Studies performed in the two past decades showed that the simple molecule of nitric oxide (NO) is a versatile regulator of numerous biochemical processes in humans and animals. It is known that NO is synthesized from L -arginine and oxygen by special enzymes-NO synthases. Today, the most well-known are three isoforms of this enzyme: two constitutive (endothelial and neuronal NO synthases; eNOS and nNOS, respectively) and one inducible iNOS). The first two NO synthases, eNOS and nNOS, are usually activated by increased concentrations of cytosolic Ca 2+ , which stimulates NO production within several minutes. These enzymes synthesize small quantities of NO (no more than tens micromoles). The inducible isoform of NO synthase, which is expressed predominantly in immunocompetent cells and nearly in all cells of the liver after stimulation with mediators of immune or inflammatory reactions, produces NO at millimolar concentrations [1]. In these cells, NO is used as an effector molecule that is involved in elimination of various pathogens (bacteria, viruses, tumor cells, etc.). A characteristic feature of iNOS in these cells is that its induction (and, therefore, NO synthesis) continues for a long time after stimulation-for several hours or even days.For example, in experimental models of endotoxemia in vivo , iNOS mRNA expression was detected for 3 h after the addition of a stimulator, whereas the maximal accumulation of iNOA was observed after 12-16 h [2]. In human hepatocytes stimulated by cytokines and LPSs, a single band of mRNA was detected as early as 4 h after stimulation; it reached maximum 8 h after stimulation and became negligible 48 h after stimulation. The level of mRNA was compared to the activity of iNOS, which was estimated by the accumulation of and in culture supernatant. The amount of these anions increased in 20-30 times 24 and 48 h after stimulation [3]. It was shown that the induction of iNOS in macrophages, neutrophils, and E. coli may be NO 2 -NO 3 -caused by ascorbic acid and that one peritoneal macrophage can produce as many as 1.5 × 10 9 NO molecules [4][5][6][7]. With regard for the fact that one arginine molecule is consumed for the synthesis of one NO molecule, a question arises as to where such a substantial amount of arginine can be taken. At such a high level of consumption, arginine should be synthesized as required. In mammals, arginine is synthesized in the liver in the urea cycle from citrulline and ammonia. It is believed that thus formed arginine is rapidly cleaved by arginase to urea and ornithine [8]. Published data on the withdrawal of arginine from the urea cycle and its function as a substrate of iNOS are absent [1,9,10]. In view of this, a question arises as to how the organism satisfies its increased requirements for arginine. In this study, we obtained data suggesting the existence of a special cycle of synthesis of arginine and NO in liver cells.Materials and methods. Ammonium chloride, citrulline, and arginine used in the study were from Acros (United States); human leuk...

Hypoxia is one of the most common states of the body. Virtually any extreme conditions of the body and any pathological process are directly or indirectly related to disturbed oxygen supply to the body. Hypoxia and associated metabolic disorders are the key pathogenetic factors of all severe complications in extreme conditions of various origins [1,2]. Studies of metabolic changes in the body showed that hypoxia is characterized by the prevalence of glycolysis rather than aerobic metabolism, a rapid depletion of reserves of glucose, glycogen, ATP, and creatine phosphate and an increase in the content of lactate [1][2][3][4]. As a result of these changes, metabolism is shifted toward catab olism, which is characterized by activation of proteol ysis, free radical processes, and lipid peroxidation [4,5]. There are no metabolic processes that would not change during hypoxia. In recent years, in connection with the discovery of the major role of nitric oxide as a factor involved in relaxation of blood vessels and a uni versal regulator of many biochemical processes in the body, it is of interest to study changes in the content of nitric oxide in blood and organs of animals under low oxygen conditions. Earlier, we studied the influence of hypoxia on the content of nitric oxide in the blood of KrushinskyMolodkina rats [6,7]. It was shown that the synthesis of NO in the blood of rats of this strain is increased as compared to Wistar rats. There is evidence indicating that hypoxia induced by placing Krushinsky-Molod kina rats to an altitude of 5000 m is accompanied by an increase in the intensity of the EPR signal of Hb NO complexes in blood. Despite the large number of stud ies on the formation of nitric oxide in the body, the question about the nature of all sources of increased nitric oxide in hypoxic conditions remains unan swered.We have investigated changes in the relative content of nitric oxide in the heart tissues of animals in hypobaric hypoxia (at the initial stages, immediately after the cessation of hypoxia) both separately and in the presence of sodium nitrite, an additional source of nitric oxide, and nitroarginine (L NNA), an inhibitor of nitric oxide synthesis by NO synthases. MATERIALS AND METHODSIn this study we used male Krushinsky-Molodkina rats 5-6 months old weighing 280-320 g. We per formed seven series of experiments (six animals in each experiment): 1-control (animals were intrap eritoneally injected with saline); 2-experiment with placing animals that were intraperitoneally injected with saline to an altitude of 5000 m (pressure chamber hypoxia); 3-experiment with the injection of L NNA in saline; 4-experiment with the injection of L NNA in saline + hypoxia; 5-experiment with the injection of NaNO 2 in saline; 6-experiment with the injection of NaNO 2 in saline + hypoxia; and 7-experiment with combined injection of NaNO 2 + L NNA in saline + hypoxia.Sodium nitrite at a dose of 0.5 mg per 100 g body weight and L NNA at a dose of 2.5 mg per 100 g of body weight were injected intraperitoneally. In ...

In experiments on mice we studied the effect of individual or combined treatment with mexidol and nitroglycerine on iron-sulfur centers of the mitochondrial respiratory chain, cytochrome P-450 of the endoplasmic reticulum, and nitric oxide formation in the liver tissue. Mexidol had a potent effect on these parameters and protected iron-sulfur centers from oxidation, including that induced by nitroglycerine.

The major task of our investigation is to study electron aspects of interaction of antitumor compounds with the cell components. At present, some nitrosourea derivatives are of significant interest. Methylnitrosourea (MNU) is the most effective antitumor compound used in therapy [ 1-31. This paper gives the results of investigation of MNU electron structure observed by ESR and quantum-chemical methods. To elucidate the nature of MNU chemical activity the nitrosourea derivatives, which are not effective inhibitors of tumor growth, were also studied. The MNU electron structure data proved to be useful in clearing up the mechanism of interaction between MNU and DNA bases. The electron structure of MNU molecule and its ion radicals were calculated by INDO means. In this program the spatial coordinates of all atoms were calculated by ECM from the predetermined values of valency links, valency angles, and dihedral angles. Geometrical parameters of molecules were chosen from the table of standard geometrical parameters [4]. The angles between valency links are: for trihedral hybridization-120", for the tetrahedral one-109.5". All structures are planar with the exception of the following: (i) in molecule I the bond C7-H8 is perpendicular to the molecule plane; the C7-HI0 and C7-H9 bonds make the angle of 30" toward the molecular plane; (ii) in molecule I1 the angle N1C203 is 135"; (iii) in molecule I11 the bond C7-Cio is perpendicular to the molecular plane and the C7-Hs bonds make the angle of 30" toward the molecular plane. The comparison of differences in electron structure of MNU and ,its derivatives should be valid since the geometry of these molecules was chosen on the basis of equal assumptions.I. Methylnitrosourea 11. Nitrosourea (NU)

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