[N-stearoylethanolamine effect on the level of 11-hydroxycorticosteroids, cytokines IL-1, IL-6 and TNFalpha in rats with nonspecific inflammation caused by thermal burn of skin].

The mechanisms of anti-inflammatory action of saturated N-acylethanolamine--N-stearoylethanolamine (NSE) were investigated on the rat model of nonspecific inflammation (thermal burns of the skin). The results showed that the NSE application in a form of aqueous suspension (10 mg/ml) on the damaged skin area during 12 days significantly accelerated the healing process of burned wounds. NSE also prevented the increase of 11-hydroxycorticosteroids content in the blood of rats with burns. There was also found a significant decrease of cytokines (IL-1beta, IL-6 and TNFalpha) levels under the NSE action. This way may be one of the mechanisms of NSE anti-inflammatory action.

[The effect of N-stearoylethanolamine on the activity of antioxidant enzymes, content of lipid peroxidation products and nitric oxide in the blood plasma and liver of rats with induced insulin-resistance].

The influence of N-stearoylethanolamine (NSE) on the content of lipid peroxidation products, activity of antioxidant enzymes and the nitric oxide level in the liver and blood plasma of rats with insulin-resistance (IR) state was investigated. IR state was induced in rats by prolonged high-fat diet (58% of energy derived from fat) for 6 months combined with one injection of streptozotocin (15 mg/kg of body weight). The existence of IR state was estimated by results of glucoso-tolerance test and blood plasma insulin content. The level of lipid peroxides products was shown to be higher in the liver of insulin resistant animals as a result of reduced superoxide dismutase and catalase activity, however, glutathione peroxidase activity was increased. The increase of nitric-oxide content in the liver and blood plasma of high-fat diet rats compared with healthy control animals was also observed. The administration of the NSE suspension per os in a dose of 50 mg/kg during 2 weeks to the rats with induced insulin-resistance state contributed to the increase of superoxide dismutase, catalase and glutathione peroxidase activity. In consequence of antioxidant enzymes activation the intensity of POL process was decreased. The NSE administration caused normalization of nitric oxide level, restoring pro-/antioxidant balance in the liver and blood plasma of rats with IR state. In conclusion, the NSE administration to the rats with insulin-resistance state restored pro-/antioxidant balance and enhanced the content of nitric oxide, therefore, improving insulin sensitivity.

Experimental study of radiomodifying properties of N-stearoilethanolamine under a combined impact of ionizing radiation and stress.

OBJECTIVE: to investigate the radiomodifying properties of N-stearoilethanolamine (NSE) in experiment under different conditions of a combined impact of ionizing radiation and stress. METHODS: biochemical, statistical. RESULTS: The radiomodifying properties of N-stearoilethanolamine were revealed under different conditions of a combined impact of ionizing radiation and stress according to the indices of plasma concentrations of TBA-active products, nitrite-anions and catalase activity. CONCLUSIONS: The radioprotective properties of NSE at a dose of 10.0 mg/kg before and after a single total 6.0 Gy irradiation of animals. The radioprotective properties of NSE are identified at a dose of 10.0 mg/kg of animal bodyweight before and after stress. The radiosensitizing properties of NSE occur upon the drug administration in a dose of 10.0 mg/kg before the combined impact of 6.0 Gy ionizing radiation and stress.

[Protective effect of N-stearoylethanolamine in acute alcohol intoxication in rats].

The influence of N-stearoylethanolamine on the nitric oxide system, the state of lipid peroxidation, antioxidant enzyme activity, content of phospholipids and fatty acids were studied under the acute ethanol intoxication (2.5 g/kg) in rats. The results of investigations show that acute ethanol intoxication caused abnormalities of the oxidative homeostasis accompanied by the accumulation of thiobarbituric acid reactive substances (TBARS). High catalase and glutathione peroxidase activity was also shown. The altered content of total and individual fatty acids of phospholipids in the rat liver tissue was found. The content of saturated fatty acids (palmitic, stearic) increased and amount of unsaturated (palmitoleic, oleic, linolenic) acids decreased under acute ethanol intoxication. The changes of nitric oxide content was found in the brain, plasma and red blood cells. N-stearoylethanolamine (NSE) in a dose of 50 mg/kg of body weight shows the pronounced antioxidative and hepatoprotective properties under these conditions. It was found that the preliminary NSE administration to rats inhibited accumulation of TBARS and caused a simultaneous increase of antioxidant enzyme activity. The NSE administration modulated also the content of total and individual fatty acids of phospholipids and the amount of nitric oxide in pathologically altered tissues. These results suggested that NSE protected the structural integrity and functional ability of cell membranes under the acute ethanol intoxication.

[Anti-inflammatory effect of N-stearoylethanolamine in experimental burn injury in rats].

The biochemical mechanisms of anti-inflammatory effect of endocannabinoid congener N-stearoylethanolamine (NSE) was studied on the model of experimental burn in rats. The animals after the thermal burn of the skin received per os during 7 days the water suspension of NSE in a doze 10 mg/kg of body weight. In the other groups of rats the suspension was applied to the wound (the concentration of NSE was 10 mg/ml). It was shown for the first time that NSE accelerated the process of burn wound healing by the inhibition of proinflammatory cytokines (TNFalpha, IL-6) production. NSE caused the normalization of the iNOS and cNOS activity and of nitrite content in plasma, erythrocytes, liver and spleen of rats. NSE also modified the antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) activity and diminished the level of lipid peroxidation. The discovered anti-inflammatory NSE properties suggest the possibility of its usage for burn treatment.

[Immunosuppressive characteristics of N-stearoylethanolamine a stable compound with cannabimimetic activity].

Results of investigation of biochemical mechanisms of N-stearoylethanolamine (NSE) influence on the processes of allergic responses of immediate and delayed type (anaphylactic shock in guinea pigs and contact hypersensitivity to 2,4-dinitrochlorobenzene in mice) are presented in the paper. NSE was given per os during two weeks. It was found that in anaphylactic animals, NSE prevented the growth of histamine levels in the heart, kidneys and spleen, suppressed NO2(-) level increase in these organs and promoted its normalization. At the same time NSE prevented the decrease of the level of stable metabolite of nitrogen oxide - nitrite-anion (NO2(-)) in the liver and to a lesser degree in the lungs, and also decreased the activity both inducible and constitutive NO-synthases. NSE normalized the content of TBA-reactive products in the lungs and decreased it in the heart, diminished the decline of activity of glutathione peroxidase, catalase and superoxide dismutase. Effects of NSE depended on its daily dose. About 70% of animals which received NSE in a dose 65 mg/kg of body weight had no fatal outcome after the induction of anaphylactic shock. NSE suppressed the delayed type hypersensitivity response and normalized NO2(-) content in the blood plasma of mice but only at the dose of 50 mg/kg of weight. In the thymus of sensitized mice NSE diminished the content of NO2(-). Thus, though NSE has no affinity for specific CB receptors, in other words, it is not a typical endocannabinoid, its ability to influence the immediate and delayed type allergic reactions opens a perspective for creation of new medications which differ principally from existing pharmacological drugs with anti-allergic and immunosuppressive properties.

[Effect of N-stearoylethanolamine on the lipid peroxidation process and lipid composition of the rat liver in acute morphine intoxication].

The effect of N-stearoylethanolamine (NSE) on the lipid peroxidation process, antioxidant enzymes activity, phospholipid and fatty acid content in the rat liver tissues under acute morphine administration was studied. It was shown that morphine administration (30 mg/kg of body weight) caused an increase of the amount of thiobarbituric acid reactive substances (TBARS), alteration of antioxidant enzymes activity, decrease the protein level, quantity of total lipids and phospholipids, phosphatidylcholine, cholesterol esters; altered the content of some individual fatty acids. NSE administration (50 mg/kg of body weight) promoted normalization of the antioxidant enzymes activity and prevented the TBARS accumulation and decreased the total lipid and phospholipid quantity, increased the content of free and total cholesterol, corrected the level of free and individual fatty acids. It was assumed that NSE possessed antioxidative, membranoprotective and adaptive properties.

[Inhibitors of arginase pathway in L-arginine metabolism as a new class of antihypertensive drugs: action of urea on oxidative and nonoxidative metabolism of L-arginine and vascular tone in chronic hypertension]. / Inhibitory arhinaznoho shliakhu metabolizmu L-arhininu iak novyi klas antyhipertenzyvnykh spoluk: diia karbamidu na okysnyi ta neokysnyi metabolizm L-arhininu i tonus sudyn pry arterial'nii hipertenziï.

It has been studied an action of chronic urea introduction (40 mg/kg, 14 and 28 days) as arginase inhibitor on nonoxidative (arginase activity, urea, polyamines content) and oxidative (NOS activity, nitrite- and nitrate-anion content) metabolism of L-arginine in aorta, heart, plasma and erythrocytes of SHR. It has been shown that urea is an inhibitor of not arginase only, but also ornitinedecarboxilase (ODK) reactions, limiting L-arginine consumption for urea and polyamines synthesis and thus facilitating its utilization for nitric oxide synthesis by NOS. These exogenous effects of urea are not accompanied by amelioration of tissue ischaemization within cardiovascular system. It has been shown that exogenous urea down regulate blood pressure without any normalization of endothelim-dependent reactions of smooth muscle cells on acetylcholine in SHR.

[Changes in vasodilator responses of vascular smooth muscles and nitric oxide system in experimental diabetes mellitus]. / Zminy vazodylatatornykh reaktsii sudynnykh hladen'kykh m'iaziv ta systemy oksydu azotu za umov eksperymental'noho tsukrovoho diabetu.

The experimental data of endothelium-dependent and endothelium-independent responses of vascular smooth muscles of isolated preparations of the thoracic aorta of rats with experimental diabetes mellitus (streptozotocin-induced diabetes) and a control group of animals are presented in the article. It has been shown that at diabetes mellitus endothelium-dependent vasodilation was deteriorated to the most extent. It resulted from dysfunction of the endothelium due to a reduce in the synthesis of NO. This conclusion was based on the data of the parameters of the contents of steady metabolites of nitric oxide (NO2- and NO3-), as well as activities of inducible and constitutive NO-synthases (iNOS and cNOS) in heart, aorta, erythrocytes and blood plasma in diabetic and control animals.

[Endothelium-dependent contractile reactions of vascular smooth muscles and content of oxygen free radicals in aging rats]. / Endoteliizalezhni skorochuval'ni reaktsiï sudynnykh hladen'kykh m'iaziv i vmist vil'nykh radykaliv kysniu u shchuriv za umov starinnia.

Endothelium-dependent and endothelium-independent reactions of vascular smooth muscles were studied in isolated preparations of thoracic part of aorta and portal vein of rats of two age groups--6.8 mo. (control) and 24-26 mo. (old animals). In old rats the disturbances occurred primarily in endothelium-dependent vascular reactions. This age-related dysfunction of endothelium resulted in inhibition of NO-dependent regulation of vascular tone. Age-related changes in the state of plasmic membranes of erythrocytes were established using a method of acid hemolysis. Age-related changes in the levels of active forms of oxygen (.O2-, H2O2, .OH-) and nitrogen (NO2-, NO3-) were determined in the myocardium, aorta, blood plasma and erythrocytes of adult and old animals.

[Effect of irbesartan--angiotensin II type I receptor inhibitor on oxidative metabolism of lipids in essential hypertension]. / Diia irbezartanu--prolonhovanoho antahonista AT1-retseptoriv anhiotenzynu II na okysnyi metabolizm lipidiv za umov hipertonichnoï khvoroby.

We evaluated the alters in plasma vasoconstriction eicosanoids (LTC4, TXB2) and diene conjugates (DC) levels in patients with essential hypertension (EH) after chronic (30 days, 235 mg per day) of irbezartane (inhibitor of ANG II type 1 receptor with prolongation action "Aprovel" from "Sanofi") oral administration. Patients with EH have significantly higher plasma both LTC4, TXB2 and DC levels then healthy controls. This imbalance can be beneficially modulated by chronic irbezartane ("Aprovel") administration. It is concluded that ANG II type 1 receptors can be involved in regulation of free arachidomc acid oxidation.

[Inhibitors of arginase in the L-arginine metabolic pathway as a new class of antihypertensive drugs: effect of carbamide on lipid oxidative metabolism and on vessel tonus during arterial hypertension]. / Inhibitory arhinaznoho shliakhy metabolizmu L-arhininu iak novyi klas antyhipertenzyvnykh spoluk: diia karbamidu na okysnyi metabolizm lipidiv i sudynnyi tonus pry arterial'nii hipertenziï.

Have studied action of chronic urea--an arginase inhibitor--introduction (40 mg/kg, 28 days) on blood pressure, endothelium-dependent reactions of aorta smooth muscle cells (SMC) and nonenzymatic (contents of diene conjugates and H2O2) and enzymatic (contents of free arachidonic acid and vasoconstrictic eicosanoids LTC4 and TXA2) oxidizing lipid metabolism of heart, aorta, plasma and erythrocytes of spontaneously hypertensive rats. Have shown, that urea down regulate blood pressure without any normalization of endothelium-dependent reactions of SMC of aorta and down regulate both enzymatic and nonenzymatic oxidizing lipid metabolism. Down regulation of two alternative (by cyclooxygenase and by lipoxygenase) enzymatic pathways of free arachidonic acid oxidizing metabolism by urea can be one of mechanisms of its antihypertensive action. The possibility of urea use at hypertension and various pathophysiological conditions are discussed.

[The C(27)-steroid hormones ecdysterone and calcitriol activate the phosphoinositol cycle in its membrane phase]. / C(27)-steroïdni hormony ekdysteron ta kal'tsytiol aktybuiut' fosfoinozytol'nyi tsykl u membrannii fazi diï.

We have examined in vivo the capacities of two C27-steroid hormones-phytoecdysteroid ecdysterone (20-hydroxyecdysone, 10(-8) M) and calcitriol (1 alpha, 25-dihydroxyvitamin D3, 10(-12) M), as a modulators of phosphoinositide cycle in the brain and heart cells. Severe lines of evidence indicate that both hormones may acts as positive regulators of phosphoinositide hydrolysis by phospholipases C and D in membrane (0.5-30 min) pre-genomic phase of its actions. Thus, our findings identify ecdysterone, like calcitriol, as a positive regulator of [Ca2+]i, and protein kinase in the mammalian cells.

[In vitro study of the early membrane effects of C27-steroid hormone ecdysterone, immobilized on the nanodispersed magnetite surface]. / Doslidzhennia in vitro rannikh membrannikh efektiv C27-steroïdnoho hormonu ekdysteronu, immobilizovannoho na poverkhni nanodyspersnoho mahnetytu.

The object of the study was to reveal the existence of receptor interactions of C27-steroid hormone ecdysterone with the surface of various cells (liver and spleen macrophages, thymus and spleen lymphocytes, erythrocytes and hepatocytes from rat organs) in experiments in vitro using ecdysterone immobilized on the nanodispersed iron surface (which did not penetrate the cell during observation) and the model of fast (during 15 s) activation of phospholipid signal system with ecdysterone. The parameters, which are characteristic of cell phospholipid signal system activation, were evaluated (the concentrations of free arachidonic acid, diene conjugates, tromboxane B2 and leukotriene C4) and its alteration in response to free and immobilized ecdysterone introduction in suspensins of intact cells and cells with the surface modified in vivo by pre-injection of antigen (human erythrocytes). Concurrent binding of immbilized ecdysterone with intact rat cells in the presence of free ecdysterone was also investigated. It was established that there are high-affinity ecdysterone-specific binding sites on the plasma membranes of all cells investigated, Kd estimated according to two different methods varied in the region of 10(-8)-10(-7) M. The characteristic features of the changes in parameters characteristic of phospholipid system activation were revealed to be queite similar in intact cells, as well as in cells with modified surfaces, under introduction of free ecdysterone and immobilized ecdysterone, which did not penetrate into cytosole. The data obtained point to the existence of ecdysterone receptors on the surface of cells plasma membranes and are indicative of the membrane effects as mechanisms of the early pregenomic phase of cells activation by ecdysterone.

C(27)-steroid hormones calcitriol and ecdysterone activates hydrolysis of neutral lipids--cholesterol esters and triacylglycerols--in its early pregenomic phase of action. / C(27)-steroïdni hormony kal'tsytriol ta ekdysteron aktyvuiut' hidroliz neitral'nykh lipidiv--efiriv kholesterolu ta tryatsylhlitseroliv--u rannii dohenomnii fazi diï.

We have examined in vivo capacities of two C27-steroid hormones-phytoecdysteroid ecdysterone (20-hydroxyecdysone, 10(-8)M) and calcitriol (1 alpha, 25-dihydroxyvitamin D3, 10(-12)M), as a modulators of neutral lipids hydrolysis in the brain and heart cells. Severe lines of evidence indicate that both hormones may acts as positive regulators of cholesterol esters and triacylglycerol hydrolysis in early (0.5-30 min) pregenomic phase of its actions, yielding known (DAG, free polyunsaturated fatty acids) and possible (free cholesterol) lipid second messengers.

The C(27)-steroid hormones calcitriol and ecdysterone in the early phase of its action activates hydrolysis of phosphatidylcholines in target animal tissues. / C(27)-steroïdni hormony kal'tsytriol ta ekdysteron u rannii fazi diï aktyvuiut' u tkaninakh-misheniakh tvaryn hidroliz fosfatydylkholiniv.

We have examined in vivo the capacities of two C27-steroid hormones--phytoecdysteroid ecdysterone (20-hydroxyecdysone, 10(-8)M) and calcitriol (1 alpha, 25-dihydroxyvitamin D3, 10(-12)M), as a modulators of phosphatidylcholine hydrolysis in the brain and heart cells of rats. Sever lines of evidence indicate that both hormones may acts as positive regulators of membrane phosphatidylcholine hydrolysis by phospholipases A2, C and D in early (0.5-30 min) membrane phase of its actions, yielding known lipid second messengers (diacylglycerol, phosphatidic acid) and soluble products, that may acts as second messengers (choline,choline phosphate, glycerophosphocholine).