[Possible mechanism of hyperemia in the skin caused by non-painful mechanical pressure].

It is believed that hyperemia in the skin, resulting from applied weak mechanical pressure delays the development of ischemia, and that it is a defensive neurovascular reaction against the local pressure, which can be considered as a critical point in terms of prevention of ischemia and, respectively, the risk for development of bedsores. Taking into account that nitric oxide can be released from autonomic nerves and make a significant contribution to the functioning of the mechanism of neurogenic vasodilation in different tissues, and the fact that the same role can also play the calcitonin gene-related peptide, the aim of this study was to clarify the role of each of these factors in the development of local hyperemia caused by non-painful, mechanical pressure on the skin. In experiments on white rats with a quantitative measurement of the intensity of skin blood flow, it was confirmed that in case of non-painful pressure acting on the skin, two-phase reaction of local blood flow appears - at first there is an increase in its level, and then an exponential decrease with stabilization at a level below the initial one. Analysis of received data allow to make conclusion that in relization of this phenomenon the role of trigger element belongs to nitric oxide, and the role of the executing unit - to calcitonin gene-related peptide. The effectiveness of this combined mechanism is limited by development of dominance of pressor-induced mechanical compression of cutaneous vessels over its vasodilator effect.

[Possible role of nitric oxide in newborns weight gain disorder caused by prolonged dexamethasone therapy (experimental study)].

Experimental studies on rats revealed that the newborns growth retardation, caused by long-term treatment with Dexamethasone in the neonatal period, can be prevented by the simultaneous with dexamethasone administration of the nitric oxide donor--L-arginine. This indicates that the mentioned Dexamethasone-induced growth disorder is caused by inhibition of Nitric Oxide Synthases activity.

Mechanism of cardioprotective effect of adenocine and non-glycoside cardiotonic drugs during experimental chronic cardiac insufficiency.

The therapeutic action of adenocine during cardiac insufficiency (heart failure) caused by ischemic (stenosis) or reperfusion (removal of ligature) injury to the myocardium prevents depletion of ATP, the major energy source for myocytes in the right and left ventricles, and a drop in NAD/NADH ratio. The development of energy shortage during heart failure cannot be eliminated by ß-acetyldigoxin, levosimendan, or milrinone: the content of ATP in the right and left ventricular myocardium remained below the normal level by 28 and 29%, 37 and 33%, 32 and 28%, respectively; the NAD/NADH ratio of the energy supply system in cardiomyocytes did not return to normal. Adenocine increased the content of NAD to the normal level in both the right and left ventricles, while it remained below the normal level after administration of ß-acetyldigoxin (by 24 and 19.5%, respectively), levosimendan (by 27 and 29%), and milrinone (by 26 and 24%). In contrast to ß-acetyldigoxin, levosimendan, and milrinone, adenocine inhibited activity of poly(ADP-ribose) polymerase in both ventricles. It is concluded that adenocine directly inhibits the key enzyme triggering apoptosis; we also hypothesized that this drug activates the regulatory and signal mechanisms arresting apoptotic alterations in the myocardium during heart failure.

Comparative therapeutic efficacy of adenocin and non-glycoside cardiotonic drugs in chronic heart failure at rest and under conditions of heart overload.

Experiments were performed on the model of chronic heart failure. Functional capacity of myocardial structures under conditions of maximum pressure overload was within the upper limit of normal after treatment with Adenocin. The myocardial functional reserve and potential capacity index were shown to increase to normal under these conditions. Dobutamine, levosimendan, and milrinone increased functional capacity under conditions of maximum pressure overload. Treatment with adenocin restored diastolic function of the heart under conditions of maximum pressure overload. The end-diastolic pressure increased, but remained 1.7 times below the level observed in heart failure. After treatment with dobutamine and milrinone, the end-diastolic pressure (8th episode of ligation) did not differ from the level observed in heart failure, while after administration of levosimendan this parameter decreased by 31%. Contraction-relaxation coupling was completely restored under the influence of Adenocin in all episodes of ligation both before and after removal of the ligature. Nearly all animals with heart failure were resistant to 8 episodes of ligation after treatment with Adenocin (89 vs. 96% under normal conditions). Under these conditions, the survival rate of animals after administration of levosimendan, milrinone, and dobutamine was 65, 60, and 61%, respectively, (the mortality rate of animals with heart failure was 75%). Adenocin, a cardiotonic drug with cardioprotective properties, in contrast to other cardiotonic drugs, has a modulatory effect on the system of cell energy supply, restores myocardial reserves, and improves myocardial function under conditions of overload.

[Possible mechanism of behavioral disorders in rats under long term treatment with dexamethasone in neonatal period].

Despite the fact that the side effects of prolonged treatment with dexamethasone are well known, information about its effects on the central nervous system is very limited. Experimental study of long-term effects of dexamethasone administration in the neonatal period on behavioral activity of rats in the open field was conducted. Four groups of newborn males were selected from the offspring of pregnant rats. The first group was left intact, the animals of second group were injected saline solution, the third group - with the dexamethasone and the fourth group - along with dexamethasone received L-arginine. Tests in an open field for all groups of animals were carried out on the 45th (first test) and 60th (second test) days after birth. The results showed that the decrease in motor activity of animals and in the number of sectors crossed in the open field with a high statistical significance was observed only in the group of animals, which for four days in the neonatal period underwent dexamethasone treatment. At the same time, another group of animals, which was also injected dexamethasone in the same doses, but additionally was injected L-arginine, the behavior in the open field did not differ from the intact animals or animals which were injected (as a control) saline solution. It was concluded that it is the lack of nitric oxide in the early neonatal period, which occurs as a result of dexamethasone treatment that causes observed changes in animals' behavior.

[The perspectives of using lectins in immunodiagnostic and gene therapy].

In this article review diagnostic value of protein group-lectins for practical oncology are presented. It is indicated, that with some carbohydrate structures lectins revealed the possibility of reversible and selective action and with earlier elaborated methods, which are based on identification of antigen determinants with antibodies, they can significantly increase of tumour diagnostic sensitivity and specificity. It is consider the mechanisms of relationship between so-called mannan-binding lectins and mannans or carbohydrate structures, which are formed from the mannose residue. The presense of such mannose-enrich structures is connecting with the process of blastomic transformation. It was shown experimentally, that mannan-bindig lectins are interacting with the carbohydrate chains of the markers of blastomic transformation, particularly with the cancer-embryonic antigen. It was established the markedly increase of lectins gene expression in transformated cells. The gene therapy, which comprises the deliver of therapeutic genes to cells and tissues by virus vectors and nonvirus systems is also analysed. The last of them are the most widely using ligands containing oligosaccharides, because on the surface of many animal origin cells were identified lectins-protein receptors. It is suggested the perspectives of using oligosaccharide probes, which are the ligands for endogenous receptors-lectins in tumour diagnostic and guiding transport of medicinal products.

[Imidazoline receptors].

An increasing number of studies suggest that the pharmacology and therapeutic potential of a family of imidazoline receptors continues to generate substantial interest of investigators. This review analyzes the functional role of imidazoline receptors, their subpopulation, distribution in the central and peripheral nervous system and action of related ligands. Besides to their brainstem location where I1-receptor sites play a significant role to regulate and modulate blood pressure, they also are found in different parts of brain with the highest densities in the striatum, pallidum, hippocampus, amygdala, substantia nigra, while I3-receptor sites were revealed in pancreas which enhances insulin secretion, I2-receptors are widely distributed in interpeduncular nucleus, arcuate and pineal gland and take a part in monoamine turnover. It is conclusion that imidazoline receptor in near future can become a therapeutic target in the treatment of diabetes, stroke, mood disorders and hyperalgesic condition.

[Comparative characteristic of angiotensin-converting enzyme inhibitor--captopril and the angiotensin II receptor blokers--losartan action on the oxidative metabolism in experimental hyperlipidemia in rabbits].

The aim of present study--comparative characteristic of captopril and of losartan action on the oxidative metabolism in experimental hyperlipidemia. Experiments carried out on rabbits,which were divided into three groups(ten animal in each group) and orally receiving during 45 days: I control group (cholesterol 500mg/kg + methylthiouracil 100mg/kg, II group-captopril 5 mg/kg + cholesterol 500mg/kg + methylthiouracil 100mg/kg, III group-losartan 8mg/kg + cholesterol-500mg/kg + methylthiouracil 100mg/kg. Activity of superoxide dismutase, catalase, level of malonic dialdehyde, osmotic resistance of erythrocytes and resistanse of LDL to oxidation and concentration of nitric oxide in the blood have been evaluated . The administration of captopril and losartan in experimental hyperlipidemia eqivalently increased activity of SOD and catalase, osmotic resistance of erythrocytes and resistanse of LDL to oxidation, whereas decreased content of malonic dialdehyde compared to the control group . Captopril was more effective than losartan in preserving of nitric oxide. We conclude that captopril and losartan inhibited oxidative stress, which are probably associated with the inhibition of angiotensin 11. Captopril and losartan are safely used in patients during cardio-vascular disease with dyslipidemia.

[The modulatory influence of moxonidine on the different link of sympatho-adrenal system and hemodynamic reactions in normo and hypertensive rats during emotional stress].

Effect of moxonidine on hemodynamic parameters, baroreflex sensitivity (BS) and sympatho-adrenal system was studied on the model of emotional stress in normotensive (N) and hypertensive (H) rats. Moxonidine was administered intravenously in daily dose 100 mcg/kg during one week prior to stress condition. It was shown that moxonidine reduced pressor reactions of arterial pressure, tachycardia and have increased BS especially in H animals, which was blunted during aversive stimulation. Moxonidine also revealed the effect of pharmacological correction of catecholamine - norepinephrine and epinephrine content in the myocardium and adrenals in stress and post stress period more markedly in H rats. The data obtained indicate the preventive antistress activity of the moxonidine.

[The modulatory role of phospholipids, phosphorylcholine ethers and alkylphosphocholines in signal transduction].

The aim of this review is to provide the molecular evidence as well as the properties and significant role of the platelet activating factor, acetylalkylglycerylic ethers analogs of phosphorylcholines and the alkylphosphocholines, a new class of pharmacophores, in signal transduction processes. These substances are involving in many cellular functions, including immune responses, differentiation, growth control, migration, tumor promotion and cell death. It was established that alkylphosphocholine have inhibitory activities on protein kinase C (PKC) and phospolipase C. Recent data showed that PKC plays an important role in intracellular signalling process and PKC pathway of signal transduction may be involved in cellular differentiation and in the induction of apoptosis. Alkylphosphocholines and their prototype hexadecylphosphocholine (miltefosine) also produce differentiation-inducing effect on hematopoetic cells in vitro and in vivo leading to leuko-and thrombocytosis. It was shown that various PKC isoenzymes regulate the expression of enzymes important for malignant phenotype and PKC suppression by milthefosine may affect tumor invasion and metastasis formation. Miltefosine is able to change immunological reactions to enhance the immune response of interleukin-2-stimulating mononuclear cells, resulting in interferon gamma gene expression and interferon gamma secretion. It has been shown after miltefosine influence a significant maturation of lymphoid tissues and increased numbers of immune cells, which is an additional conformation of miltefosine influence of cell differentiation. It is evident that phosphocholilipids and phosphocholines interact with signal transduction pathways which can lead to alteration of different biological effects.

Role of leukotrienes in stress-induced damage to the heart.

Experiments on rabbits with epinephrine-induced damage to the heart showed that progression of necrotic degenerative processes in the myocardium is augmented by increased content of prostaglandin F(2alpha)and predominance of constrictive over vasodilatory effects in the E and F(2alpha)prostaglandin system. Twenty-four hours after injection of epinephrine we observed an increase in blood concentrations of myofibrillar fraction of creatine phosphokinase, serotonin and histamine, and the F(2alpha)/E prostaglandin ratio. The concentration of leukotriene B(4)increased during the urgent adaptation period, which correlated with a decrease in elastic properties of erythrocytes. In vitro passage of erythrocytes through a 2.5-micro capillary sieve sharply decreased, which played an important role in the progression of myocardial and cerebral hypoxia and ischemia. Myocardial necrosis and endothelial dysfunction developed 24 h later aggravate these pathological shifts.

Use of zafirlucast, cysteine-containing leukotriene antagonist, in epinephrine-induced heart injury.

Combination of preventive and repeated (after 12 h) injections of zafirlucast in a daily dose of 40 mg/kg to animals with epinephrine-induced heart injury essentially decreased the content of leukotriene C(4), but did not prevent the increase of leukotriene B(4)content in the blood, though decreased its content in comparison with the level observed 24 h after epinephrine injection by 11%. Two injections of zafirlucast had a favorable impact on serotonin content in the myocardium (this parameter decreased by 19%), promoted a decrease in epinephrine content and normalization of the norepinephrine/epinephrine ratio, did not change prostaglandin content and ratio, and slightly decreased histamine content in the myocardium. The effect of zafirlucast can be explained by a decrease of oxidative stress. Zafirlucast decreased blood content of myofibrillar fraction of creatine phosphokinase (by 22%) and slightly improved elastic characteristics of erythrocytes. These results suggest that zafirlucast can be added to combined therapy of necrotic, stress-induced, hypoxic, and ischemic injuries of the myocardium.