the old dogs to levorin had a significant effect on the microvilli membranes of the intestinal epithelial cells. It was evident from a lower ratio of cholesterol/phospholipids in the membranes and stimulation of the alkaline phosphatase activity. It is supposed that the changes in the state of the microvilli membranes of the small intestinal mucosa due to levorin play a definite role in the mechanism of its hypercholesterolemic action.

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The effect of prolonged oral use of levorin on chromatin from the hypertrophic prostate of old dogs was studied. It was found that the chromatin from the hypertrophic prostate of old animals was characterized by a decrease in the relative content of non-histone proteins, the melting temperature and hyperchromism value. The results of the electrophoretic analysis of the histone fraction composition showed its proteolytic degradation. The matrix activity of chromatin in the RNA-polymerase system remained unchanged. Administration of levorin had no effect on the structural and functional characteristics of the chromatin isolated from the hypertrophic prostate of the old dogs.

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The effects of amphotericin B drug containing sodium deoxycholate (DOC) and those of DOC and nistatin on the activities of Na+, K+-ATPase and 5'-nucleotidase of canine kidney plasma membranes were studied. It was found that the activities of Na+, K+-ATPase and 5'-nucleotidase were markedly inhibited only after intravenous injection of amphotericin B, whereas the other agents tested caused no changes in the enzyme activities. Similar results were obtained in vitro. In the presence of amphotericin B the activity of Na+, K+-ATPase was noticeably inhibited already at the antibiotic concentration of 0,1 mkg per mg of membrane protein. It was found that the injection of amphotericin B, DOC and nistatin did not qualitatively or quantitatively affect the phospholipid composition of the plasma membranes. This is indicative of the lack of correlation between the enzyme activities and changes in the phospholipid composition of the plasma membranes under effects of amphotericin B. The pyrimidine derivative--amygluracyl--markedly removes the inhibiting effect of amphotericin B on the enzyme activity of plasma membranes.

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Intraveneous injection of amphotericin B significantly affects the protein composition of canine kidney nuclear membranes. Electrophoresis in polyacrylamide gel showed that injection of this antibiotic results in a considerable loss or complete disappearance of the histone fractions H1 and H4 (depending on the dose) and a decrease in the content of fraction H3 in the membrane proteins. The fractionation spectrum of other nuclear membrane proteins also shows deviations from normal. One of possible reasons for that is the increased enzymatic degradation of the proteins. It is also probable that the changes in the protein composition of nuclear membranes are due to the presence of sodium deoxycholate in the antibiotic drug and may be accounted for by the nephrotoxic effect of polyenoic antibiotics.

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The effect of amphotericin B on the number of the ribosomes bound with the endoplasmic membranes in the dog kidney cells was studied in vitro. The binding of the ribosomes was evident from the RNA/protein ratio. It was found that the RNA/protein ratio in the rough membranes treated with amphotericin B in a concentration of Igamma/ml remained at the normal level. An increase in the antibiotic concentration up to 100 gamma/ml did not either change the number of the ribosomes bound to the membranes. On the basis of the results of the study it was possible to conclude that the toxic effect of amphotericin B on the kidneys was not associated with damaging of the ribosomal-membrane complexes in the kidney cells.

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Activity of Na+, K+-ATP- ase and 5'-nucleotidase, the lipid composition of the liver plasmic membranes with toxic and alimentary-alcohol fat dystrophy were studied on rats exposed to water-soluble sodium levorin. It was found that the above forms of the liver fat dystrophy did not change the activity of the enzymes in the membranes but caused significant shifts in the composition of the membrane lipids. The shifts were evident from an increased level of phospholipids in the plasmic membranes. Administration of levorin at the very beginning of the development of both the toxic and the alimentary-alcohol liver fat dystrophy aggravated the increase in the phospholipid level in the membranes. It was supposed that the increase in the phospholipid level due to levorin in the membranes of the liver with fat dystrophy was one of the mechanisms of the drug therapeutic effect in case of such pathology type. Levorin increased the amount of phospholipids in the dystrophic membranes and thus changed the membrane permeability resulting in decreased accumulation of neutral lipids in the hepacytes and subsequently in decreased levels of the liver fat dystrophy.

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The protein composition of the nuclear membranes of the dog kidneys after intravenous infusion of amphotericin B in a dose of 3 mg/kg and sodium desoxycholate in a dose of 1.2 mg/kg for 8 days was studied. It was found that administration of amphotericin B and sodium desoxycholate was accompanied by pronounced changes in the membrane proteins. The changes were evident from a decreased content of histones in the nuclear membranes, elimination of the high molecular components, a decreased quantitative content of some fractions and appearance of low molecular bands. The effect of sodium desoxycholate on the nuclear membrane proteins was shown to be less pronounced than that of amphotericin B. The significance of the data is discussed in connection with high toxicity of polyenic antibiotics. The data provide elucidation of the causes of the nephrotoxic effect of the polyenic antibiotics.

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Effect of amphotericin B and nistatin on ATPase activity of dog kidney nuclear membranes is studied in vivo and in vitro. Long-term intravenous injections of the antibiotics do not change the ATPase activity of kidney nuclear membranes. However, short-term injections of polyenic antibiotics have some effect on ATPase activity on nuclear membranes: amphotericin B, considerably activates the enzyme . In vitro incubation of isolated dog kidney nuclei with amphotericin and nistatin at concentrations of 1 and 10 mcg/ml does not affect the activity of nuclear membrane ATPase, while increased concentrations of polyenic antibiotics, (up to 200 mcg/ml) results in a slight inhibition of the enzyme activity. The role of the data obtained for solving molecular basis of the toxic effect of polyenic antibiotics.

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The effect of amphotericin B and nystatin on mitochondria isolated from the dog kidneys was studied. It was shown that incubation of the isolated kidney mitocondria with amphotericin B or nystatin at a wide range of their concentrations, i.e. from 0.1 to 100 gamma per 0.5 mg of the mitochondrial protein did not affect the activity of succinate dehydrogenase of these cell microstructures. The absence of changes in the succinate dehydrogenase activity of the mitochondria under the effect of the polyenic antibiotics is significant from the viewpoint of elucidating their molecular mechanisms of the nephrotoxic effect.

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Penetration of 14C-amphotericin AM-2 into the cells of the tissue culture of the human embryon kidneys was studied by means of light autoradiography after incubation with the antibiotic. Microscopic examination of the autographs of the cell slices revealed the presence of the radioactive label in the cytoplasm and nucleoplasm of the cells. The revealed intracellular localization of the label was evident of the antibiotic penetration into the cells.

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The effect of amphotericin B and its combination with amigluracyl on the dog kidney lyzosomes was studied in vitro. It was found that on incubation of the lyzosomes with the antibiotic in a concentration of 1 gamma/ml the latter stimulated liberation of proteases from them. At the same time, when the lyzosomes were exposed to amphotericin B in combination with amigluracyl, a significant decrease in the rise of the proteolytic activity in the incubation medium due to the antibiotic was observed. It was found that the combined use of amphotericin B with amigluracyl resulted in an intensive inhibition of the enzyme activity; The data are indicative of the fact that amigluracyl decreases the damaging effect of the antibiotic on the dog kidney lyzosomes.

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Amphotericin B at concentration of 0.1-1 mcg/ml is found to increase the yield of proteases from isolated dog kidney lysosomes. Further increase of amphotericin B concentration results in the decrease of proteolytic activity in the incubation medium, which is due to a considerable inactivation of proteases by high concentrations of antibiotic. Like amphotericin B, sodium deoxycholate, which is a part of many drugs, sharply inhibits the activity of enzyme, but, in contrast to the antibiotic, it almost does not release proteases from lysosomes. It is suggested that early described degradation of proteins of plasmic membranes and chromatin in dog kidney cells under the injection of amphotericin B is a result of the damage of lysosome membranes by the antibiotic.

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