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The significant humoral effect of the renin-angiotensin-aldosterone system on the regulation of the cardiovascular system and blood pressure has long been widely known. However, the identification and interpretation of new components of renin-angiotensin-aldosterone system in recent years can significantly expand the range of its potential effects on the body. The anti-inflammatory effect of drugs that block angiotensin II and its receptors, including in rheumatic diseases, can become practically significant for General therapists by their effect on reducing the concentration of inflammatory mediators and angiogenesis processes. The organoprotective and anti-inflammatory potentials of drugs that reduce the production of at demonstrated in vitro and in vivo experiments allow us to consider them as first-line angiotropic agents in patients with rheumatoid arthritis, especially in the presence of pathology of the cardiovascular system and kidneys.Значимое гуморальное влияние ренин-ангиотензин-альдостероновой системы на регуляцию деятельности сердечно-сосудистой системы и уровня артериального давления издавна и широко известно. Однако идентификация и расшифровка новых компонентов ренин-ангиотензин-альдостероновой системы в последние годы позволяет значительно расширить диапазон ее потенциального воздействия на организм. Практически значимым для терапевтов широкого профиля может стать противовоспалительный эффект препаратов, блокирующих ангиотензин II и его рецепторы, в том числе и при ревматических заболеваниях, посредством их воздействия на снижение концентрации медиаторов воспаления и процессов ангиогенеза. Продемонстрированные в экспериментах in vitro и in vivo органопротективные и противовоспалительные потенциалы лекарственных препаратов, уменьшающих выработку ангиотензина, позволяют рассматривать их как ангиотропные средства 1-го ряда у пациентов с ревматоидным артритом, особенно при наличии патологии сердечно-сосудистой системы и почек.

Being the most common malignancy in men, prostate cancer (PCa) is a significant social and medical problem. The development of new approaches to the diagnosis, prognosis, and treatment of PCa is one of the most important tasks of current urological oncology.The renin-angiotensin cascade plays a crucial role in the regulation of most physiological and pathophysiological conditions in the human organism, including vascular tone, blood pressure, development and progression of atherosclerosis, and key metabolic processes. The classical regulation axis of the renin-angiotensin system (RAS) is well known and includes angiotensin converting enzyme (ACE)/angiotensin II/ angiotensin II receptors. Recently, new RAS elements have been found and described, such as ACE2 (homologue of ACE), angiotensin isoforms 1—7, alamandin, etc. This resulted in the discovery of many new alternative axes of RAS regulation, including ACE2/angiotensin-(1—7)/ MAS receptor, prorenin/(pro)renin receptor/MAP kinase, and angiotensin A/almandin/receptor D (MrgD). The prostate gland has a local RAS; all main components of RAS are expressed in prostate tissues.This review analyzes molecular mechanisms underlying carcinogenic effects of RAS, as well as classical and alternative pathways of RAS regulation in PCa. We have described the results of studies evaluating individual RAS parameters in PCa, which confirm the existence of a complex network between various elements of local RAS and molecular and cellular mechanisms of prostate carcinogenesis. RAS has been proved to play an important role in PCa development and progression.We have also covered new therapeutic targets for PCa treatment, presumable mechanisms of action, and prospects of using RAS inhibitors for PCa.

Diabetic retinopathy (DR) is becoming more and more widespread disease. Investigation of local changes of metabolic pathways in the eye improves our knowledge about diabetic retinopathy pathogenesis and provide perspective for the development of new pathogenetically based and individually focused therapy of this disease.Purpose of the study was to determine the concentrations of angiotensin II (AII), angiotensin-converting enzyme (ACE) and matrix metalloprotease-9 (MMP-9) in tears and serum of patients with diabetic retinopathy, estimate their significance for the evaluation of diabetic retinopathy severity and choice of treatment.Patients and methods. Tear and serum samples from 31 patients with diabetic retinopathy were analysed. Control group consisted of healthy volunteers of the same sex and age. Concentrations of angiotensin II, angiotensin-converting enzyme and matrix metalloprotease-9 were measured using the ELISA kits.Results: in controls angiotensin II concentration was 9.8 ± 5.5 pg/ml, in tears — 11.8 ± 6.6 pg/ml, angiotensin-converting enzyme concentration in serum was 82.6 ± 10.9 ng/ml, in tears it was 40 times lower: 2.5 ± 0.5 ng/ml, matrix metalloprotease-9 concentration in serum was 186.3 ± 8.9 ng/ml while in tears it was 100 times lower: 2.0 ± 0.9 ng/ml. In tears of patients with diabetic retinopathy levels of all 3 substances were significantly higher than in controls. Concentration of angiotensin II was 8 times higher, angiotensin-converting enzyme concentration 5 times higher and matrix metalloprotease-9 level 3 times higher. In serum angiotensin II concentration was increased 9 times, angiotensin-converting enzyme — 2 times. No difference in serum matrix metalloprotease-9 levels was observed. Thus diabetic retinopathy cause a significant activation of local and systemic rennin-angiotensin system. Local changes are more marked than systemic. Estimation of angiotensin II, angiotensin-converting enzyme and matrix metalloprotease-9 concentrations in tears can serve as an objective test for the diabetic retinopathy diagnostic and a pathogenetic rationale for the development of a new method of therapy — topical use of angiotensin-converting enzyme inhibitors.

The article describes the possibility of using a new class of angiotensin II/neprilysin receptor inhibitor - sacubitrile/valsartan for the treatment of chronic heart failure (CHF). The role of the natriuretic peptide system in the pathogenesis of CHF and the importance of neurohormonal modulation in modern therapy of patients with heart failure are emphasized. Strategies for introducing exogenous natriuretic peptides and blocking the destruction of natriuretic peptides in the human body are described. The questions of influence on the enzyme neprilysin, which is involved in the metabolism of natriuretic peptides and angiotensin II, are considered. In this regard, the simultaneous inhibition of non-lysine with the suppression of the renin-angiotensin system is promising. The first experience in this direction was the development and study of the drug omapatrilat. The results of multicenter studies of OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) and OCTAVE (Omapatrilat Cardiovascular Treatment vs. Enalapril) are presented. An obstacle for the use of omapatrilat in clinical practice was the high frequency of angioedema. To reduce the risk of this complication, a combined drug LCZ696 was designed, consisting of a neprilysin inhibitor - sacubitrile (AHU377) and an angiotensin II receptor blocker (ARB) - valsartan, which, unlike ACE inhibitors, does not inhibit the breakdown of bradykinin. The presence in the composition of LCZ696 of a substance acting on the system of neutral endopeptidases, made this drug the first of a new class of drugs. The results of the PARADIGM-HF study (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial) served as the basis for including the drug sacubitril/valsartan in 2016 in the ACC/AHA/HFSA and ESC guidelines, and later in the Russian recommendations. The article discusses modern approaches to the use of the drug sacubitril/valsartan.

The SARS-CoV-2 virus is a pathogen causing the coronavirus infection that culminated in a worldwide pandemic in 2020. It belongs to β-coronaviruses and has high genetic similarity to the SARS-CoV virus that is responsible for an outbreak of severe acute respiratory syndrome in 2002–2003. The analysis of molecular interactions shows that SARS-CoV-2 has higher virulence due to lower binding free energy in interaction with the angiotensin-converting enzyme 2 (ACE2), which is used by the virus to enter the host cell. At the time of the global coronavirus pandemic, the thorough study of ACE2 as a key component of the disease pathogenesis comes to the fore. The detailed study of the enzyme, which is a receptor located on the surface of different tissues and which normally catalyzes the conversion of angiotensin II to angiotensin (1–7), led to diverging conclusions. Being non-tissue specific, the receptor is abundantly present in the heart, kidneys, small intestine, testes, thyroid, and adipose tissue. Besides regulating blood pressure, it suppresses inflammation, mainly in the lung tissue, participates in amino acid transport and maintains the activity of the gut microbiome. With all its essential positive functions, the role of ACE2 is highly ambiguous, specifically in coronavirus infection. The influence on the renin-angiotensin system can be seen as a promising therapeutic route in treatment of coronavirus infection. The preliminary data on using of ACE2 inhibitors, soluble forms of ACE2, and angiotensin II receptor blockers demonstrate their effectiveness and, consequently, improvement in symptoms and prognoses for patients with coronavirus infection. The review presents information about ACE2 distribution in human tissues, explores its interaction with SARS-CoV-2, provides a theoretical basis for medications involving ACE2 metabolic pathways and for using them in treatment of coronavirus infection and its prevention.

Septic shock, as the most severe form of sepsis, is characterized by high mortality reaching 40% despite the use of the most modern standards of diagnosis and treatment. In the thanatogenesis of septic shock, vasoplegia plays a leading role, respectively, and therapy of the condition under discussion involves the use of vasoconstrictors, along with the standard prescription of infusion therapy, antibiotics and symptomatic treatment. The choice of a specific vasoactive drug is a difficult task for a practicing anesthetist, as along with undoubtedly positive properties, vasoconstrictors each have their own spectrum of undesirable side effects, which, of course, must be taken into account when determining treatment tactics.The aim of review: A comprehensive assessment of the multifactorial effect of various vasoconstrictors on the patient to determine the criteria for choosing the optimal drug (or a combination of drugs) in septic shock.The search was carried out using PubMed and Scopus databases, the final selection of 89 articles was carried out in accordance with the following criteria: relevance to the topic of this review and the nature of the article — only randomized controlled trials, guidelines and analytical reviews were included in the final analysis.External and internal mechanisms of vascular tone regulation are considered, including factors produced by endothelium (nitric oxide, prostacyclin, endothelin); vasoactive metabolites and autocoids — signal molecules of local action (serotonin, prostaglandins, thromboxane A2). Accordingly, drugs were analyzed the mechanism of action of which is related to the effect on adrenergic (adrenaline, dopamine, norepinephrine, phenylephrine, dobutamine), vasopressin (vasopressin, terlipressin, selepressin) receptors, synthetic analogues of angiotensin (angiotensin II) and drugs the non-vasopressor effect of which is not linked with the receptor apparatus (methylene blue, levosimendan, hydrocortisone).Conclusion. The high effectiveness of norepinephrine, its positive hemodynamic effects make the drug under discussion, in many ways, a universal remedy for the relief of septic shock. However, refractory shock may require the introduction of such high doses of norepinephrine that the occurrence of adverse reactions will become practically inevitable. The combined use of adrenergic and ligand V receptors, terlipressin, is intended to prevent these complications. However, to date, there are no clear recommendations on the use of terlipressin in septic shock, which limits its use in clinical practice.

The second part of the review considers different classes of drugs affecting blood pressure in increased activity of the sympathetic nervous system. Additional possibilities are discussed on how to reduce the negative effect of sympathetic hyperactivity on cardiovascular system and improve the prognosis.

According to modern concept of the etiopathogenesis of essential hypertension, immune cells play an important role in its development. Mediators produced by immunocompetent cells participate in the initiation and maintenance of chronic systemic inflammation and promote the development of vascular remodeling which is an important part of the pathogenesis of the disease and target organ damage. The immune mechanisms underlying blood pressure elevation include the activation of innate and adaptive immune cells. Endothelial damage triggers an inflammatory cascade, causing migration of the immune cells to the inflammatory site, mediated by chemokines and adhesion molecules. Macrophage infiltration of perivascular tissue contributes to impaired vasodilation and damage to target organs due to the production of active forms of oxygen. Angiotensin II also causes T cell infiltration of perivascular adipose tissue and adventitia and an increased production of tumor necrosis factor alpha and interferon gamma. In addition, T lymphocytes express the mineralocorticoid receptor involved in the development of systemic hypertension. An important role in the progression of hypertension belongs to interleukin-17, which is involved in blood pressure elevation and vascular remodeling. The review also contains data on the effect of gut microbiota on the regulation of blood pressure and the development of hypertension.

Данная работа посвящена влиянию коронавируса COVID-19 и вируса гриппа на ренин-ангиотензиновую систему человека. В работе исследовалась ферментативная активность ангиотензинпревращающего фермента (АПФ) и карбоксипептидазы-N, Ð²Ñ Ð¾Ð´ÑÑ‰Ð¸Ñ Ð² ренин-ангиотензиновую систему, в ÑÑ‹Ð²Ð¾Ñ€Ð¾Ñ‚ÐºÐ°Ñ ÐºÑ€Ð¾Ð²Ð¸ пациентов с коронавирусной и гриппозной инфекциями. В качестве субстрата для АПФ был использован ангиотензин I, для карбоксипептидазы-N – брадикинин. Известно, что ангиотензин II обладает сосудосуживающим действием, а брадикинин сосудорасширяющим действием. Таким образом они являются участниками регуляции кровяного давления. Использование ингибиторов АПФ улучшает Ð¸ÑÑ Ð¾Ð´Ñ‹ сердечно-ÑÐ¾ÑÑƒÐ´Ð¸ÑÑ‚Ñ‹Ñ Ð·Ð°Ð±Ð¾Ð»ÐµÐ²Ð°Ð½Ð¸Ð¹, однако есть опасения, что они могут ÑƒÑ ÑƒÐ´ÑˆÐ¸Ñ‚ÑŒ прогноз пациентов с коронавирусной инфекцией. Цитокиновый шторм, вызванный COVID-19, и повышенная активация РААС могут усилить воспаление в Ð»ÐµÐ³ÐºÐ¸Ñ Ð¸ Ð´Ñ€ÑƒÐ³Ð¸Ñ Ð¾Ñ€Ð³Ð°Ð½Ð°Ñ . Следовательно, существует острая Ð½ÐµÐ¾Ð±Ñ Ð¾Ð´Ð¸Ð¼Ð¾ÑÑ‚ÑŒ в разработке рекомендаций по применению ÑÑ‚Ð¸Ñ Ð¿Ñ€ÐµÐ¿Ð°Ñ€Ð°Ñ‚Ð¾Ð² при заражении SARS-COV-2. В данной работе измерения проводились с помощью метода масс-спектрометрического анализа. Были подобраны оптимальные условия для оценки Ð¾Ð±Ñ€Ð°Ð·Ð¾Ð²Ð°Ð²ÑˆÐ¸Ñ ÑÑ в Ñ Ð¾Ð´Ðµ гидролиза пептидов. Были обнаружены различия между тремя исследуемыми группами пациентов, что свидетельствует о влиянии заболевания на активности АПФ. Также было выявлено, что коронавирусная инфекция влияет на активность карбоксипептидазы N., This work is devoted to the influence of the coronavirus COVID-19 and the influenza virus on the human renin-angiotensin system. The work investigated the enzymatic activity of angiotensin-converting enzyme (ACE) and carboxypeptidase-N, included in the renin-angiotensin system, in the blood serum of patients with coronavirus and influenza infections. Angiotensin I was used as a substrate for ACE, and bradykinin for carboxypeptidase-N. It is known that angiotensin II has a vasoconstrictor effect, and bradykinin has a vasodilator effect. Thus, they are involved in the regulation of blood pressure. The use of ACE inhibitors improves the outcomes of cardiovascular disease, but there are concerns that they may worsen the prognosis of patients with coronavirus infection. The cytokine storm caused by COVID-19 and increased RAAS activation can increase inflammation in the lungs and other organs. Therefore, there is an urgent need to develop recommendations for the use of these drugs when infected with SARS-COV-2. In this work, measurements were carried out using the method of mass spectrometric analysis. Optimal conditions were selected for assessing the peptides formed during hydrolysis. Differences were found between the three study groups of patients, which indicates the effect of the disease on ACE activity. It was also found that coronavirus infection affects the activity of carboxypeptidase N.

The article describes current data on the relationship of renin-angiotensin system and related drugs with the risk of COVID-19 infection and its outcomes. Analysis of the latest publications did not reveal association of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with any risk of an unfavorable outcomes, and there was no data for withdrawal of these drugs.

Objective. To determine the clinical and genetic risk factors for the development and progression of carotid vascular remodeling according to the prospective observation after five years in patients with essential arterial hypertension (AH). Material and methods. The repeat clinical and instrumental examination with assessment of concomitant cardiovascular risk factors (obesity, smoking, alcohol consumption, physical activity level, hyperglycemia, hypercholesterolemia, signs of depression) was performed in 78 patients with AH. The ultrasound examination of carotid arteries included evaluation of intima-media complex thickness (IMT) and the presence of atherosclerotic plaques. The polymorphism of the genes of the renin-angiotensin-aldosterone system analyzed by polymerase chain reaction and polymorphism of restriction fragment lengths. Results. Progression of vascular remodeling was observed in 26 patients (33.3%) according to the results of carotid arteries examination after 5 years. Age (r=0.53; p=0.001), degree of AH (r=0.43; p=0.0001), level of office systolic blood pressure (r=0.295; p=0.0090), presence of the mutant C allele polymorphism A1166C of the angiotensin II type 1 receptor gene - AGTR1 (r=0.387; p=0.0001), blood glucose (r=0.30; p=0.010), waist circumference (r=0.258; p=0.023) were associated with an increase IMT common carotid artery (CCA) in patients with AH. The multiple linear regression analysis identified independent factors influencing on the IMT CCA - age (b=0.62; p=0.01), males (b=0.321; p=0.01) and the mutant C allele carrier polymorphism A1166C of AGTR1 gene (b=0.312; p=0.01). Conclusions. The progression of carotid vascular remodeling risk factors in patients with AH were age, male gender and polymorphism of A1166C gene AGTR1.

Цель исследования - изучение гендерных особенностей содержания в сыворотке крови молекулярных маркеров артериальной гипертензии у мужчин и женщин с оптимальным артериальным давлением и предгипертонией. Методика. Обследовано 115 лиц мужского (n49) и женского пола (n66) в возрасте 48-49 лет с оптимальным давлением, (АД120/80 мм рт. ст., n63,) и предгипертонией (АД120-139/80-89 мм рт. ст., n52). С помощью твердофазного иммуноферментного анализа с использованием оригинальных и коммерческих тест-систем в сыворотке крови определяли содержание биомаркеров: пептидов, ангиотензина II, HLDF24, белков S100b, эндотелина и аутоантител к ним, а также васкулоэндотелиального фактора роста сосудов. Методами математического анализа проведено сравнение содержания биомаркеров у мужчин и женщин с оптимальным АД и предгипертонией. Результаты. В сыворотке крови мужчин и женщин с оптимальным АД и предгипертонией обнаружены статистически значимые различия в содержании ряда молекулярных маркеров. У мужчин с предгипертонией по сравнению с лицами мужского пола, имеющими оптимальное АД, документировано значимое повышение содержания эндотелина и титров аутоантител к белку S100b. Вместе с тем, у женщин с предгипертонией выявлено статистически значимое снижение содержание ангиотензина II. Как у мужчин, так и у женщин в сыворотке крови обнаружено статистически высоко значимое снижение уровня пептида HLOF24 при предгипертонии по сравнению с лицами, имеющими оптимальное АД. Заключение. Документированные гендерные особенности содержания биомаркеров в крови отражают, по-видимому, ключевые молекулярные события при развитии предгипертонии у мужчин и женщин в исследованной возрастной когорте. Полученные результаты представляют интерес для понимания патогенеза предгипертонии и разработки методов её персонифицированной коррекции., The aim of the study was to investigate features of the content of serum molecular markers for arterial hypertension in men and women with optimal blood pressure (BP) and prehypertension. Methods. The study evaluated 115 males (n 49) and females (n 66) aged 47.6 0.7 with an optimal BP (120/80 mm Hg, n 63) and prehypertension (120-139 / 80-89 mm Hg, n 52). Serum concentrations of biomarkers, including peptides, angiotensin II, HLDF24, S100b protein, endothelin, and respective autoantibodies, and vascular endothelial vascular growth factor, were measured using ELISA with original and commercial kits. Serum concentrations of biomarkers were compared in men and women with optimal BP and prehypertensive subjects using mathematical analysis. Results. Serum concentrations of some molecular markers were significantly different in men and women with optimal BP and prehypertension. Endothelin levels and autoantibody titers to S100b were higher for men with prehypertension than with optimal BP. Furthermore, prehypertensive women had a significantly lower level of angiotensin II. However, both prehypertensive men and women had highly significant decreases in the level of HLOF24 compared to individuals with optimal BP. Conclusion. The observed gender features of biomarker levels apparently reflect key molecular events during the development of prehypertension in men and women of the studied age cohort. The study results are of interest for understanding pathogenetic mechanisms of prehypertension and for development of methods for its individualized correction., №4 (2019)

Цель исследования - изучение гендерных различий в сердечно-сосудистой системе у крыс c алкогольной кардиомиопатией. Методика. Алкогольную кардиомиопатию у крыс воспроизводили, предоставляя им в качестве единственного источника питья 10-ный водный раствор этилового спирта в течение 24 нед. Для оценки размеров левого желудочка сердца и его инотропной функции использовали эхокардиографию. С помощью полимеразной цепной реакции в реальном времени определяли экспрессию ряда рецепторов и регуляторных белков в миокарде левого желудочка и грудной аорте. Результаты. Сравнительный анализ показал, что у интактных самок по сравнению с самцами размеры левого желудочка сердца значительно меньше, в то время как фракции укорочения и выброса выше. Принудительная алголизация в течение 24-х нед как у самцов, так и у самок вызывает развитие алкогольной кардиомиопатии, эхокардиографически проявляющейся увеличением размеров левого желудочка сердца и угнетением его сократительной функции. Однако у самок увеличение размеров левого желудочка выражено в значительно большей степени. В биоптатах левого желудочка сердца животных обоего пола изменения уровня экспрессии мРНК рецепторов эндогенных трансмиттеров: катехоламинов (1- и 2-AR), ангиотензина II (AT1A-R), эндотелина-1 (ETA-R) и регуляторных белков (Eрас1, Ерас2 и CaM) при алкогольной кардиомиопатии носит однонаправленный характер. В аорте самок повышается экспрессия мРНК ключевых вазоконстрикторных рецепторов (1-R, ETA-R, VIA-R, AT1A-R), тогда как в аорте самцов, напротив снижается. Заключение. Таким образом, как у самок, так и самцов крыс 24-недельное систематическое потребление алкоголя приводит к формированию алкогольной кардиомиопатии, однако у самок выявленные патологические изменения прогностически более неблагоприятны., Aim. To study sex-related differences of changes in the cardiovascular system in rats with alcoholic cardiomyopathy (AСMP). Methods. Alcoholic cardiomyopathy was induced in rats by offering them a 10 aqueous solution of ethyl alcohol as the only source of fluid for 24 weeks. Echocardiography was used to assess the size and inotropic function of the left ventricle. Expression of receptors and regulatory proteins in the left ventricular myocardium and thoracic aorta was determined using real-time polymerase chain reaction. Results. Comparative analysis showed that the left ventricle was much smaller in intact females than in males whereas shortening and ejection fractions of the female left ventricle were greater. Forced alcoholization for 24 weeks induced ACMP in both males and females, which was evident on echocardiogram as enlargement of the left ventricle and depression of its contractility. However, the increase in left ventricular size was considerably more pronounced in females. In biopsy samples of the left ventricle, the expression of mRNA of genes for endogenous transmitter receptors catecholamines (1 and 2-AR), angiotensin II (AT1-R), endothelin-1 (ETA-R) and regulatory proteins (Epac1, Epac2 and CaM) changed in the same direction in both males and females. The mRNA expression of key vasoconstrictor receptor genes (1-R, VIA-R, ATIA-R) was increased in the female aorta but reduced in the male aorta. Conclusion. In both female and male rats, the 24-week alcohol consumption on a regular basis resulted in ACMP however, in females, pathological changes were prognostically more adverse., №4 (2019)

Aim. To assess the neurohumoral state, specifics of clinical presentation, prevalence and prominence of cardiovascular and behavioral risk factors in males of young age with masked arterial hypertension (MAH).Material and methods. To the full coverage screening study, 643 participants included, age 18-30 y. o. (mean age 22). Complete clinical and laboratory, instrumental assessments performed, with analysis of neurohumoral activity by the levels of adrenaline, noradrenaline, angiotensin II. All participants were selected to groups: MAH (n=61), manifest AH (n=46), normotonics (n=536). Diagnostics of MAH was done in case of positive test of 30 second respiration pause and 24 hour blood pressure (BP) monitoring.Results. In males, MAH was found in 9,5% cases, manifest AH in 7,1%, normotonia in 83,4%. In MAH and manifest AH participants the level of adrenaline was higher than in normotonics: 4,55 pM/L [3,53; 5,1], 6,25 pM/L [4,75; 8,65] and 2,1 pM/L [1,2; 4,5], respectively. Males with MAH had almost 2 times higher level of noradrenaline (19,5 pM/L [18,8; 22,8]) comparing to “normotonics” (8 pM/L [6; 12,1]) and 1,5 times higher than in manifest AH (13,1 pM/L [11,5; 14,4]). Angiotensin II assessment showed that in MAH males it was higher (18,5 pM [15,75; 21,9]), than in normotonics (15,7 pM [13;18,3]), but lower than in manifest AH (20,15 pM [18,9; 21,9]). Food related behavior assessment as of a factor of sodium overconsumption, the higher values were found in MAH patients and in manifest AH (50% and 50%) comparing to normotonics (25%). Early age of smoking beginning found in 28% of MAH males, more prevalent than in normotonics (24%) and manifest AH (15%).Conclusion. In young males MAH is revealed more often than manifest AH. Development of MAH in young males is related to hypersympathicity with raised catecholamines level, disordered 24 hour rhythm “non-dipper”, disorder of BP variability and higher smoking level, than in normotonics.

To investigate the plasma concentrations of cytokines and vasoactive molecules in patients with coronary heart disease (CHD) in the presence of hypertension in relation to the angiotensin-converting-enzyme (ACE) inhibitor level reflecting the degree of renin-angiotensin-aldosterone system (RAAS) inhibition.72 patients with NYHA functional class (FC) II-III angina pectoris and 40 healthy persons at the age of 47-65 years were examined in a controlled cohort study. Enzyme immunoassay was employed to determine the serum concentrations of interleukins (IL) (IL-2, IL-12, IL-17A, and IL-24), the vasoactive molecules of bradykinin, serotonin, ACE, angiotensin-II (AT-II), NO, and endothelin-1 (ET-1), and plasma renin activity. In addition, the plasma level of the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro was used as a marker for ACE inhibition.The patients with CHD occurring in the presence of hypertension compared with the apparently healthy individuals displayed decreased ET-1 and NO production along with elevated levels of serotonin, AT-II, as well as IL-17A and IL-12. The found changes were accompanied by reduced renin activity. Thus, the individuals with low ACE inhibitor levels showed more pronounced production of the proinflammatory cytokine IL-17A, as well as high plasma concentrations of ACE and NO. The high ACE inhibitor level that reflects patient adherence to appropriate antihypertensive therapy is associated with the reduced production of IL-2 and with the minimum serum levels of ACE, AT-II, and NO, being characterized by the high production of IL-12 and serotonin at the same time.In patients with CHD and hypertension, the high plasma enzyme inhibitor concentration that reflects the activity of appropriate antihypertensive therapy, by contributing to the strengthening of the mechanisms of relaxation of blood vessels, is associated with the risk for proinflammatory activation of whole blood cells and platelets. The mean ACE inhibitor levels that reflect moderate RAAS suppression and are characterized by a relatively low proinflammatory activation of mononuclear cells may be more preferable than the maximum ones, from the point of view of slowing the progression of the subclinical inflammatory process of the vascular wall and preventing possible CHD exacerbations. This determines the feasibility of estimating the plasma level of an ACE inhibitor to control the depth of inhibition of RAAS activity.Цель исследования. Изучение концентрации в плазме крови больных ишемической болезнью сердца (ИБС), протекающей на фоне артериальной гипертонии (АГ), цитокинов и вазоактивных молекул в зависимости от уровня ингибитора ангиотензинпревращающего фермента (АПФ), отражающего степень угнетения ренин-ангиотензин-альдостероновой системы РААС. Материалы и методы. В ходе контролируемого когортного исследования обследовали 72 пациентов со стенокардией напряжения II-III функционального класса (ФК) по классификации NYHA и 40 здоровых в возрасте 47-65 лет. Методом иммуноферментного анализа в сыворотке крови определяли концентрацию интерлейкинов (ИЛ-2, ИЛ-12, ИЛ-17А, ИЛ-24), вазоактивных молекул брадикинина, серотонина, ангиотензинпревращающего фермента (АПФ), ангиотензина-II (АТ-II), NO, эндотелина-1 (ЭТ-1), а также активность ренина плазмы. Кроме того, в качестве маркера ингибирования АПФ использовали уровень в плазме крови тетрапептида N-ацетил ser-asp-lys-pro. Результаты. У больных ИБС, протекающей на фоне АГ, по сравнению с практически здоровыми лицами наблюдается уменьшение продукции ЭТ-1 и NO, сочетающееся с повышением уровня серотонина, АТ-II, а также ИЛ-17А и ИЛ-12. Выявленные изменения сопровождаются пониженной активностью ренина. При этом у лиц с низким уровнем ингибитора АПФ отмечается более выраженная продукция провоспалительного цитокина ИЛ-17А, а также высокая концентрация в плазме АПФ и NO. Высокий уровень ингибитора АПФ, отражающий приверженность пациентов к соответствующей гипотензивной терапии, ассоциируется с пониженной продукцией ИЛ-2, минимальным уровнем в сыворотке АПФ, АТ-II и NO, характеризуясь в то же время высокой продукцией ИЛ-12 и серотонина. Заключение. У пациентов с ИБС и АГ высокая концентрация ингибитора АПФ в плазме, отражающая активность соответствующей гипотензивной терапии, способствует усилению механизмов расслабления сосудов, ассоциируется с риском провоспалительной активации клеток цельной крови и тромбоцитов. При этом средние уровни ингибитора АПФ, отражающие умеренную степень подавления РААС, характеризующиеся сравнительно низкой провоспалительной активацией мононуклеарных клеток, могут быть более предпочтительны, чем максимальные, с точки зрения замедления прогрессирования субклинического воспалительного процесса в сосудистой стенке и предупреждения возможных обострений ИБС. Это определяет целесообразность определения содержания ингибитора АПФ в плазме для контроля глубины угнетения активности РААС.

Angiotensin-converting enzyme (ACE) inhibitors have anti-inflammatory and antiproliferative properties and can affect the processes of angiogenesis, by reducing the effects of angiotensin II (ATII). The use of ACE inhibitors in the combination therapy of rheumatoid arthritis (RA) can be also effective for monitoring disease activity and for reducing a cardiovascular risk. Objective: to evaluate the efficacy of an ACE inhibitor in the combination therapy of RA. Patients and methods. Eighty-four patients with RA and endothelial dysfunction were examined; the mean age was 40.12±10.2 years; the mean disease duration was 4.22±3.43 years. All the patients had a blood level of ATII of >9 pg/ml. Enzyme immunoassay was used to measure the levels of tumor necrosis factor-α (TNF-α) (Vector-Best, Russia), intercellular adhesion molecules 1 (ICAM-1) (Diaclone, France), vascular endothelial growth factor (VEGF) and ATII (Diagnostic, Canada). Wrist ultrasonography using the Doppler ultrasound apparatus ESAOTE MyLAB40 was carried out to assess synovial vascularization. The patients were divided into two groups. Group 1 included 43 patients who were assigned to receive standard therapy for RA according to the rheumatic disease treatment protocols; Group 2 comprised 41 patients who received the standard therapy plus ACE inhibitors 2.5–5 mg/day. Results. The use of ACE inhibitors in the 12-month combination therapy of RA patients led to an improvement in the endothelial regulation of vascular tone, to a decrease in the blood concentration of ICAM-1, to a reduction in the intensity of synovial angiogenesis and in the blood level of VEGF by 39%, and a more significant drop in the levels of CRP and TNF-? and in DAS28 by 1.2 scores as compared to those in the standard therapy.

Actuality. The effect of drugs on adaptation to abnormal temperatures is one of the most important questions put to practical medicine by the heat waves of recent years. One of the controversial issues - safety of use during the heat wave of calcium channel blockers (ACC) and blockers of receptors for angiotensin II (ARBS). The goal is to evaluate the efficacy and security of treatment of patients with arterial hypertension (AH) during the heat wave of a fixed combination of ARBS+ACC (Lortenza, KRKA). Materials and methods. Included 26 patients with hypertension 1 and 2 degrees from 42 to 81 years. All patients underwent measurement of office blood pressure, electrocardiography, body sphygmography with the determination of the pulse wave velocity and selectively CAVI, biochemical analysis of blood, estimation of osmolarity of blood, questionnaire: visual analogue scale, a questionnaire for patients exposed to heat, the test of adherence to treatment Moriscos-Green. Estimated diaries of self-control of blood pressure. The inclusion visit took place in spring 2016, 1st visit was in May - June 2016, 2nd - during heat waves, 3rd - September - October 2016. Results. The observed decrease in systolic blood pressure and diastolic blood pressure (p=0.000) to the target values, preserved for the whole period of observation. According to the diaries of self-control of blood pressure controlled blood pressure 81% of patients. During a heat wave, this value decreased to 58%, in autumn - to 63%. The 3rd visit achieved a reduction in heart rate at -6.0 (-11.1; and 2.8) beats/min; p=0.007. A noticeable decrease of the pulse wave velocity from 15.2±3.4 to 14.4 V±3.0 m/s; p=0.01 and CAVI in of-2.1 (to -2.9; -0.65); p=0.01; the decline in uric acid level c of 415.3 to 346.2 mmol/l (p=0.04) and creatinine on the 2nd visit compared to baseline (p=0.02). Electrolyte shifts and increasing the osmolarity of the blood during heat waves have not been identified. There is a growing commitment therapy (p=0.04) and quality of life to 20.0 (7.4; 23.3); p=0.000 by visual analogue scale. Conclusion. Fixed combination of losartan and amlodipine (Lorenza) is an effective, safe and may be recommended for patients receiving AG in the hottest period.

Objective. To analyze the structure of the gene polymorphisms of hemostasis, platelet receptors and enzymes of the folate cycle in patients with metabolic syndrome (MS) and a complicated pregnancy in history. Materials and Methods. The study included 115 patients with MS. Of these, group 1 (64 patients) had a complicated course of pregnancy in anamnesis and group 2 (51 patient) with no pregnancies in anamnesis. The control group consisted of 50 somatically healthy mothers. All the patients were carried out molecular analysis of gene polymorphisms of the hemostatic polymorphisms of platelet receptor genes, polymorphisms of genes of folate cycle enzymes by polymerase chain reaction. Results. In all patients with MS was identified pathology of genes of hemostasis, platelet recept ors or enzymes of the folate cycle, and in all cases attended a multigenic (more than two defect genes) form of pathology. In the study, the patients with MS was significantly higher frequency of polymorphism in the gene for inhibitor of tissue plasminogen activator, in the gene of tissue plasminogen activator, fibrinogen gene, in the gene for angiotensin-converting enzyme gene of the receptor of angiotensin II 1 type. Gene polymorphisms of platelet receptors were also found significantly more often in patients with MS. Results of the study of folate cycle enzymes genes showed the prevalence of pathological polymorphisms in this group of genes in the genotype of patients with MS. In patients with MS and a complicated pregnancy in history was revealed not only a large frequency of occurrence of a pathological gene polymorphisms, but also the predominance in the structure the homozygous forms of these polymorphisms. Conclusion. Thus, it becomes obvious pathogenetic role of latent thrombophilic states in the development of various obstetric complications in patients with MS and the reason underlying this condition is a multigenic structure of the gene polymorphisms of hemostasis, platelet receptors and enzymes of the folate cycle in all MS patients.

Цель обзора анализ данных о роли ангиотензина II в регуляции толерантности сердца к действию ишемии/реперфузии, а также анализ данных о кардиопротекторных свойствах ингибиторов ангиотензинпревращающего фермента (АПФ) и антагонистов АТ1рецептора ангиотензина II. Установлено, что ангиотензин II оказывает инфарктлимитирующий эффект, который, по одним данным, связан с активацией АТ1рецептора, по другим является следствием стимуляции АТ2рецептора. Кроме того, ангиотензин способствовал улучшению сократимости сердца в реперфузионном периоде, эффект был связан с активацией AT1рецептора. Установлено, что ангиотензин II и АТ1рецептор участвуют в инфарктлимитирующем эффекте ишемического прекондиционирования. Экспериментальные данные о способности антагонистов AT1рецептора влиять на размер инфаркта носят противоречивый характер: есть сообщения о способности этих антагонистов оказывать инфарктлимитирующий эффект, есть данные об отсутствии у них подобного эффекта. Экспериментальные данные свидетельствуют, что ингибиторы АПФ оказывают инфарктлимитирующий эффект, который связан с увеличением уровня брадикинина и усилением продукции NO. Нет убедительных данных о том, ингибиторы АПФ и антагонисты АТ1рецептора оказывают инфарктлимитирующий эффект у пациентов с острым инфарктом миокарда. Однако ингибиторы АПФ и антагонисты АТ1рецептора препятствуют постинфарктному ремоделированию сердца., The review analyzes reports on the role of angiotensin II in regulation of heart tolerance to ischemia/reperfusion and cardioprotective properties of angiotensin converting enzyme (ACE) inhibitors and angiotensin II AT1receptor antagonists. Angiotensin II is known to have an infarctlimiting effect, which according to some reports is associated with activation of the AT1 receptor and according to other reports results from stimulation of the AT2 receptor. In addition, angiotensin improves heart contractility during reperfusion, which is associated with activation of the AT1 receptor. Angiotensin II and AT1 receptor are also involved in the infarctreducing effect of ischemic preconditioning. Experimental data on the ability of AT1 receptor antagonists to influence the infarct size are inconsistent one study showed that these antagonists can exert an infarctlimiting effect whereas there is some evidence against such effect. Experimental studies have suggested that ACE inhibitors can restrict the infarct size, which is associated with increased bradykinin level and NO production. There is no convincing evidence that ACE inhibitors and AT1 receptor antagonists can restrict the infarct size in patients with acute myocardial infarction. However, ACE inhibitors and AT1 receptor antagonists prevent postinfarction heart remodeling., №3 (2019)

Cardiovascular (CV) disease is a major factor in mortality rates around the world and contributes to more than one-third of deaths in the US. The underlying cause of CV disease is atherosclerosis, a chronic inflammatory process that is clinically manifested as coronary artery disease, carotid artery disease, or peripheral artery disease. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Consequently, developing a treatment regimen that can slow or even reverse the atherosclerotic process is imperative. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with CV risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. Since the renin– angiotensin–aldosterone system (RAAS) plays a key role in vascular inflammatory responses, hypertension treatment with RAAS-blocking agents (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers [ARBs]) may slow inflammatory processes and disease progression. Reduced nitric oxide (NO) bioavailability has an important role in the process of endothelial dysfunction and hypertension. Therefore, agents that increase NO and decrease oxidative stress, such as ARBs and ACEIs, may interfere with atherosclerosis. Studies show that angiotensin II type 1 receptor antagonism with an ARB improves endothelial function and reduces atherogenesis. In patients with hypertension, the ARB olmesartan medoxomil provides effective blood pressure lowering, with inflammatory marker studies demonstrating significant RAAS suppression. Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS). Although CV outcomes were not assessed in these studies, the observed benefits in surrogate endpoints of disease suggest that RAAS suppression with olmesartan medoxomil may potentially have beneficial effects on CV outcomes in these patient populations.

The extent to which the clinical effects of angiotensin receptor blockers (ARB) are related to ambient renin system activity remains poorly defined. Therefore, we measured blood pressure (BP), large (C1) and small (C2) arterial compliance, systemic vascular resistance (SVR), plasma renin activity (PRA), and the 24-h urinary excretion of sodium (UNaV) and aldosterone before and 1, 2, 4, and 24 h after administration of single doses of placebo, and 5, 20, and 40 mg of the ARB olmesartan medoxomil to 12 unmedicated normotensive subjects. In the basal state, SVR was inversely related to UNaV (r=-0,3,p=0,04); the greater the UNaV, the more vasodilated the subject. Indices of arterial compliance, both C1 (r=-0,32,p=0,03) and C2 (r=-0,35,p=0,02) were inversely related to the basal PRA. Renin also predicted olmesartan-induced changes in C1 (r=0,43,p=0,004) and C2r=0,33,p=0,04). The greater the basal PRA, the less the arterial compliance, and the more compliance improved after olmesartan. Both systolic (p=0,003) and diastolic (pr=-0,414,p=0,012; diastolic BP:r=-0.561,pr=-0,44,p=0,007). Finally, aldosterone excretion fell (sig=0,05) on each dose of olmesartan compared with placebo. We conclude that 1) the inverse relation of UNaV and SVR illustrates the reciprocal role of volume versus constrictor factors in maintaining normal BP; and 2) PRA is a physiologic determinant of arterial compliance in normal individuals and of the response to the ARB olmesartan. Measurement of PRA may help to predict clinical ARB responses in individual subjects.

The object of this study is to evaluate the long-term effects of olmesartan on hypertension and the renin-angiotensin-aldosterone system in hypertensive patients. This study evaluated 26 hypertensive male and female outpatients, 38-69 years of age, with a systolic blood pressure > or = 160 mmHg and/or a diastolic blood pressure > or = 95 mmHg. Oral doses of 5 to 40 mg olmesartan were administered once daily. Blood pressure and renin-angiotensin-aldosterone parameters (plasma renin activity and plasma angiotensin I, II, and aldosterone concentrations) were evaluated at 12-16 weeks, 6 months, and 1 year after the start of olmesartan administration. Systolic and diastolic blood pressures were significantly decreased following the administration of olmesartan. The observed decreases in systolic and diastolic blood pressures after 1 year of treatment were 28.8+/-2.1 mmHg and 15.8+/-1.3 mmHg, respectively. No change was observed in the pulse rate. The plasma renin activity increased significantly from a baseline premedication mean of 1.26+/-0.31 ng/ml/h to a mean of 2.58+/-0.74 ng/ml/h and 2.87+/-0.72 ng/ml/h after 6 months and 1 year of treatment, respectively. Angiotensin II levels decreased significantly from a baseline of 20.4+/-3.2 pg/ml to a mean of 8.6+/-2.1 pg/ml and 6.8+/-1.8 pg/ml after 6 months and 1 year of treatment, respectively. The plasma aldosterone level also decreased significantly after 6 months of treatment. In hypertensive patients, the long-term administration of olmesartan, a novel AT1 receptor antagonist, decreased both blood pressure and plasma angiotensin II levels.

Background Most patients with hypertension require more than one agent to control blood pressure (BP). The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ). Methods This was a randomized, double-blind, factorial design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic blood pressure (SeDBP) of 100 to 115 mm Hg were randomized to one of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20, or 40 mg/day, HCTZ monotherapy (12.5 or 25 mg/day), or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary endpoint was the change in mean trough SeDBP from baseline at week 8. Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses, but did not compare BP reductions with different combination doses. Results Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure (SeSBP) at week 8 than did monotherapy with either component. All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner. Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg, 20.1/16.4 mm Hg, and 26.8/21.9 mm Hg with placebo, olmesartan medoxomil/HCTZ 20/12.5 mg, and olmesartan medoxomil/HCTZ 40/25 mg, respectively. All treatments were well tolerated. Conclusions Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated.

Aim. May blockade of the angiotensin II type 1 receptor (AT1) with an angiotensin receptor blocker reverse vascular pathology independent of blood pressure (BP) lowering. Material and methods. Stage I hypertensive, nondiabetic patients (61% male; age 38 to 67 years) were randomized after a 4-week washout period to olmesartan medoxomil 20 to 40 mg or atenolol 50 to 100 mg plus additional agents (hydrochlorothiazide, amlodipine, or hydralazine) as needed for a goal BP

The aim of the present work was to review published studies investigating the dose-related efficacy on blood pressure (BP) of olmesartan and of other commercially available angiotensin II type I receptor blockers (ARBs). Patient population comprises mild to moderate hypertensive adult patients. We selected studies with comparable design and dose ranges. Dose-effect relationship plots were fitted for diastolic (DBP) and systolic (SBP) BP to the simplified E(max) model. We also examined controlled studies of olmesartan vs. other individual ARBs. Our overview was based on 7280 patients, of which 5769 received an ARB and 1511 received placebo. Except for losartan, the data fitted correctly to the E(max) model, with correlation coefficients ranging from 0.77 to 0.99. BP-lowering efficacy defined as E(max) was superior with olmesartan, (DBP/SBP mmHg: -9.0/-12.4) when compared with candesartan (-6.7/-11.3), irbesartan (-6.5/-11.2) and valsartan (-6.3/-8.9). Head-to-head comparisons of olmesartan to each of the other ARBs used at per-label 'recommended doses', support the finding of a greater BP-lowering effect of olmesartan. This overview suggests that clinically relevant differences in maximal efficacy, as well as in efficacy of per-label recommended doses can be evidenced among individual ARBs. Olmesartan efficacy was consistently at the highest end of the range of efficacy of ARBs studied.

Background— Experimental studies revealed proinflammatory properties of angiotensin II. We evaluated antiinflammatory effects of the angiotensin II subtype 1 receptor antagonist olmesartan medoxomil alone and in cotherapy with the HMG-CoA reductase inhibitor pravastatin in patients with essential hypertension and microinflammation. Methods and Results— We measured a panel of vascular inflammation markers, including high-sensitivity C-reactive protein, and lipid levels during 12 weeks of therapy with olmesartan (n=100) or placebo (n=99) in a prospective double-blind multicenter study. Pravastatin was added to the double-blind therapy at week 6 in both treatment arms. Blood pressure control was achieved with addition of hydrochlorothiazide. Olmesartan treatment had already significantly reduced serum levels of high-sensitivity C-reactive protein (−15.1%; P P P P P P P P Conclusions— Angiotensin II receptor blockade significantly reduces vascular microinflammation in patients with essential hypertension by as early as week 6 of therapy. This antiinflammatory action of angiotensin II receptor antagonists may contribute to their beneficial cardiovascular effects.