Nitrogen Oxide Metabolites Research Articles

Derivatives of 3-Hydroxypyridine in The Correction of Disorders in The Structural and Functional Properties of Erythrocytes in Experimental Acute Destructive Pancreatitis Due to Chronic Ethanol Intoxication

At present, acute pancreatitis only in some areas is a rather well-studied disease of the abdominal organs, however, the destructive forms of this disease have various developmental patterns, complications and, often unfavorable outcomes. The aim of the research is to establish the possibilities to correct the disorders in the functional and structural features of erythrocytes by 3-hydroxypyridine derivatives in experimental acute destructive pancreatitis due to chronic ethanol intoxication. In experimental acute destructive pancreatitis due to a 60-day ethanol intoxication there was a decrease in the content of proteins (a - ? ß -spectrin, ankyrin, anion transport protein, actin, gyceraldehyde-3-phosphate dehydrogenase, glutation-S transferase) and lipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophospholipids, sphingomyelin, phospholipids, triacylglycerol, sum of mono- and diacylglycerol), an elevated level of band 4.1 and 4.5 proteins, pallidin, dematin, tropomyosin and lipids (lysophosphatidylcholine, cholesterol, it’s esters, non-esterified fatty acids), a disorder in intrinsic cellular metabolism of erythrocytes (an increased concentration of lipid peroxidation products, a decreased activity of catalase, superoxide dismutase, degree of stable metabolites of nitrogen oxide and sorption indicators of membrane) in the erythrocyte membrane. The study has revealed that the greatest efficiency in correction of disorders in the functional and structural feutures of erythrocytes from among the derivatives of 3-hydroxypyridine has a compound ß - hydroxynicotinoylhydrazon 2-methyl-3-hydroxy-4-formyl-5-oxymethylpyrydine dihydrochloride, and the least one - 2-ethyl-6- methyl-3-hydroxypyrydine malate (etoxydol), the administration of 2-ethyl-6-methyl-3-hydroxypyrydine succinate (mexidol) has shown an intermediate result.

Особливості системних патобіохімічних реакцій на ішемію-реперфузію головного мозку у щурів із цукровим діабетом

The objective of the research was to study the signs of oxidative stress, the state of proteolysis, and the proteinase-inhibiting system of the blood plasma in rats with streptozotocin-induced diabetes mellitus (60 mg/kg intra-abdominally), complicated by cerebral ischemia-reperfusion. Levels of products of lipid peroxide oxidation, protein oxidative modification, nitrogen oxide metabolites, and activity of the antioxidant protection enzymes were determined by means of biochemical methods one hour after completion of the reperfusion period and on the 12th day. Increased intensity of lipid peroxidation was found to occur in the blood plasma of rats without diabetes mellitus in both terms of observation. This was accompanied by an increase in the activity of all the antioxidant enzymes, while in animals with diabetes the amount of lipid peroxidation products decreased in the ground of prevailing depression of all the antioxidant protection enzymes. Irrespective of a tendency of changes in the amount of POM products with cerebral ischemia-reperfusion, their content is reliably higher in animals with diabetes mellitus in both terms of observation than those in animals without diabetes, which is indicative of a higher intensity of their oxidation. Without diabetes, the proteolytic activity of the blood plasma reacts by increasing the values of the studied parameters against the background of suppression of the proteinase inhibitory system during the entire observation period, in rats, with diabetes the parameters of plasma proteolysis and the state of the proteinase-inhibiting system remain without changes in both terms of the observation. The data obtained allowed us to state that diabetes mellitus considerably modifies the response of the systemic pathobiochemical indices to cerebral ischemia-reperfusion.

Endothelin-1 and nitrogen oxide metabolites in risk diagnostics of arterial hypertension in persons of young and middle ages occupied in harmful working conditions.

Hypertension is a global public health problem. One of the reasons contributing to the development of arterial hypertension is endothelial dysfunction, which is expressed in the imbalance of vasoactive indicators of vascular tone - nitrogen oxide and endothelin-1. Monitoring the indicators of endothelial dysfunction in workers exposed to harmful occupational factors will help to identify a risk group for the development of occupationally caused diseases of the cardiovascular system and, in particular, arterial hypertension, for early implementation of preventive measures. This study aims to identify the relationship between endothelin-1, nitrogen oxide metabolites and blood pressure in young and middle-aged people occupied in harmful working conditions, to evaluate the studied parameters as possible markers for diagnosing the risk of hypertension. Two hundred thirty-six (236) employees of young and middle age were examined of one of the metallurgical plants of the Nizhny Novgorod region. In order to characterize the state of vascular tone, a coefficient was used that represents the ratio of the concentration of nitrogen oxide (μmol/L) to endothelin-1 (pg/ml) (NOx/ET-1). It was revealed that in one-third of people with normal and high normal blood pressure, the NOx/ET-1 value was 2-3 times less than in people with optimal blood pressure, which indicates the occurrence of endothelial dysfunction and the possible development of persistent arterial hypertension. Harmful occupational factors negatively affect vascular tone - the value of NOx/ET-1 in individuals exposed to harmful factors was 3-4 times less than in individuals not subjected to such exposure. The NOx/ET-1 coefficient can be used as an informative indicator when monitoring health conditions with an in-depth examination of working people; it can be a criterion for the risk of developing hypertension.

Стан судинного ендотелію у пацієнтів з хронічними запальними захворюваннями кишечника i різним нутритивним статусом

Актуальність. Визначення ендотеліальної функції за допомогою неінвазивних методів відіграє основну роль у прогнозуваннi перебігу різних захворювань, ризику розвитку ускладнень та оцінцi лікування. Мета: оцінка ендотеліальної функції в пацієнтів iз хронічними запальними захворюваннями кишечника (ХЗЗК) залежно від їхнього нутритивного статусу шляхом визначення стану судинного ендотелію в пробі з реактивною гіперемією та вмісту метаболітів оксиду азоту (МОА) в сироватці крові. Матеріали та методи. Сто двадцять пацієнтів iз ХЗЗК (81 — iз неспецифічним виразковим колітом (НВК) та 39 пацієнтів із хворобою Крона (ХК)) були розподілені на групи залежно від антропометричних характеристик: І — зі зниженим нутритивним статусом (n = 70); ІІ — iз нормальним (n = 20); ІІІ — iз підвищеним нутритивним статусом (n = 30). У сироватці крові пацієнтів вимірювали рівень МОА за В.А. Метельською. Для оцінки ендотеліальної функції визначали ендотелійзалежну вазодилатацію плечової артерії в пробі з реактивною гіперемією. Результати. На основі проведених досліджень встановлено вірогідне зниження вмісту МОА в сироватці крові: у пацієнтів iз НВК — у 1,7 раза (р < 0,01) та з ХК — в 1,9 раза (р < 0,001). Зниження вмісту МОА в сироватці крові не залежало від нутритивного статусу пацієнтів iз ХЗЗК. Порушення функції судинного ендотелію виявлено в 76,7 % випадків: зниження функції ендотелію — у 49,2 %, дисфункція — у 27,5 %. Зміни функції судинного ендотелію зареєстровано в 75,7 % пацієнтів І групи, 75 % — ІІ та у 83,4 % пацієнтів ІІІ групи, переважно внаслiдок зниження функції ендотелію. Висновки. Показано, що в 71 % пацієнтів iз ХЗЗК відбувається вірогідне зниження вмісту МОА в сироватці крові, що не залежить від їхнього нутритивного статусу. У хворих iз НВК спостерігалися більш виражені зміни у частотi виявлених порушень та більш значне зростання діаметра плечової артерії порівняно iз пацієнтами з ХК. Зниження нутритивного статусу супроводжувалося змінами функції судинного ендотелію в 75,4 % випадків.

The role of recovered thiols in venous endothel adaptation in case of autovenous reconstruction of lower limb arteries

Purpose. To evaluate the role of thiol status and its correlative relationship with the level of nitric oxide metabolites and vascular endothelial growth factor A (VEGF-A) in the blood plasma of patients with critical lower limb ischemia (CLI) after autovenous reconstructions of femoropopliteal segment’s arteries in the setting of venous endothelium of the arterial bed. Materials and methods . 54 patients with critical lower limb ischemia had been examined and divided into groups: synthetic prosthesis, in situ autovenous bypass procedure and reversed vein autovenous bypass procedure. Peripheral venous blood was taken on the 1 st and 10th days, and in 1, 3 and 6 months after the operation. Nitric oxide metabolites level was examined with photocolorimetric method by reaction with Griess reagent on a microplate analyzer (Awareness Technology, USA). VEGF-A number estimation was done by ELISA test (PersonalLab, Italy) with the use of Human VEGF-A Platinum ELISA. The level of thiol (SH-) groups was estimated with the use of Ellman’s reagent (SERVA, Germany) on spectrophotometer (Saint-Petersburg, Russian Federation). Results. The concentration of VEGF-A and the level of SH-groups increase on the 10th day and after 1 month in the group of patients operated on using a synthetic prosthesis. The level of NO metabolites, the concentration of VEGF-A, and the content of SH-groups increase statistically significantly and then decrease to the initial values in the group of patients operated on by reversed vein autovenous bypass procedure. In the group of patients operated on by the in situ method, the level of nitric oxide metabolites increases, the concentration of VEGF-A increases on the 10th day, the level of SH-groups increases, and a positive correlation was found between the content of SHgroups and the concentration of VEGF-A. Conclusion . NO metabolites contribute to the build-up of SH groups and VEGF-A in patients operated by the “reversed vein” method, and in patients in the in situ group, the concentration of VEGF-A and the level of SH groups are not affected, which may be of clinical importance when prescribing NO donors. The revealed patterns of change in the level of recovered thiols, nitrogen oxide metabolites, VEGF-A in combination with analysis of early and late postoperative complications make it possible to conclude the advantage of autovenous reconstruction of the femoropopliteal segment due to functional adaptation of the venous endothelium compared to the group of patients, operated on by the method of “synthetic prosthesis”. Method in situ on biochemical and angiological indicators proved to be more favorable in terms of the clinical course, than the “reversed vein” method.

Оцінювання ефективності комплексної цитопротективної терапії вагітних із затримкою росту плода

The objective: estimate efficiency and influence of complex, cytoprotective therapy of pregnant women with fetal growth delay on biochemical indexes and results of delivery. Materials and methods. 93 women with monocyesis at term of 28-34 gestation weeks took part in the research. Group І includes 30 pregnant women with fetal growth delay (FGD). The pregnant women of the present group were prescribed with complex, cytoprotective therapy. It includes prescription of thiotriazolin in complex with L-arginine and diosmin. Group ІІ is presented by 33 pregnant women with FGD whose management of pregnancy and delivery is provided by valid orders of Ministry of Healthcare of Ukraine. Group ІІІ (the control one) consists of 30 pregnant women without FGD. Research of protein oxidative modification (POM) markers and level of stable nitrogen oxide metabolites (NO) were estimated in blood serum with spectrophotometric method. Reduced glutathione (GSH) was determined with calculation of its level according to the calibration curve. Results. Primary estimation of their content showed statistically valid (p < 0.05) lower GSH and NO in comparison of indexes of pregnant women without FGD (ІІІ group) with indexes of pregnant women with FGD (both І and ІІ groups). This fact indicates decrease of antioxidant protection and deficit of the main vessel dilator in the present group. Further estimation of biochemical indexes in dynamics of pregnancy permitted to determine considerable progress of imbalance between oxidants and antioxidants and absence of significant changes of NO level among pregnant women of II group. In pregnant women of I group who got the proposed complex cytoprotective therapy, on contrary, statistically valid (p < 0.05) decrease of POM indexes together with increase of GSH and NO level that indicates its positive influence were found. By means of analysis of special features of the pregnancy course in research group there was stated that the rate of habitual pregnancy non-carrying (HPN) in group II made 39.4% and considerably exceeded relevant indexes of І (20.0%) and ІІІ (16.7%) groups. Hypertensive disorders during pregnancy and labour are diagnosed only in pregnant women of І (6.7%) and ІІ (9.1%) groups. Average index of giving birth in І and ІІІ groups made 38.5±0.6 weeks and 39.4 ± 0.5 weeks correspondingly and in group ІІ it was lower 37.2±0.6 weeks. Index of preterm delivery (PD) rate in І group made 3.3% and was 6 times lower than appropriate index of ІІ group (21.2%). PD rate was absent in ІІІ group. Rate of the fetus distress in ІІ group (18.2%) was 2.7 times higher than the relevant index of І group (6.7%) and in ІІІ group it made 3.3%. Condition of newborns in research groups was estimated under Apgar scale. Both at the 1-st and 5-th minute the general index under appropriate scale was statistically valid (p < 0.05) and lower than in ІІ group as compared to indexes of І and ІІІ groups. During description of perinatal complications there was stated considerable percentage of neonatal encephalopathy and jaundice in ІІ group, namely 33.3% and 36.4% correspondingly. In І group their rate made 10.0% and 3.3%, correspondingly. In structure of perinatal pathology prematurity was in 21.2% of newborns of ІІ group that is 6 times higher than appropriate index of І group (3.3%). Mentioned complications were not determined in ІІІ group. In calculation under weight and height parameters of newborns the rate of FGD in ІІ group was the highest and made 88.6%. Mentioned index in І and ІІІ groups made 60.0% and 10.0%, correspondingly. Conclusion. The proposed complex cytoprotective therapy including combined use of thiotriazolin, L-arginine and diosmin (that considerably increases anti-ischemic, antioxidant and endothelium protective action of complex therapy) in women with fetal growth delay has the positive effect on oxidative-reductive hemeostasis and thiol-disulfide balance of mother-placenta-fetus system. Obstetric and perinatal results of delivery in the present group of pregnant women are characterized by statistically valid (р < 0.05) prevalence of estimation indexes under Apgar scale and correspondingly processes of adaptation as well as results of anthropomorphic measurements of newborns, their weight and height parameters and lower rate of neonatal encephalopathy and delivery of premature babies. Keywords: pregnancy, fetus growth inhibition, protein oxidative modification, antioxidant defense system, oxidative stress, obstetric and perinatal complications, cytoprotective therapy.

S‑1‑Propenylcysteine, a sulfur compound in aged garlic extract, alleviates cold‑induced reduction in peripheral blood flow in rat via activation of the AMPK/eNOS/NO pathway

Aged garlic extract (AGE) has been shown to improve peripheral circulatory disturbances in both clinical trials and experimental animal models. To investigate the effect of S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, on cold-induced reduction in tail blood flow of rat, Wistar rats were individually placed in a restraint cage and given the treatment with cold water (15˚C) after the oral administration of AGE or its constituents S1PC, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC). After the cold-treatment the tail blood flow of rats was measured at the indicated times. The pretreatment with AGE (2 g/kg BW) and S1PC (6.5 mg/kg BW) significantly alleviated the reduction of rat tail blood flow induced by cold treatment. The effect of S1PC was dose-dependent and maximal at the dose of 6.5 mg/kg BW, whereas SAC and SAMC were ineffective. To gain insight into the mechanism of S1PC action, the concentration of nitrogen oxide metabolites (NOx) in the plasma and the levels of phosphorylated endothelial nitric oxide synthase (eNOS) and 5'-AMP-activated protein kinase (AMPK) in the aorta were measured. The pretreatment with S1PC significantly increased the plasma concentration of NOx as well as the level of phosphorylated form of AMPK and eNOS in the aorta after cold-treatment. The present findings suggest that S1PC is a major constituent responsible for the effect of AGE to alleviate the cold-induced reduction of peripheral blood flow in rat by acting on the AMPK/eNOS/NO pathway in the aorta.

The dynamics of endothelial dysfunction markers among patients with pulmonary hypertension on the background of chronic obstructive pulmonary disease under the influence of treatment

The objective of the research - to determine the dynamics of endothelial dysfunction markers among patients with pulmonary hypertension on the background of chronic obstructive pulmonary disease under the influence of treatment.Material and methods. The results of the study are based on data from a comprehensive survey of 170 patients with chronic obstructive pulmonary disease (COPD) aged from 40 to 65 years, 123 of which had pulmonary hypertension and 47 ones had no pulmonary hypertension. Also 31 almost healthy people were examined on an outpatient basis. Patients with pulmonary hypertension on a background of COPD were divided into two subgroups of observations depending on the treatment. The first subgroup was used as the background therapy and the second subgroup - background therapy with the roflumilast. Markers of endothelial function were determined during screening and after 12 months of follow-up.Results. The median level of endothelin-1 in the group of patients with pulmonary hypertension on the background of COPD was 3.17 [2.19 ; 4.14] fmol/ ml and was significantly higher, both against the value of 1.78 [1.25 ; 2.18] fmol/ml in the group of COPD patients without pulmonary hypertension (p < 0.05), and 10.2 times higher than versus the level of 0.31 [0.19 ; 0.36] fmol/ml in the group of healthy individuals (p<0.05). The amount of nitrogen oxide metabolites (NO2+NO3) was significantly lower (by 15.8 %) in the group of patients with pulmonary hypertension on the background of COPD versus the value of 22.00 [21.00 ; 23,00] mmol/l in the group of COPD patients without pulmonary hypertension, and is 37 % lower than in the group of healthy individuals, where the level of this indicator was 26,00 [25,00 ; 28,00] mmol/l (p<0.05). Then a correlation analysis was performed. Significant relationships were determined between the following indicators: duration of COPD and NO3 level (R = -0.29, p = 0.001); duration of COPD and NO2+ NO3 level (R - 0.26, p = 0.003); mean pulmonary artery pressure and endothelial-1 level (R = +0.70, p = 0.001); mean pulmonary artery pressure and NO2 level (R = -0.59, p = 0.001); mean pulmonary artery pressure and NO2+ NO3 (R = -0.50, p = 0.001). The level of endothelin-1 and nitrogen oxide metabolites in the blood plasma of patients was comparable between the first and second subgroups of observation during screening (p > 0.05). After 12 months, there was a statistically significant decrease of Δ1% = -57.53 % endothelin-1 to 1.87 [1.44; 2.36] fmol/ml in the first subgroup and Δ2% = -82.34 % to 1.62 [1.37; 1.92] fmol/ml in the second subgroup. After 12 months of therapy in both subgroups, the level of total nitrogen oxide metabolites in blood plasma significantly increased Δ1% = 10.00 % to 21.00 [18.00 ; 23.00] mmol/l in the basic therapy subgroup, and Δ2% = 19.05 % to 24.00 [22.00; 26.00] mmol/l in the roflumilast subgroup, (p < 0.05). A statistically significant difference in endothelin-1 levels and the amount of nitrogen oxide metabolites between subgroups was determined after 12 months of treatment.Conclusions. Among patients with COPD, endothelial dysfunction occurs, characterized by an increase in the concentration of endothelin-1 and a decrease in nitrogen oxide metabolites in the blood plasma. An increase in the level of endothelin-1 in blood plasma has a direct correlation with the value of the mean pulmonary artery pressure. Background therapy among patients with pulmonary hypertension on the background of COPD improves the state of endothelial function, with increased nitrogen oxide metabolites in the blood plasma. When added to background therapy, roflumilast significantly reduced the concentration of endothelin-1 in blood plasma.

Expediency of сitoprotective treatment of patients with acute myocardial infarction, who were performed percutaneous coronary intervention

The aim of the study was to increase the efficiency of treatment of patients with Acute Miocardial Infarction by incorporating the protocol therapy for the course of parenteral use of L-arginine and L-carnitine.Material and methods.A total of 45 patients with acute coronary syndrome with ST segment elevation were investigated, who had undergone urgent balloon angioplasty and stenting of a heart attack-dependent coronary artery. The study selected patients aged on average (59,57 ± 8,07) years. The experimental group consisted of 30 patients, who received standard protocol treatment of ACS (MI) and additionally were prescribed 4.2 g L-arginine and 2.0 g L-carnitine in the 100 ml solution for infusion once daily for 5 days intravenously. The control group included 15 patients with ACS (MI) who also had percutaneous coronary intervention, but this group received only standard protocol treatment.In addition to general clinical, instrumental and laboratory methods (general blood test, MB Creatinephosphokinase fraction (CFC-MB), Troponin T, oxygen saturation of arterial blood (SpO2), ECG in 12 standard leads, etc.), performed an echocardiography in the B-mode with the definition of linear and volume indicators of the left ventricle, as well as the global (by the ejection fraction (EF) and local contractile activity of the myocardium by the Simpson method. The functional state of the vascular endothelium was determined by the concentration of endothelin-1 (ET-1) in the blood plasma and the content of stable NO metabolites [5]. The determination of endothelin-1 (ET-1) in serum was carried out using for determining the ultimate stable metabolites of NO in the blood. Results. It has been established that patients with ACS (MI) after percutaneous coronary intervention often develop reperfusion syndrome with manifestations of left ventricular insufficiency and rhythm disturbances. Substantial clinical and functional improvement was noted under the influence of standard medical treatment in patients of control group. At the same time postinfarction remodeling with systolic and diastolic function of the heart, with the development of heart failure syndrome and endothelial dysfunction of blood vessels, and also remained resistant to extrasystole therapy, progressed.Patients in the experimental group under the influence of complex medical treatment with the inclusion of L-arginine and L-carnitine marked a significant decrease in the frequency of violations of rhythm and conduction for the second day of observation, as well as a decrease in the manifestations of post-infarction remodeling of LV, which ultimately manifested a significant improvement in myocardial contractility (EF increased by 13%) and decreased diastolic dysfunction. Improvement of the inotropic function of the heart and a significant reduction in the frequency and severity of reperfusion arrhythmias was achieved precisely due to cardiometabolic effects of L-carnitine. In addition, in patients undergoing additional treatment with L-arginine and L-carnitine after 10 days of treatment, the activity of ET-1 was significantly lowered and the concentration of nitrogen oxide metabolites in the blood plasma increased and reach the level of healthy subjects (P> 0,05). So, they recovered the endothelial function of the vessels.Conclusions: In the first day after percutaneous coronary intervention on the background of standard drug therapy was most often diagnosed with reperfusion syndrome with manifestations of acute left ventricular failure and arrhythmias and conduction.The use of complex drug therapy with the inclusion of L-arginine and L-carnitine on the background of an individualized cardiorehabilitation program led to a significant improvement in the parameters of central cardiohemodynamics and restoration of vascular endothelial function, was accompanied by a significant decrease in the frequency of development and severity of such complications of ACS (MI) as reperfusion arrhythmias and acute left ventricular failure.

Therapeutic potential of a biomedical cellular product in rats with lower limb ischaemia

Critical ischaemia of lower limbs is a cause of death and invalidity in the whole world. Stem cells and products of their secretion find wide application in treatment of vascular diseases, including critical ischaemia of the lower limbs. Erythropoietin promotes an increase in the angiogenic potential of stem cells. The authors examined the therapeutic potential of a biomedical cellular product (mesenchymal stem cells and products of their secretion) and mesenchymal stem cells with erythropoietin on the processes of restoration of vessels in the hind legs of Wistar male rats following induction of lower limb critical ischaemia. Mesenchymal stem cells were derived from the bone marrow of male Wistar rats. Critical ischaemia of hind legs was modulated by transaction of the femoral artery. The parameters of microcirculation in the foot were assessed with the help of laser Doppler flowmetry. In the blood serum and crural muscles by means of solid-phase enzyme immunoassay we examined the levels of cytokines, growth factors, and persistent metabolites of nitrogen oxide - nitrites. Muscles morphology and the number of blood vessels were assessed by the findings of histological examination. It was shown that the biomedical cellular product alone and in combination with erythropoietin stimulated angiogenesis. The results of Doppler flowmetry revealed restoration of the parameters of microcirculation in the lower limb by 35-75% of the baseline values. Besides, we observed a decrease of muscle necrosis, connective tissue proliferation, and an increase in the number of the vessels supplying the muscles in the experimental groups. It was also determined that the biomedical cellular product influenced the levels of cytokines in blood serum and crural muscles. Hence, the obtained findings proved the therapeutic potential of the biomedical cellular product in critical ischaemia of lower limbs.

Влияние активации ванилоидных рецепторов эводиамином на содержание кальцитонин-ген-родственного пептида в крови крыс в норме и при гипертензии, вызванной потреблением фруктозы

Background: Calcitonin-gene-related peptide (CGRP) is a neurotransmitter of capsaicin-sensitive nerves, one of the most powerful vasodilators, in mediation of vasoactive action of which the nitrogen oxide (NO) takes part. The aim of this study was to evaluate the CGRP and NO blood levels in normal rats and rats with fructose-induced hypertension, with unaffected transient receptor potential vanilloid 1 (TRPV1) receptors, and after the administration of their agonist evodiamine. Male Wistar Rats were given to drink either 12.5% fructose solution or tap water (control) for 10 weeks. Evodiamine (10 mg/kg), a TRPV1 agonist, was administered intraperitoneally every other day, for 2 weeks, starting 8 weeks after the start of the fructose intake. The systolic blood pressure was measured using a noninvasive technuque. The glucose levels, fasting and 1 hour after the glucose load (2g/kg, i.p), were measured by a glucometer in the blood sampled from the caudal vein. Concentrations of CGRP, NO metabolites (NOx), triglycerides (TG) and lipid peroxidation products (LPO) were measured in the blood serum of rats. The fructose consumption led to hypertension, impaired glucose tolerance, increased the blood levels of LPO products and TG, and decreased the CGRP blood content. The evodiamine introduction to fructose-consuming rats restored the blood CGRP content to the control values, reduced the blood pressure, LPO products and TG levels, and improved the glucose tolerance. The NOx levels did not differ from the control in all groups. We suggest that CGRP is involved in the development of the fructose-induced hypertension and in mediating the therapeutic effect of the evodiamine.

The Possible Ways of Correction of Some Systemic Inflammation Indices During Combination Treatment of the Patients with Hypertensive Disease in Comorbidity Conditions

The objective: was to study and analyze influence of combination treatment with using of nitrogen oxide donator and selenium-containing drug upon dynamics of the change of some systemic inflammation indices in the patients with hypertensive disease (HD) and comorbid duodenal peptic ulcer (DPU).Materials and methods. The results of the treatment of 40 males and 29 females with HD of the II stage and comorbid DPU (the mean age was 44,4±2,8 years) were analyzed; 32 of them were standard treated, and 37 of them used additionally combination of tivortine aspartate and selenium active. The content of blood serum cytokines (Ck) (TNFα, IL-1β, IL-10) by immunoenzyme method, the content of diene conjugates (DK), malondialdehyde (MDA), total content of nitrogen oxide metabolites (NOХ) in blood serum and ristomycin-induced platelet aggregation (RIPA) by means of spectrophotometry were studied before treatment and in one month of the treatment.Results. The analysis of systemic inflammation indices during initial study established an increase of pro-inflammatory blood serum activity, caused by high content of pro-inflammatory Ck (TNFα, IL-1β) mainly, in conditions of oxidative stress (increase of DK, MDA), endothelial dysfunction (decrease of NOХ) and increase marker of thrombogenic risk (RIPA). Negative correlation relationship between pro-inflammatory Ck and NOХ, NOХ and RIPA and positive correlation relationship between pro-inflammatory Ck and RIPA was established. It is fact significative of their community in the formation mechanisms of revealed disorders. The comparison of obtained results after treatment established significant decrease of intensity of Ck imbalance (TNFα/IL-10, IL-1β/IL-10) mainly due to decrease of TNFα and IL-1β, decrease of lipoperoxidation activity, increase of nitrogen oxide metabolism and decrease of ristomycin-induced platelet aggregation. Besides, positive dynamics of decrease of chronic systemic inflammation indices was more significant in the patients with combination treatment.Conclusion. Carried out study established significant increase of chronic systemic inflammation markers in the patients with HD and comorbid DPU. Besides, significant dynamics of their decrease was noted in case of including of combination of nitrogen oxide donator and selenium-containing drug in the treatment.

Adaptogenic effect of phlojodicarpus sibiricus extract on cerebral ischemia

The aim of the study was to determine the adaptogenic effect of the extract from the roots of Phlojodicarpus sibiricus during ischemic influence on the left hemisphere of the brain. Experiments were conducted on Wistar rats of both sexes weighing 200-220 g. Unilateral cerebral ischemia was induced by permanent occlusion of the left common carotid artery under ether anesthesia. Adaptogenic anti-ischemic effect of Ph. sibiricus was determined by the number of desquamated endotheliocytes, nitrogen oxide metabolites – nitrites in the blood, by the content of lipid peroxidation products – malondialdehyde (MDA) and the activity of the antioxidant defense system in the brain tissue. It is established that Ph. sibiricus has an anti-ischemic effect, reduces the number of endotheliocytes desquamated, increases the level of nitric oxide in the blood (p ≤ 0.05), stimulates SOD and catalase activity, reducing the intensity of lipid peroxidation and the accumulation of MDA in the brain during ischemic exposure (p ≤ 0.05). Preventive administration of Ph. sibiricus extract has an adaptogenic effect in unilateral cerebral ischemia, which consists in reducing desquamated endotheliocytes, increasing the production of nitric oxide by endothelium, increasing the antioxidant defense system and reducing the intensity of oxidative reactions in the brain. Adaptogenic effect of Ph. sibiricus extract is caused by endothelium protective and antioxidant effects.

Clinical Effectiveness of Cardiocytoprotective Therapy in Patients with Acute Coronar Syndrome (ACS) – Myocardial Infarction (MI), Who Were Performed Balloon Angioplasty and Coronary Artery Stenting

The aim of the study was to increase the efficiency of restorative treatment of patients with Acute Coronary Syndrome (Miocardial Infarction) by incorporating the protocol therapy for the course of parenteral use of L-arginine and L-carnitine (Tivorel).
 It has been determined that patients with ACS (MI) after percutaneous coronary intervention often develop reperfusion syndrome with manifestations of left ventricular insufficiency and rhythm disturbances. Substantial clinical and functional improvement was noted under the influence of standard medical treatment in patients of control group. At the same time postinfarction remodeling with systolic and diastolic function of the heart, with the development of heart failure syndrome and endothelial dysfunction of blood vessels, and also remained resistant to extrasystole therapy, progressed.
 Patients in the experimental group under the influence of complex medical treatment with the inclusion of L-arginine and L-carnitine marked a significant decrease in the frequency of violations of rhythm and conduction for the second day of observation, as well as a decrease in the manifestations of post-infarction remodeling of LV, which ultimately manifested a significant improvement in myocardial contractility (EF increased by 13%) and decreased diastolic dysfunction. Improvement of the inotropic function of the heart and a significant reduction in the frequency and severity of reperfusion arrhythmias was achieved precisely due to cardiometabolic effects of L-carnitine. In addition, in patients undergoing additional treatment with L-arginine and L-carnitine after 10 days of treatment, the activity of ET-1 was significantly lowered and the concentration of nitrogen oxide metabolites in the blood plasma increased and reach the level of healthy subjects (p>0.05). So, they recovered the endothelial function of the vessels.

Effects of flavonol quercetin on activity of lipid peroxide oxidation in experimental bacterial-immune periodontitis.

The article presents the results of lipid peroxidation activity in blood serum, which were assessed on the base changes in the level of oxidative modification of proteins, TBA-active products, and total amount of nitrogen (II) oxide metabolites (NO2− + NO3−). Indices were determined on the 14th day of development in experimental periodontitis both without correction, and in condition treatment with a water-soluble flavonol quercetin (corvitin). The treated animals take intramuscular injections of corvitin in a dose 100 mg/kg weight for 7 days. For further testing, blood serum was selected. The results were statistically analyzed using parametric and non-parametric indices. In this investigation, characterized dynamics of changes in the indices of oxidative processes activity were revealed both during the period of formation and the course of periodontitis. In particular, it was found that, for the period of the most expressed inflammatory reaction in the periodontal complex, intensive increase in the level of reactive forms of oxygen. The treatment with flavonol quercetin for 7 days resulted in stabilization of free radical processes and the suppression of the inflammatory reaction.

A SYSTEMATIC ANALYSIS OF RELATIONSHIPS BETWEEN BIOCHEMICAL INDICES IN PERSONS EXPOSED TO MERCURY

Introduction. Changes in biochemical indices characterizing the state of lipid peroxidation processes - antioxidant protection and lipid metabolism are observed during the occupational contact with mercury. These changes play a certain pathogenic role in the formation of disorders in the nervous system during mercury intoxication. In this regard, the aim was to study the relationship between biochemical indices at different stages of the development of mercury intoxication to justify approaches to therapeutic and preventive measures. Material and methods. A prospective cohort examination of persons exposed to the mercury vapor with signs of disorders in the nervous system, patients with chronic mercury intoxication and working in contact with mercury more than 5 years without signs of pathology was carried out. To study the relationship of features between biochemical indices, the sum of the square of correlation relations between the indices was calculated, the ranks of the influence of the system components on other factors and their dependencies were determined. Results. The decline in the level of nitric oxide metabolites was found to be one of the initial, long-term persisting in the pathogenesis of biochemical abnormalities, formed due to the contact with mercury. The development of the nervous system pathology under the mercury influence is accompanied by a change in the ratio of pro- and anti- oxidative processes, lipid metabolism disorders have an independent pathogenic significance. The long-term period of the chronic mercury intoxication is characterized by the formation of complex relationships in the biochemical system, the presence of several closed subsystems, which include nitrogen oxide metabolites. Conclusion. Given peculiarities of systemic interactions between biochemical indices, determining the role of certain factors in the overall system, as well as the presence/absence and composition of subsystems, pathogenic approaches to the correction of metabolic disorders at various stages of the mercury intoxication formation should be different.

Peculiarities of metabolites changes of nitrogen (ІІ) oxide and endothelin-1 in acute lung injury in experiment

Introduction. Structural damage to the alveoli is observed when acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which develops within hours and days after the end of the primary damaging factor. Pulmonary epithelium is an important component in the mechanisms of development and course of ALI/ ARDS. This justifies the research of new mechanisms of the influence of damaging factors on the pulmonary tissue and the organism of ARDS patients. The aim of the study – to learn the content of metabolites of nitrogen (II) oxide and the concentration of endothelin-1 in the lung tissues and to justify their role in the pathogenesis of acute lung injury in the experiment. Research Methods. Experiments were conducted on 54 white nonlinear male-rats, which were modulated acute lung injury by intratracheal administration of hydrochloric acid at pH 1.2 at a dose of 1.0 ml/kg per breath. The content of nitrite anion was determined in homogenates of lung tissues by spectrophotometric method, the level of endothelin-1 by the enzyme immunoassay method. Results and Discussion. Analysis of the nitrite anion in the lungs of rats with ALI indicates a sharp increase in the index under study after 12 hours of experiment, which lasts until the end of the day. It was noted that after 2 and 6 hours, the level of NO2 - increased by 20.38 % and 40.76 %, respectively, compared with the control (p <0.001). In the fourth research group, the nitrite anion content increases by 2.43 times, in relation to the 3rd test group, and by more than three times as compared with the results of the control. It should be noted that in determining endothelin 1 at 2 and 6 hours, its level increases by 17.43 % and 75.68 %, respectively, compared with the control (p <0.001). In the 4th study group, the endothelin 1 concentration increased 1.52 times compared to the 3rd experimental group and 2.67 times compared to the control group. Conclusions. In experimental acute lung injury, activation of nitroxidergic processes occurs due to a significant increase in nitrogen oxide metabolites in the lung homogenate. Acute lung damage in rats is accompanied by an increase in the level of endothelin-1 in the lung homogenate with the highest values after 24 hours of observation.

THE FUNCTIONAL ACTIVITY OF INNATE IMMUNITY CELLS IN BACTERIAL INFECTION ON BACKGROUND OF THERMAL STRESS

Maintenance of thermo homeostasis under the coordinating influence of the hypothalamus is ensured by integrative interaction of various systems organisme, including the immune system. Temperature stress in infectious diseases activates the reaction of heat shock, the biochemical consequence of which is the initiation of the organism’s defense against the pathogen. Cells of innate immunity (neutrophils and macrophages) are the first line of protection against pathogenic agents and play a primary role in the development of bacterial infections. Of particular interest is the study of the duration of the effect of hyperthermia to achieve a balance between the bioenergetic costs of these cells, as well as the study of the course of the pathological process in an organism previously exposed to hige temperature. The functional status of neutrophils and macrophages, including phagocytosis, the activity of enzymes of the oxygen-dependent system: lactate dehydrogenase, cytochrome oxidase, myeloperoxidase, cellular stimulation (intracellular AMPase content) and the content of nitrogen oxide metabolites have been studied in the model of animals exposed to low and high temperatures. It has been established that under hyperthermia conditions, the change in the functional activity of cells by enzyme level is more pronounced than when exposed to animals with low temperature, especially 4 h exposure. In animals pre-exposed to heat stress, manifestations of pseudotuberculosis infection were more severe with an increase in mortality rates by 2.6 times, compared to animals infected by bacteria. These animals had a high stimulation of effector cells of inflammation in the initial periods (at 7 days) their metabolism was enhanced, which was expressed of the activity of enzymes of the oxygen-dependent system, as well as in high nitroxide-producing activity. In target organs (lung, liver, spleen) of experienced animals the severe disturbance of blood circulation in combination with significant destructive changes typical for generalized infection were showed. At dead animals on the background of marked hemorrhagic component pathological process and weak cell inflammatory response observed depletion of the immune system (delimphatization), indicating a decrease in defense reactions and the development of immunodeficiency. Thus, under conditions of heat stress (+30°С), the intensity of the reaction of innate immunity cells in terms of enzyme’s functional activity was higher than when exposed to animals of low temperature (+4°C). Under these temperature conditions, a high level of cell priming was determined, which reduced their killing potential. These data indicate the adequacy of the model used to reproduce induced secondary immunodeficiency in a congenital defense system. Moreover, in the pathogenesis of pseudotuberculosis infection against the background of prolonged action high temperature, the effects of phagocytes oxidative stress in the structural changes of immunocompetent organs were detected.

Improvement of fetus growth restriction diagnostics in pregnant women by means of biochemical markers that characterize the disorder of stress-adaptation

Object of the work. Regulatory and adaptive processes of the system “mother –placenta – fetus” state determination and detection of pregnant women adaptive capabilities specific features in case of fetus growth restriction based on a number of the blood plasma biochemical indicators.Materials and methods. Markers of oxidative stress were detected spectrophotometrically in the blood plasma according to generally accepted methods: oxidative modification of proteins, stable metabolites of nitrogen oxide, L-arginine, malondialdehyde, thiol compounds and reduced glutathione. Statistical processing of data was made by methods of variational statistics with Microsoft Office Excel 2010, Statistica 6.0.Results. The use applicability of the number of biochemical markers which are predictors of perinatal complications has been scientifically substantiated. Using biochemical diagnostic technique it has been shown that fetus growth restriction syndrome is accompanied by disorders of regulatory and adaptive processes of the system “mother –placenta – fetus”. In particular, the level of proteins and lipids oxidative modification increases, nitric oxide synthase activity decreases and reserves of L-arginine and thiol compounds decrease in the blood plasma.Conclusions. Comparative analysis of a number of biochemical markers determination results of stress-realizing system activity in pregnant women with fetus growth restriction and in women with a physiological pregnancy has revealed a significant (P ≤ 0.05) increase in markers of protein oxidative modification blood levels (the level of dinitrophenylhydrazones of aliphatic aldehyd of basic amino acid residues and dinitrophenylhydrazones of carbonyl compounds of basic amino acid residues in the spontaneous sample increased by 14.2 % and 16.3 %, respectively, and in the stimulated sample by 46.6 % and 43.0 %), the level of malondialdehyde increased by 42.9 %. Reduction of the stress-limiting system activity in pregnant women with fetus growth restriction is indicated by a decrease in the content of stable metabolites of nitric oxide in blood plasma by 51.2 %, reduction of L-arginine content by 55.5 %, glutathione by 45.9 % and free thiols by 52.4 %. The aforementioned changes aggravate fetal trophism and can effect negatively on the process of cervix preparing for delivery.

Clinical Implications

HomeHypertensionVol. 71, No. 3Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published1 Mar 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.10860Hypertension. 2018;71:367Cardiovascular Disease in Primary Aldosteronism (p 530)Download figureDownload PowerPointAldosterone causes organ damage in animal models, and the prevalence of cardiovascular disease (CVD) among patients with primary aldosteronism (PA) is reportedly high. There have been several clinical studies examining the factors associated with CVD in these people; but the results are controversial. In some studies, the prevalence of CVD was distributed nearly equally across the spectrum of plasma aldosterone or serum potassium levels, whereas other studies reported that hypokalemic patients with PA had an elevated rate of CVD. Of the 2582 patients with PA studied in this study, the prevalence of CVD was higher than in age-, gender-, and blood pressure-matched patients with essential hypertension. Hypokalemia (≤3.5 mEq/L) and the unilateral subtype was associated with significantly higher adjusted odds ratios for CVD. Although plasma aldosterone concentration (PAC) was not linearly related to the adjusted odds ratios for CVD, patients with high PAC (≥125 pg/mL) had significantly higher adjusted odds ratios for CVD than patients with lower PAC (<125 pg/mL). Our result suggests PA patients with PACs higher than the upper limit of normal as well as with hypokalemia or unilateral subtype are at higher risk of developing CVD and, therefore, have a greater need for PA-specific treatment. In contrast, PA patients with normokalemia, the bilateral subtype, and PACs lower than the upper limit of normal are at lower risk of CVD and may not need immediate PA-specific treatment.Left Ventricular Function and Cognitive Impairment (p 429)Download figureDownload PowerPointA growing literature is revealing connections between cardiovascular disease and cognitive impairment/dementia. However, the relationships between subclinical cardiac dysfunction and cognitive performance is not been well established in the general population. In this issue of Hypertension, we investigated longitudinally cardiac magnetic resonance measures of left ventricular structure and function in relation to cognitive performance and incident dementia in a large multiethnic population free of cardiovascular disease at baseline. A total of 4999 participants with cardiac magnetic resonance images at baseline were followed for a median of 12 years. Left ventricular hypertrophy and remodeling were strongly associated with lower cognitive function and a higher risk of future hospitalization with dementia. Additionally, lower left ventricular sphericity (increased conicity) was associated with increased risk of future dementia. These associations were independent of demographic confounders, cardiovascular risk factors, and cardiovascular events. Measures of left ventricular function were not associated with risk of future dementia or cognitive function. This study provides 2 avenues of important insight into the link between cardiac and cerebral involvement in dementia. First, cardiac structural and functional abnormalities may be useful in the identification of individuals at risk of future cognitive impairment. Second, these data suggest that potential common pathophysiological mechanisms could underlie both cardiovascular and cerebrovascular structural remodeling (eg, microvascular disease) leading or contributing to cardiac concentric remodeling and vascular dementia.VEGF Inhibitor–Induced Hypertension and Renal NO (p 473)Download figureDownload PowerPointVEGF (vascular endothelial growth factor) is critically involved in tumor angiogenesis and is therefore an important target in the pharmacological treatment of many cancer diseases. Clinical use of VEGF inhibitors is associated with a preeclampsia-like syndrome characterized by rapid development of hypertension and proteinuria and has revealed an important role of VEGF in blood pressure regulation. The underlying mechanisms of VEGF inhibitor–induced hypertension are only partly understood but may include decreased systemic nitrogen oxide (NO) and increased plasma endothelin-1. Pazopanib is one of the recommended first line treatments in advanced renal cell carcinoma patients and in a prospective, single center observational study in a cohort of pazopanib-treated patients, significant hypertension developed during the first 4 weeks of treatment. Hypertension was accompanied by proteinuria, decreased plasma NO metabolites and increased endothelin-1. In addition, results showed decreased urinary excretion of NO metabolites without change in urine endothelin-1 or renal function. The kidneys are important in long-term regulation of blood pressure, and data support a significant role of reduced renal NO bioavailability in VEGF inhibitor–induced hypertension. Sufficient blood pressure control is necessary in this group of patients to prevent impaired treatment options of cancer targeted therapy. Based on mechanistic evidence, long-acting NO donors or cGMP-based drug interventions seem particularly well suited for organ protection and blood pressure reduction. Previous Back to top Next FiguresReferencesRelatedDetails March 2018Vol 71, Issue 3 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.118.10860PMID: 30543472 Originally publishedMarch 1, 2018 PDF download Advertisement