Regulation Of Vascular Tone Research Articles

Endothelial-platelet interaction in sepsis

Introduction. Endothelial cells and platelets are actively involved in pathogenetic processes in sepsis — an unregulated reaction of the host organism in response to infection, leading, on the one hand, to the development of prothrombotic, and on the other hand, to hemorrhagic readiness.Aim — to summarize the current information on the mechanisms of intercellular interaction between endotheliocytes and platelets in sepsis.Main findings. The development of multiple organ failure, which increases the likelihood of an unfavorable outcome of sepsis, is partly due to endothelial dysfunction, as well as the involvement of platelets in the pathogenetic process. Under physiological conditions, an anatomically and functionally intact endothelium is important to prevent microvascular thrombosis. Although platelets are most associated with hemostasis, they perform many other functions, including participation in inflammatory processes through complement activation, interaction with leukocytes and monocytes, participation in host defense against infection, and regulation of vascular tone. There is also abundant evidence that suggests that the processes regulating hemostasis evolved as a component of the inflammatory response to infection. Many of these interaction points occur on the surface of endothelial cells, linking these two cell types, endotheliocytes and platelets, in initiating and regulating blood clotting and inflammation. Various mechanisms may contribute to direct and indirect platelet activation in sepsis, including pathogen-induced platelet activation, pathogen- and inflammation-induced endothelial and leukocyte activation, and complement-mediated platelet activation.

Sport as a factor in the improvement of the stability of the nervous system to the exhaustion and expansion of students' orthostatic reactions

Purpose: to reveal the influence of sports on indicators of psychophysiological functions and orthostatic reactions of students of various faculties of pedagogical universities.
 Material and methods. 812 students of pedagogical institutions of higher education of Ukraine took part in the study: 88 students of the faculty of elementary education, 76 students of history, 130 of natural sciences, 131 of foreign philology, 93 of the faculty of preschool education, 198 of Ukrainian language, 25 of the faculty of physical education and sports, 24 students from the Faculty of Arts, 47 students from the Faculty of Psychology and Sociology. Psychophysiological testing was carried out according to the Psychodiagnostics program and involved determining the speed of a simple visual-motor reaction, determining the speed of a choice of two elements out of three. During psychophysiological testing, the reaction time and the number of errors were determined for each test.
 The results. Sports have a positive effect on the indicators of the strength of nervous processes according to the results of the number of errors in the test for the reaction to the choice of two elements out of three (p<0.05). Also, playing sports has a positive effect on the quality of autonomic regulation of vascular tone, which is reflected in lower values ​​of the heart rate during the transition from a horizontal position of the body to a vertical one in students who play sports (p<0.05).
 Conclusions. Sports are recommended for students of all faculties of pedagogical universities. The type of sport should correspond to the individual inclinations of the student and his professional direction.

Separate extraction of human eccrine sweat gland activity and peripheral hemodynamics from high- and low-quality thermal imaging data

Sweat gland activity and peripheral hemodynamics, which characterize the function of sympathetic cholinergic nerve fibers and the manifestation mechanisms of vascular tone regulation, respectively, can be detected via dynamic thermography of the skin. Thus, they are useful parameters for diagnosing various forms of neuropathy and functional circulatory disorders. Both parameters affect the dynamics of the skin temperature; therefore, for an adequate description of thermographic data, it is necessary to build models that consider both these coexisting components simultaneously. PurposeThe objective of this study was to determine the spatiotemporal and statistical features of dynamic thermograms of skin areas with sweat glands and to develop methods for the extraction of temperature components mediated by sweat gland activity (Tsweat) separately from hemodynamics (Tblood) based on thermograms of high and low temperature resolutions. MethodsTo separate the Tsweat and Tblood components, simultaneous thermographic and photoplethysmographic (PPG) measurements were performed in the area of the fingers during a deep inspiratory gasp (DIG). PPG data, which were obtained solely by hemodynamics, were converted into a temperature signal (Tblood) using the spectral filtering approach. By calculating the difference between the skin (Tskin) and blood (Tblood) temperature components, the Tsweat component was determined, which characterizes sweat gland activity and the integrity of the cholinergic sympathetic nerve fibers that innervate them. The Tsweat component was compared with the active sweat pore count curve, which was determined by the adaptive detection of local temperature minima. Thermographic and PPG measurements were performed for 3 min on a group of 15 volunteers during the DIG test. The skin temperature was measured using a cooled thermal imaging camera in the spectral range of 8–9 μm with a temperature sensitivity of 0.02 °C. PPG measurements were performed using a reflectance sensor with a central wavelength of 800 nm. Wavelet analysis with the Morlet basis function was used to preliminarily determine the spectrum of spontaneous temperature oscillations in an area of the skin with and without sweat pores. Statistical parameters of the histogram, such as the standard deviation and the statistical pore activation index (SPAI) - which is proposed in this paper were used in the DIG test to detect sweat gland activity with low-temperature resolution thermograms. The temporal dynamics of the statistical parameters were compared with the dynamics of the sweat pore count. ResultsThe Tsweat component was correlated with the sweat pore count on the thermogram with a coefficient of 0.75, confirming the dependence of this temperature component on the sweat gland activity and the need for considering this activity in the analysis of the spatiotemporal dynamics of the human skin temperature. The use of the proposed SPAI and standard deviation allows the detection of sweat gland activity even with thermograms of a low temperature resolution. The use of an integrated map of the sweat gland activity will help the specialist to assess the degree of integrity of the innervation of skin areas in a single image. The primary assessment of the spectrum of temperature oscillations at rest indicated that spontaneous sweat gland activity is accompanied by high-frequency oscillations in the skin temperature localized in the area of sweat pores, within the frequency range of 0.07–0.3 Hz. This suggests the possibility of spectral separation of the temperature component mediated by sweat gland activity from the hemodynamic component, which dominates in the region of <0.1 Hz. The proposed two-component approach for the analysis of skin temperature dynamics allows separate assessment of sympathetic innervation and rhythms of hemodynamic regulation using dynamic thermograms.

Role of NADPH Oxidases in Blood-Brain Barrier Disruption and Ischemic Stroke.

NADPH oxidases (Nox) are one of the main sources of reactive oxygen species (ROS) in the central nervous system (CNS). While these enzymes have been shown to be involved in physiological regulation of cerebral vascular tone, excessive ROS produced by Nox1-5 play a critical role in blood–brain barrier (BBB) dysfunction in numerous neuropathologies. Nox-derived ROS have been implicated in mediating matrix metalloprotease (MMP) activation, downregulation of junctional complexes between adjacent brain endothelial cells and brain endothelial cell apoptosis, leading to brain microvascular endothelial barrier dysfunction and consequently, increases in BBB permeability. In this review, we will highlight recent findings on the role played by these enzymes in BBB disruption induced by ischemic stroke.

Chloride Ions, Vascular Function and Hypertension.

Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl−) are a type of anions accumulated by anion exchangers and the anion–proton cotransporter system, and efflux of Cl− through Cl− channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl− regulatory pathways, emerging evidence suggests that upregulation of the Ca2+-activated Cl− channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl− in vascular smooth muscle cells through the increased activity of Na+–K+–2Cl− cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension. In this review, we discuss recent findings regarding the role of Cl− in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1.

Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic

Nitric oxide (NO) is a signal molecule and plays a critical role in the regulation of vascular tone, displays anti-platelet and anti-inflammatory properties. While our earlier and current studies found that low NO doses trigger a rapid heme insertion into immature heme-free soluble guanylyl cyclase β subunit (apo-sGCβ), resulting in a mature sGC-αβ heterodimer, more recent evidence suggests that low NO doses can also trigger heme-maturation of hemoglobin and myoglobin. This low NO phenomena was not only limited to sGC and the globins, but was also found to occur in all three nitric oxide synthases (iNOS, nNOS and eNOS) and Myeloperoxidase (MPO). Interestingly high NO doses were inhibitory to heme-insertion for these hemeproteins, suggesting that NO has a dose-dependent dual effect as it can act both ways to induce or inhibit heme-maturation of key hemeproteins. While low NO stimulated heme-insertion of globins required the presence of the NO-sGC-cGMP signal pathway, iNOS heme-maturation also required the presence of an active sGC. These effects of low NO were significantly diminished in the tissues of double (n/eNOS−/−) and triple (n/i/eNOS−/−) NOS knock out mice where lung sGC was found be heme-free and the myoglobin or hemoglobin from the heart/lungs were found be low in heme, suggesting that loss of endogenous NO globally impacts the whole animal and that this impact of low NO is both essential and physiologically relevant for hemeprotein maturation. Effects of low NO were also found to be protective against ischemia reperfusion injury on an ex vivo lung perfusion (EVLP) system prior to lung transplant, which further suggests that low NO levels are also therapeutic.

Arterial hypertension as a consequence of endothelial glycocalyx dysfunction: a modern view of the problem of cardiovascular diseases

Arterial hypertension (AH) is a leading risk factor for the development of cardiovascular, cerebrovascular, and renal diseases, which are among the top 10 most common causes of death in the world. The etiology of hypertension has not been fully elucidated, but it has been established that endothelial dysfunction is the most significant pathogenetic link in the formation and progression of the disease. The data obtained in the last 10-15 years on endothelial glycocalyx (eGC) studies indicate that endothelial dysfunction is preceded by destabilization and shedding of eGC with the appearance of its soluble components in the blood, which is equivalent to a process that can be designated as eGC dysfunction. Signs of eGC dysfunction are expressed in the development of hypertension, diseases of the cardiovascular system, and their complications. The purpose of this review is to analyze and substantiate the pathophysiological role of eGC dysfunction in hypertension and cardiovascular diseases and to describe approaches for its assessment and pharmacological correction. Abstracts and full-size articles of 425 publications in Pubmed/MEDLINE databases over 20 years were studied. The review discusses the role of eGC in the regulation of vascular tone, endothelial barrier function, and anti-adhesive properties of eGC. Modifications of eGC under the influence of pro-inflammatory stimuli, changes in eGC with age, and with increased salt load are considered. The aspect associated with eGC dysfunction in atherosclerosis, hyperglycemia and hypertension is covered. Assessment of eGC dysfunction is difficult but can be performed by indirect methods, in particular by detecting eGC components in blood. A brief description of the main approaches to pharmacoprevention and pharmacocorrection of hypertension is given from the position of exposure effects on eGC, which currently has more a fundamental than practical orientation. This opens up great opportunities for clinical studies of eGC dysfunction for the prevention and treatment of hypertension and justifies a new direction in the clinical pharmacology of antihypertensive drugs.

Abstract P038: Tissue-specific Regulation Of Ceramide De Novo Biosynthesis In Type 1 Diabetes. Role Of Metformin

Endothelial cell (EC) dysfunction precedes the onset of cardiovascular diseases (CVD), main complications of diabetes. Sphingolipids (SL) are essential components of cell membranes and bioactive lipids regulating different cellular functions in health and diseases. Dysregulation of SL, such as ceramides (Cer) accrual, has been implicated in diabetes and CVD, although specific mechanisms remain poorly understood. Whereas Cer accrual impairs endothelial nitric oxide synthase (eNOS) activity, low ceramides disrupt endothelial signal transduction and vascular tone regulation. To date, how Cer changes in diabetic EC in vivo is unknown. Metformin (Met), first-line therapy for diabetes, was shown to lower Cer in liver and muscle in mice. This study investigates the role of sphingolipid metabolism in diabetes and whether Met directly regulates this pathway.We discovered that Met can directly downregulate serine palmitoyltransferase activity, catalyzing the first step of the de novo biosynthesis of SL, thus refraining Cer from accrual. To assess this effect in vivo , we used non-obese diabetic mice, a model of type 1 diabetes, and nondiabetic mice as control. Diabetic mice were treated with Met (300mg/Kg/d) or vehicle for 5 weeks. Diabetic mesenteric arteries showed an impaired vasodilation to acetylcholine and exaggerated response to vasoconstrictors. Met treatment significantly improved endothelial function, by restoring acetylcholine-vasodilation and increasing phosphorylation of vasodilator stimulated phosphoprotein, index of eNOS-cGMP signaling. Interestingly, whereas Cer and sphingomyelins (SM) increased in the heart and liver, they were significantly decreased in myocardial EC, suggesting that in diabetes SL are differentially regulated. Met refrained Cer/SM from accrual in the heart and liver, while further decreased Cer/SM in EC. In conclusions, Met prevents Cer accrual in the heart and liver, thus limiting its deleterious effects. Contrary to the current believe, Cer are suppressed in diabetic EC in vivo , and might contribute to the progression of dysfunction. Most likely, Met downregulation of sphingolipid de novo biosynthesis, already suppressed in diabetic EC, does not underlie beneficial effects of Met on the endothelium.

Abstract P333: Influence Of RSK2 On Blood Pressure In Aging

Hypertension (HTN) is highly prevalent and is a significant risk factor for CVD. Excessive vasoconstriction contributes to HTN. Recently, p90 ribosomal S6 kinase, isoform 2 (RSK2) signaling has been shown to play a significant role in the regulation of basal vascular tone and BP control by phosphorylating RLC20 to promote smooth muscle contractility. Young adult Rsk2 KO mice have lower BP than WT littermates. Here, we examine the role of RSK2 in a geriatric HTN mouse model. Male &gt;2-year old WT and Rsk2 KO mice underwent daily BP measurements using tail cuff manometry. After 2 weeks of training, baseline (BL) BP was recorded, followed by 2 weeks of HTN induced by 20 mg/kg/day of L-N G -Nitroarginine methyl ester (L-NAME) via drinking water. Echocardiographic studies were performed at BL. WT mice had significant mortality (7 of 11 died), not seen in KO (1 of 8 died). At BL, WT mice had a significantly higher SBP compared to KOs (123±10 vs. 99±12 mmHg). L-NAME elevated SBP in WT but not KO mice (137±2 vs. 97±8 mmHg). Echocardiographic studies at BL showed no differences between genotypes. However, when ejection fraction (EF) was correlated with SBP, EF was negatively correlated with SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6) but not KO mice (p = 0.15, n = 7). Clinically, HTN-associated mortality and morbidity primarily affects older populations. Here, we show that the loss of RSK2 reduces BP in geriatric mice, similar to findings in young adult mice, and that it also abolished the hypertensive effects of L-NAME. Aged Rsk2 KO mice appear to be protected from cardiovascular effects of aging. RSK2 is a potential target for pharmacologic inhibition to treat HTN and related risks in geriatric populations.

The drp-1-mediated mitochondrial fission inhibitor mdivi-1 impacts the function of ion channels and pathways underpinning vascular smooth muscle tone

Mdivi-1 is widely used as a pharmacological tool to inhibit dynamin-related protein-1-mediated mitochondrial fission. Whether this compound may interact directly or indirectly with ion channels or cellular pathways fundamental for the regulation of vascular smooth muscle tone remains unknown. The present study aimed to assess the effect of mdivi-1 on CaV1.2 and KCa1.1 channels, both in vitro and in silico as well as on the mechanical activity of rat aorta rings. Mdivi-1 was an effective CaV1.2 channel blocker, docking in a CaV1.2 channel antagonist binding region, stimulated KCa1.1 channel current, binding to a sensing region common to other stimulators, and possibly inhibited the Rho-kinase pathway. These effects contributed to its vasorelaxant activity observed in rings stimulated with high KCl, phenylephrine, or NaF. Neither structurally different dynamin inhibitors nor a stimulator affected the Ca2+ antagonistic and vasorelaxant activities of the compound. However, mito-tempol reduced its vasorelaxant potency towards phenylephrine. Finally, mdivi-1 antagonized mitochondrial fission triggered by phenylephrine. In conclusion, mdivi-1 is an effective in vitro vasorelaxant agent at concentrations routinely employed to block dynamin-related protein-1. Ion channels and pathways key to the maintenance of vessel active tone are involved in this mechanism. These yet undiscovered off-target effects raise caution for the interpretation of mitochondrial fission signalling.

Prostacyclin Synthase as an Ambivalent Regulator of Inflammatory Reactions.

Prostacyclin (PGI2) synthase (PGIS) and microsomal prostaglandin (PG) E synthase-1 (PGES-1) are PG terminal synthases which functionally couple with inducible cyclooxygenase-2 (COX-2) as their upstream enzymes to produce PGI2 and PGE2, respectively. Non-steroidal anti-inflammatory drugs exert their pharmacological effects by the inhibition of COX-2 and thereby suppression of the biosynthesis of these PGs. PGIS is abundantly expressed in vascular endothelial and smooth muscle cells and has been shown to be critical for regulation of platelet aggregation and vascular tone. In addition to its role in vascular regulation, PGIS has been shown to be expressed in inflammatory cells including macrophages, and the proinflammatory roles of PGIS has been demonstrated. On the other hand, several investigators have recently reported that PGIS functions as an anti-inflammatory mediator by macrophage polarization and have indicated that PGIS is an ambivalent regulator of inflammatory reactions. In this review, we summarize the current understanding of proinflammatory and anti-inflammatory functions of PGIS and discuss its potential as a novel anti-inflammatory therapeutic target.

Possibilities of Multilayer Perceptron in Complexing Risk Factors of Diabetic Foot Syndrome.

The levels of markers of endothelial dysfunction, MMP9, and polymorphisms of genes of vascular tone regulation factors, platelet receptors, vascular wall remodeling and prothrombotic factors, and markers of endothelial dysfunction were studied in patients with complicated and uncomplicated diabetes mellitus. It was found that the neural network analysis of these data makes it possible to predict the development of diabetic foot syndrome with an accuracy of 92.9%. The high accuracy of neural network analysis is due to the multifactorial nature of the diabetic foot syndrome.

Three ages of spironolactone. Evolution of views on spironolactone capabilities in the treatment of patients with heart failure.

The article describes the history of the discovery of aldosterone and the creation of its antagonist, spironolactone. The effects of aldosterone associated with the stimulation of two types of receptors. Long-term effect (nuclear or genomic) and fast - term (membrane). They are manifested not only by the influence on the water-salt metabolism and the volume of extracellular fluid, but also in the regulation of vascular tone and elasticity of the vascular wall and, most interestingly, the effect on cardiac remodeling. Early after its development Spironolactone was considered as a medicine for water-salt metabolism regulation, diuresis and normalization of blood pressure. In the following period, Spironolactone embraced a new area - systolic heart failure. The drug was considered not only to enhance safe diuresis, but also to eliminate the phenomenon of escape of the antialdosterone effect angiotensin-converting enzyme inhibitors. The change in the paradigm of heart failure towards the prevailing changes in her diastolic phenotype, which is based on excessive diffuse myocardial fibrosis, changed role of spironolactone in the treatment of heart failure. Currently, it is considered as an independent drug, due to its powerful antifibrotic effect, blocking which controls the whole complex of endo- and paracrine effects of aldosterone.

Hemorheological and microvascular disturbances in patients with type 2 diabetes mellitus.

In the blood vessels the impaired hemorheological parameters in patients with type 2 diabetes mellitus (T2DM) could lead to elevated flow resistance, increased forces at the endothelial wall and to microvascular disturbances. The aim of the study is to investigate the hemorheological variables and the changes of the skin blood flow responses to cold stress in T2DM patients. The basic hemorheological parameters: hematocrit (Ht), fibrinogen (Fib), whole blood viscosity (WBV) and plasma viscosity (PV) were examined in 20 patients with T2DM and a control group of 10 healthy age and sex matched controls. The mechanisms of vascular tone regulation were investigated using the wavelet analysis of the skin temperature oscillations (WAST). The degrees of the microvascular tone changes were determined during a cold test in the endothelial (0.02-0.0095 Hz), neurogenic (0.05- 0.02 Hz) and myogenic (0.05- 0.14 Hz) frequency ranges. Significant increase of Fib and WBV in the patients in comparison to controls was found. The mean values of the amplitudes of the skin temperature (ST) pulsations decreased significantly during the cold stress only in the endothelial frequency range for the diabetic patients. The results of our study reveal parallel impairment of the blood rheological parameters and the cutaneous microcirculation in T2DM patients.

Sports activities and professional specialty influence on psychophysiological functions and orthostatic reactions indicators of pedagogical universities students

Purpose: to identify the influence of the professional orientation of education and lifestyle (sports) on the indicators of psychophysiological functions and orthostatic reactions of students of various faculties of pedagogical universities.&#x0D; Material and methods. 812 students of pedagogical institutions of higher education of Ukraine took part in the study: 88 students of the faculty of elementary education, 76 students of history, 130 of natural sciences, 131 of foreign philology, 93 of the faculty of preschool education, 198 of Ukrainian language, 25 of the faculty of physical education and sports, 24 students from the Faculty of Arts, 47 students from the Faculty of Psychology and Sociology. Psychophysiological testing was carried out according to the Psychodiagnostics program and involved determining the speed of a simple visual-motor reaction, determining the speed of a choice of two elements out of three. During psychophysiological testing, the reaction time and the number of errors were determined for each test.&#x0D; The results. Students of the faculties of elementary education, preschool education, and the faculty of natural sciences have a significantly shorter reaction time in the test for a simple visual-motor reaction (p&lt;0.05), and, accordingly, the best indicators of the mobility of nervous processes in comparison with students of other faculties of pedagogical universities. These faculties have the largest number of errors in the test for the choice of two elements out of three (p&lt;0.05), and, accordingly, the lowest strength of nervous processes.&#x0D; Conclusions. Sports have a positive effect on the indicators of the strength of nervous processes according to the results of the number of errors in the reaction test for choosing two items out of three (p&lt;0.05). Also, playing sports has a positive effect on the quality of vegetative regulation of vascular tone, which is reflected in lower values ​​of the heart rate during the transition from a horizontal position of the body to a vertical one in students who play sports (p&lt;0.05).

Anti-inflammatory, anti-oxidant and cardio-protective properties of novel fluorophenyl benzimidazole in L-NAME-induced hypertensive rats

BackgroundChronic inflammation and oxidative stress play important role in development of hypertension. Recently, we have reported novel fluorophenyl benzimidazole (FPD) for vasorelaxation and antihypertensive activity in SHRs. The present study envisaged the anti-inflammatory, anti-oxidant and cardio-protective properties of FPD in L-NAME model of hypertension with special emphasis on reversal of vascular remodeling, gene expression and restoration of hemodynamic. MethodsAntihypertensive activity of FPD was evaluated in L-NAME treated Wistar rats, and the parameters studied were anti-inflammatory activity, histomorphological changes, gene expression profile and anti-oxidant properties. ResultsFPD at 50 and 100 mg kg−1 once daily for 15 days significantly reduced SBP, DBP and MAP in L-NAME treated rats and the values were well comparable to vehicle control group. Further, FPD treatment showed a significant increase in hepatic GSH content, SOD, catalase activity, decreased MDA level and restoration of pro and anti-inflammatory cytokine levels. The mRNA expression profile of genes associated with regulation of vascular tone, remodeling and inflammation showed a significant level of alteration by chronic L-NAME treatment and was dose-dependently restored upon treatment with FPD. Further, FPD treatment restored serum lipid profile, CK, CK-MB and LDH level and also reversed the histomorphological changes like intimal wall thickening, hyperplasia of cardiomyocytes and ventricular wall thickening. ConclusionsTaken together, FPD produced potent antihypertensive activity in L-NAME model through vasorelaxation, anti-oxidative and anti-inflammatory properties leading to restoration of serum lipid profile, cardiac biomarker, expression profile of target genes and reversal of histomorphological changes.

ACTIVITY OF NITRO-OXIDATIVE PROCESSES IN PREGNANT WOMEN WITH IDIOPATHIC ARTERIAL HYPOTENSION

Primary violation of vascular tone and reactivity is considered the main hemodynamic link in the pathogenesis of idiopathic arterial hypotension (IAH). Two gaseous messengers - nitric oxide (NO) and hydrogen sulfide (H2S) play an important role in the regulation of vascular tone.&#x0D; The research aims at determining the state of the NO system and the level of H2S in women with IAH and their effect on the uteroplacental blood flow.&#x0D; Material and Methods. A number of 20 pregnant women with IAH at 40-41 weeks of gestation were examined (group I); the second group included 20 pregnant women with normotony at 39-40 weeks of gestation. The concentration of the complex of nitrates and nitrites was determined by the reaction of formation of a colored complex by Griss reagent. The content and production of peroxynitrite in alkali and alkaline earth metals were determined according to the procedure described by Vanuffelen et al. Detection of hydrogen sulfide content in blood plasma was performed by the method of Dombkowski et al. Studies of uteroplacental blood flow were performed on ultrasonic diagnostic device "SA-8000 EX" using color Doppler mapping and pulse mapping dopplerometry of the blood flow in the uterine arteries (UA). The assessment of blood flow velocity curves was carried out by determining the pulsation index (PI) in both arteries taking into account the average value.&#x0D; Results. The results of the study showed that an average level of nitrites and nitrates in pregnant women with IAH was 37.0% higher than in women with normotension, and peroxynitrite values were 2.4 times higher, respectively. In contrast, the concentration of H2S in pregnant women with IAH was almost 1.4 times lower, than in pregnant women with normal blood pressure. Doppler study of blood flow indices in UA showed a moderate increase in PI in 28.0% of pregnant women with IAH. Thus, indices of vascular resistance in UA of pregnant women with IAH were higher, on average, by 19.0% than in pregnant women with normotension.&#x0D; Conclusions. High levels of nitrites and nitrates in pregnant women with IAH form the basis for the development of nitrosatous stress, which is accompanied by increasing concentration of highly toxic peroxynitrite. Significant increase in peroxynitrite is one of the causes of endothelial dysfunction. In pregnant women with IAH due to the low content of H2S - its vasoconstrictive effects are prevalent, which may indicate an indirect interaction between both of these systems of vasoregulation.

Downregulation of eNOS and preserved endothelial function in endothelial-specific arginase 1-deficient mice

Arginase 1 (Arg1) is a ubiquitous enzyme belonging to the urea cycle that catalyzes the conversion of l-arginine into l-ornithine and urea. In endothelial cells (ECs), Arg1 was proposed to limit the availability of l-arginine for the endothelial nitric oxide synthase (eNOS) and thereby reduce nitric oxide (NO) production, thus promoting endothelial dysfunction and vascular disease. The role of EC Arg1 under homeostatic conditions is in vivo less understood. The aim of this study was to investigate the role of EC Arg1 on the regulation of eNOS, vascular tone, and endothelial function under normal homeostatic conditions in vivo and ex vivo. By using a tamoxifen-inducible EC-specific gene-targeting approach, we generated EC Arg1 KO mice. Efficiency and specificity of the gene targeting strategy was demonstrated by DNA recombination and loss of Arg1 expression measured after tamoxifen treatment in EC only. In EC Arg1 KO mice we found a significant decrease in Arg1 expression in heart and lung ECs and in the aorta, however, vascular enzymatic activity was preserved likely due to the presence of high levels of Arg1 in smooth muscle cells. Moreover, we found a downregulation of eNOS expression in the aorta, and a fully preserved systemic l-arginine and NO bioavailability, as demonstrated by the levels of l-arginine, l-ornithine, and l-citrulline as well as nitrite, nitrate, and nitroso-species. Lung and liver tissues from EC Arg1 KO mice showed respectively increase or decrease in nitrosyl-heme species, indicating that the lack of endothelial Arg1 affects NO bioavailability in these organs. In addition, EC Arg1 KO mice showed fully preserved acetylcholine-mediated vascular relaxation in both conductance and resistant vessels but increased phenylephrine-induced vasoconstriction. Systolic, diastolic, and mean arterial pressure and cardiac performance in EC Arg1 KO mice were not different from the wild-type littermate controls. In conclusion, under normal homeostatic conditions, lack of EC Arg1 expression is associated with a down-regulation of eNOS expression but a preserved NO bioavailability and vascular endothelial function. These results suggest that a cross-talk exists between Arg1 and eNOS to control NO production in ECs, which depends on both L-Arg availability and EC Arg1-dependent eNOS expression.

GENETIC DETERMINATION OF ENDOTHELIAL FUNCTION AND «INTIMA-MEDIA» THICKNESS OF CAROTID ARTERIES IN PATIENTS WITH ARTERIAL HYPERTENSION

Endothelial regulation of vascular tone is an important component of the infl uence onblood pressure (BP).Objective – to study the changes in endothelial function and the «intima- media» thickness(IMT) of the carotid arteries depending on the genes polymorphism GNB3 (rs5443) andNOS3 (rs2070744) in essential arterial hypertension (EAH).Materials and methods. 100 patients with EAH 2nd stage and 48 practically healthypersons (control group) participated in the study. Soluble Vascular Cell AdhesionMolecule (sVCAM-1), total NO metabolites (NO2–+NO3–), transcriptional activity ofNOS3 gene, Endothelium- Dependent Flow- Mediated Dilation of the Brachial Artery(FMD BA) and carotid IMT were studied. NOS3 (rs2070744) and GNB3 (rs5443) geneswere investigated by Real- Time PCR.Results. Severe EAH is accompanied by an IMT increase 50.0-57.14% (p&lt;0.01), NOS3gene expression after mRNA level decrease 34.54% (p=0.003), more often atheroscleroticplaques on the carotid arteries 24.77-27.62% (p&lt;0.05). The polymorphic site of theNOS3 gene (rs2070744) is associated with a total NO metabolites value decrease,transcriptional activity of the NOS3 gene decrease (F=71.11 and F=8.71; p&lt;0.001)and sVCAM-1 level elevation (F=6.96; p=0.002), especially in minor C-allele carriers(more severe in CC-genotype). ANOVA has not shown an association of the GNB3 gene(rs5443) with endothelial function and carotid artery IMT in EAH patients.Conclusions. The polymorphic site of the NOS3 gene (rs2070744) is associated withendothelial function changes and does not aff ect the IMT of the carotid arteries.

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive

BackgroundCerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes.MethodsThis was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score.ResultsOne hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p < 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1–2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1–2 in 42%) (p < 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05).ConclusionsCommon pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored.