endothelial dysfunction. Endothelial dysfunction in patients with chronic cerebral ischemia and the possibility of its pharmacological correction

The pathology of the cardiovascular system continues to occupy the main place in the structure of morbidity, mortality and primary disability, causing a decrease in the overall duration and deterioration in the quality of life of patients both around the world and in our country. An analysis of the indicators of the health status of the population of Ukraine shows that the incidence and mortality from circulatory diseases remain high and account for 61.3% of the total mortality rate. Therefore, the development and implementation of measures aimed at improving the prevention and treatment of cardiovascular diseases (CVD) is an urgent problem in cardiology.

According to modern concepts, in the pathogenesis of the onset and progression of many CVDs - coronary disease heart (IHD), arterial hypertension(AH), chronic heart failure (CHF) and pulmonary hypertension(PH) — one of the main roles is played by endothelial dysfunction (ED).

The role of the endothelium in normal

As is known, the endothelium is a thin semi-permeable membrane that separates the blood flow from the deeper structures of the vessel, which continuously produces a huge amount of biologically active substances, and therefore is a giant paracrine organ.

The main role of the endothelium is to maintain homeostasis by regulating the opposite processes occurring in the body:

vascular tone (balance of vasoconstriction and vasodilation);
the anatomical structure of the vessels (potentiation and inhibition of proliferation factors);
hemostasis (potentiation and inhibition of factors of fibrinolysis and platelet aggregation);
local inflammation (production of pro- and anti-inflammatory factors).

The main functions of the endothelium and the mechanisms by which it performs these functions

The vascular endothelium performs a number of functions (table), the most important of which is the regulation of vascular tone. More R.F. Furchgott and J.V. Zawadzki proved that the relaxation of blood vessels after the administration of acetylcholine occurs due to the release of endothelial relaxation factor (EGF) by the endothelium, and the activity of this process depends on the integrity of the endothelium. A new achievement in the study of the endothelium was the determination of the chemical nature of EGF - nitrogen oxide (NO).

Main functions of the vascular endothelium

Functions of the endothelium	Main enabling mechanisms
Athrombogenicity of the vascular wall	NO, t-RA, thrombomodulin and other factors
thrombogenicity of the vascular wall	Willebrand factor, PAI-1, PAI-2 and other factors
Regulation of leukocyte adhesion	P-selectin, E-selectin, ICAM-1, VCAM-1 and other adhesion molecules
Regulation of vascular tone	Endothelium (ET), NO, PGI-2 and other factors
regulation of vascular growth	VEGF, FGFb and other factors

Nitric oxide as an endothelial relaxation factor

NO is a signal molecule, which is an inorganic substance with the properties of a radical. Small size, lack of charge, good solubility in water and lipids provide it with high permeability through cell membranes and subcellular structures. The lifetime of NO is about 6 s, after which, with the participation of oxygen and water, it turns into nitrate (NO2) And nitrite (NO3).

NO is formed from the amino acid L-arginine under the influence of NO synthase (NOS) enzymes. Currently, three isoforms of NOS have been identified: neuronal, inducible, and endothelial.

Neuronal NOS expressed in nervous tissue, skeletal muscles, cardiomyocytes, bronchial and tracheal epithelium. This is a constitutional enzyme modulated by the intracellular level of calcium ions and is involved in the mechanisms of memory, coordination between nervous activity and vascular tone, and the implementation of pain stimulation.

Inducible NOS localized in endotheliocytes, cardiomyocytes, smooth muscle cells, hepatocytes, but its main source is macrophages. It does not depend on the intracellular concentration of calcium ions, it is activated under the influence of various physiological and pathological factors (pro-inflammatory cytokines, endotoxins) in cases where this is necessary.

endothelialNOS- a constitutional enzyme regulated by calcium content. When this enzyme is activated in the endothelium, the physiological level of NO is synthesized, leading to the relaxation of smooth muscle cells. NO formed from L-arginine, with the participation of the NOS enzyme, activates guanylate cyclase in smooth muscle cells, which stimulates the synthesis of cyclic guanosine monophosphate (c-GMP), which is the main intracellular messenger in the cardiovascular system and reduces the calcium content in platelets and smooth muscles. Therefore, the end effects of NO are vascular dilatation, inhibition of platelet and macrophage activity. The vasoprotective functions of NO consist in modulating the release of vasoactive modulators, blocking the oxidation of low-density lipoproteins, and suppressing the adhesion of monocytes and platelets to the vascular wall.

Thus, the role of NO is not limited to the regulation of vascular tone. It exhibits angioprotective properties, regulates proliferation and apoptosis, oxidative processes, blocks platelet aggregation and has a fibrinolytic effect. NO is also responsible for anti-inflammatory effects.

So, NO has multidirectional effects:

direct negative inotropic action;
vasodilatory action:

- anti-sclerotic(inhibits cell proliferation);
- antithrombotic(prevents adhesion of circulating platelets and leukocytes to the endothelium).

The effects of NO depend on its concentration, the site of production, the degree of diffusion through the vascular wall, the ability to interact with oxygen radicals, and the level of inactivation.

Exist two levels of NO secretion:

Basal secretion- under physiological conditions, maintains vascular tone at rest and ensures non-adhesiveness of the endothelium in relation to blood cells.
stimulated secretion- increased NO synthesis with dynamic tension of the muscular elements of the vessel, reduced oxygen content in the tissue in response to the release of acetylcholine, histamine, bradykinin, noradrenaline, ATP, etc. into the blood, which ensures vasodilation in response to blood flow.

Violation of the bioavailability of NO occurs due to the following mechanisms:

Decrease in its synthesis (deficiency of the NO substrate - L-arginine);
- decrease in the number of receptors on the surface of endothelial cells, irritation of which normally leads to the formation of NO;
- enhancement of degradation (destruction of NO occurs before the substance reaches its site of action);
- increasing the synthesis of ET-1 and other vasoconstrictor substances.

In addition to NO, endothelial vasodilating agents include prostacyclin, endothelial hyperpolarization factor, C-type natriuretic peptide, etc., which play an important role in the regulation of vascular tone with a decrease in NO levels.

The main endothelial vasoconstrictors include ET-1, serotonin, prostaglandin H 2 (PGN 2) and thromboxane A 2 . The most famous and studied of them - ET-1 - has a direct constrictor effect on the wall of both arteries and veins. Other vasoconstrictors include angiotensin II and prostaglandin F 2a , which act directly on smooth muscle cells.

endothelial dysfunction

Currently, ED is understood as an imbalance between mediators that normally ensure the optimal course of all endothelium-dependent processes.

Some researchers associate the development of ED with a lack of production or bioavailability of NO in the arterial wall, others with an imbalance in the production of vasodilating, angioprotective and angioproliferative factors, on the one hand, and vasoconstrictor, prothrombotic and proliferative factors, on the other. The main role in the development of ED is played by oxidative stress, the production of powerful vasoconstrictors, as well as cytokines and tumor necrosis factor, which suppress the production of NO. With prolonged exposure to damaging factors (hemodynamic overload, hypoxia, intoxication, inflammation), the function of the endothelium is depleted and perverted, resulting in vasoconstriction, proliferation and thrombus formation in response to ordinary stimuli.

In addition to these factors, ED is caused by:

Hypercholesterolemia, hyperlipidemia;
- AG;
- vasospasm;
- hyperglycemia and diabetes mellitus;
- smoking;
- hypokinesia;
- frequent stressful situations;
- ischemia;
- overweight;
- male;
- elderly age.

Therefore, the main causes of endothelial damage are risk factors for atherosclerosis, which realize their damaging effect through increased oxidative stress processes. ED is the initial stage in the pathogenesis of atherosclerosis. In vitro a decrease in NO production in endothelial cells in hypercholesterolemia was established, which causes free radical damage to cell membranes. Oxidized low density lipoproteins enhance the expression of adhesion molecules on the surface of endothelial cells, leading to monocytic infiltration of the subendothelium.

With ED, the balance between humoral factors that have a protective effect (NO, PHN) and factors that damage the vessel wall (ET-1, thromboxane A 2 , superoxidanion) is disturbed. One of the most significant links that are damaged in the endothelium during atherosclerosis is a violation in the NO system and inhibition of NOS under the influence of elevated levels of cholesterol and low density lipoproteins. Developed at the same time, ED causes vasoconstriction, increased cell growth, proliferation of smooth muscle cells, accumulation of lipids in them, adhesion of blood platelets, thrombus formation in vessels and aggregation. ET-1 plays an important role in the process of atherosclerotic plaque destabilization, which is confirmed by the results of examination of patients with unstable angina and acute infarction myocardium (MI). The study noted the most severe course of acute MI with a decrease in NO levels (based on the definition final products metabolism of NO - nitrites and nitrates) with the frequent development of acute left ventricular failure, rhythm disturbances and the formation of a chronic aneurysm of the left ventricle of the heart.

Currently, ED is considered as the main mechanism for the formation of AH. In AH, one of the main factors in the development of ED is hemodynamic, which impairs endothelium-dependent relaxation due to a decrease in NO synthesis with preserved or increased production of vasoconstrictors (ET-1, angiotensin II), its accelerated degradation and changes in the cytoarchitectonics of blood vessels. Thus, the level of ET-1 in the blood plasma in patients with hypertension already at the initial stages of the disease significantly exceeds that in healthy individuals. The greatest importance in reducing the severity of endothelium-dependent vasodilation (EDVD) is given to intracellular oxidative stress, since free radical oxidation sharply reduces NO production by endotheliocytes. ED, which interferes with the normal regulation of cerebral circulation, in hypertensive patients is also associated with a high risk of cerebrovascular complications, resulting in encephalopathy, transient ischemic attacks, and ischemic stroke.

Among the known mechanisms for the involvement of ED in the pathogenesis of CHF, the following are distinguished:

1) increased activity of endothelial ATP, accompanied by an increase in the synthesis of angiotensin II;
2) suppression of the expression of endothelial NOS and a decrease in NO synthesis due to:

Chronic decrease in blood flow;
- an increase in the level of pro-inflammatory cytokines and tumor necrosis factor, which suppress the synthesis of NO;
- an increase in the concentration of free R (-), inactivating EGF-NO;
- an increase in the level of cyclooxygenase-dependent endothelial constriction factors that prevent the dilating effect of EGF-NO;
- decreased sensitivity and regulatory influence of muscarinic receptors;

3) an increase in the level of ET-1, which has a vasoconstrictor and proliferative effect.

NO controls pulmonary functions such as macrophage activity, bronchoconstriction, and dilatation of the pulmonary arteries. In patients with PH, the level of NO in the lungs decreases, one of the reasons for which is a violation of the metabolism of L-arginine. Thus, in patients with idiopathic PH, a decrease in the level of L-arginine is noted along with an increase in arginase activity. Impaired metabolism of asymmetric dimethylarginine (ADMA) in the lungs can initiate, stimulate, or maintain chronic lung disease, including arterial PH. Elevated ADMA levels are noted in patients with idiopathic PH, chronic thromboembolic PH, and PH with systemic sclerosis. Currently, the role of NO is also being actively studied in the pathogenesis of pulmonary hypertensive crises. Increased NO synthesis is an adaptive response that counteracts an excessive increase in pressure in pulmonary artery during acute vasoconstriction.

In 1998, the theoretical foundations were formed for a new direction of fundamental and clinical research on the study of ED in the pathogenesis of AH and other CVDs and methods for its effective correction.

Principles of treatment of endothelial dysfunction

Insofar as pathological changes Since endothelial function is an independent predictor of poor prognosis for most CVDs, the endothelium appears to be an ideal target for therapy. The goal of therapy in ED is to eliminate paradoxical vasoconstriction and, with the help of increased NO availability in the vessel wall, to create a protective environment against factors leading to CVD. The main objective is to improve the availability of endogenous NO by stimulating NOS or inhibiting degradation.

Non-drug treatments

In experimental studies, it was found that the consumption of foods high in lipids leads to the development of hypertension due to increased formation free radicals oxygen, inactivating NO, which dictates the need to limit fats. High salt intake suppresses the action of NO in peripheral resistive vessels. Physical exercise increase the level of NO in healthy individuals and in patients with CVD, therefore, the known recommendations regarding the reduction of salt intake and data on the benefits of physical activity in hypertension and coronary artery disease find their other theoretical justification. It is believed that the use of antioxidants (vitamins C and E) can have a positive effect on ED. The administration of vitamin C at a dose of 2 g to patients with coronary artery disease contributed to a significant short-term decrease in the severity of EDV, which was explained by the capture of oxygen radicals by vitamin C and, thus, an increase in the availability of NO.

Medical therapy

Nitrates. For a therapeutic effect on coronary tone, nitrates have long been used, which are capable of donating NO to the vascular wall regardless of the functional state of the endothelium. However, despite the effectiveness in terms of vasodilation and a decrease in the severity of myocardial ischemia, the use of drugs of this group does not lead to a long-term improvement in the endothelial regulation of the coronary vessels (the rhythm of changes in vascular tone, which is controlled by endogenous NO, cannot be stimulated by exogenously administered NO).
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor inhibitors. The role of the renin-angiotensin-aldosterone system (RAS) in relation to ED is mainly related to the vasoconstrictor efficacy of angiotensin II. The main localization of ACE is the membranes of endothelial cells of the vascular wall, which contain 90% of the total volume of ACE. It is the blood vessels that are the main site for the conversion of inactive angiotensin I to angiotensin II. The main RAS blockers are ACE inhibitors. In addition, drugs of this group exhibit additional vasodilating properties due to their ability to block the degradation of bradykinin and increase its level in the blood, which contributes to the expression of endothelial NOS genes, an increase in NO synthesis and a decrease in its destruction.
Diuretics. There is evidence that indapamide has effects that, in addition to diuretic action, have a direct vasodilatory effect due to antioxidant properties, increase the bioavailability of NO and reduce its destruction.
calcium antagonists. Blocking calcium channels reduces the pressor effect of the most important vasoconstrictor ET-1 without directly affecting NO. In addition, drugs of this group reduce the concentration of intracellular calcium, which stimulates the secretion of NO and causes vasodilation. At the same time, platelet aggregation and expression of adhesion molecules decrease, and macrophage activation is also suppressed.
Statins. Since ED is a factor leading to the development of atherosclerosis, in diseases associated with it, there is a need to correct impaired endothelial functions. The effects of statins are associated with a decrease in cholesterol levels, inhibition of its local synthesis, inhibition of proliferation of smooth muscle cells, activation of NO synthesis, which contributes to the stabilization and prevention of atherosclerotic plaque destabilization, as well as reducing the likelihood of spastic reactions. This has been confirmed in numerous clinical research.
L-arginine. Arginine is a conditionally essential amino acid. The average daily requirement for L-arginine is 5.4 g. It is an essential precursor for the synthesis of proteins and biologically important molecules such as ornithine, proline, polyamines, creatine and agmatine. However, the main role of arginine in the human body is that it is a substrate for NO synthesis. L-arginine taken with food is absorbed in the small intestine and enters the liver, where its main amount is utilized in the ornithine cycle. The rest of L-arginine is used as a substrate for NO production.

Endothelium dependent mechanismsL-arginine:

Participation in NO synthesis;
- decrease in adhesion of leukocytes to the endothelium;
- reduction of platelet aggregation;
- decrease in the level of ET in the blood;
- increased elasticity of the arteries;
- restoration of EZVD.

It should be noted that the system of synthesis and release of NO by the endothelium has significant reserve capabilities, however, the need for constant stimulation of its synthesis leads to the depletion of the NO substrate, L-arginine, which is to be replenished by a new class of endothelial protectors, NO donators. Until recently, a separate class of endothelioprotective drugs did not exist; drugs of other classes with similar pleiotropic effects were considered as agents capable of correcting ED.

Clinical effects of L-arginine as an N donorO. Available data indicate that the effect of L-arginine depends on its plasma concentration. When L-arginine is taken orally, its effect is associated with an improvement in EDVD. L-arginine reduces platelet aggregation and reduces monocyte adhesion. With an increase in the concentration of L-arginine in the blood, which is achieved by its intravenous administration, effects are manifested that are not associated with the production of NO, and a high level of L-arginine in the blood plasma leads to nonspecific dilatation.

Influence on hypercholesterolemia. Currently, there is evidence-based medicine on the improvement of endothelial function in patients with hypercholesterolemia after taking L-arginine, confirmed in a double-blind, placebo-controlled study.

Under the influence of oral administration of L-aprinine in patients with angina pectoris, exercise tolerance increases according to the test with a 6-minute walk and with a bicycle exercise. Similar data were obtained with short-term use of L-arginine in patients with chronic coronary artery disease. After infusion of 150 µmol/l L-aprinine in patients with coronary artery disease, an increase in the diameter of the vessel lumen in the stenotic segment by 3-24% was noted. The use of an oral arginine solution in patients with stable angina II-III functional class (15 ml 2 times a day for 2 months) in addition to traditional therapy contributed to a significant increase in the severity of EDVD, increased exercise tolerance and improved quality of life. In patients with hypertension, a positive effect has been proven when L-arginine is added to standard therapy at a dose of 6 g / day. Taking the drug at a dose of 12 g / day helps to reduce the level of diastolic blood pressure. In a randomized, double-blind, placebo-controlled study, a positive effect of L-arginine on hemodynamics and the ability to perform physical activity in patients with arterial PH who took the drug orally (5 g per 10 kg of body weight 3 times a day) was proven. A significant increase in the concentration of L-citpylline in the blood plasma of such patients was established, indicating an increase in NO production, as well as a decrease by 9% in mean pulmonary arterial pressure. In CHF, taking L-arginine at a dose of 8 g/day for 4 weeks contributed to an increase in exercise tolerance and an improvement in acetylcholine-dependent vasodilation of the radial artery.

In 2009, V. Bai et al. presented the results of a meta-analysis of 13 randomized trials performed to study the effect of oral administration of L-arginine on the functional state of the endothelium. These studies examined the effect of L-arginine at a dose of 3-24 g/day in hypercholesterolemia, stable angina, diseases of peripheral arteries and CHF (duration of treatment - from 3 days to 6 months). The meta-analysis showed that oral administration L-arginine, even in short courses, significantly increases the severity of EVR of the brachial artery compared with placebo, which indicates an improvement in endothelial function.

Thus, the results of numerous studies conducted over the past years indicate the possibility of effective and safe use of L-arginine as an active NO donor in order to eliminate ED in CVD.

Konopleva L.F.

It has been proven that endothelial cells of the vascular bed, synthesizing locally acting mediators, are morphofunctionally oriented towards optimal regulation of organ blood flow. The total mass of the endothelium in humans ranges from 1600-1900 g, which is even more than the mass of the liver. Since endothelial cells secrete a large number of various substances into the blood and surrounding tissues, therefore, their complex can be considered as the largest endocrine system.

In pathogenesis and clinic arterial hypertension, atherosclerosis, diabetes and their complications, one of the important aspects is the violation of the structure and function of the endothelium. In these diseases, it appears as a primary target organ, since the endothelial lining of blood vessels is involved in the regulation of vascular tone, hemostasis, immune response, migration of blood cells into the vascular wall, synthesis of inflammatory factors and their inhibitors, and performs barrier functions.

Currently, endothelial dysfunction is understood as an imbalance between mediators that normally ensure the optimal course of all endothelium-dependent processes.

Disturbances in the production, action, destruction of endothelial vasoactive factors are observed simultaneously with abnormal vascular reactivity, changes in the structure and growth of blood vessels, which are accompanied by vascular diseases.

The pathogenetic role of endothelial dysfunction (EDF) has been proven in a number of the most common diseases and pathological conditions: atherosclerosis, arterial hypertension, pulmonary hypertension, heart failure, dilated cardiomyopathy, obesity, hyperlipidemia, diabetes mellitus, hyperhomocysteinemia. This is facilitated by such modifiable risk factors for cardiovascular diseases as smoking, hypokinesia, salt load, various intoxications, disorders of carbohydrate, lipid, protein metabolism, infection, etc.

Doctors, as a rule, are faced with patients in whom the consequences of endothelial dysfunction have already become symptoms of cardiovascular disease. Rational Therapy should be aimed at eliminating these symptoms (clinical manifestations of endothelial dysfunction may be vasospasm and thrombosis).

Treatment of endothelial dysfunction is aimed at restoring the dilatory vascular response.

Drugs with the potential to affect endothelial function can be divided into 4 main categories:

1. replacing natural projective endothelial substances (stable analogs of PGI2, nitrovasodilators, r-tPA);

2. inhibitors or antagonists of endothelial constrictor factors (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, TxA2 synthetase inhibitors and TxP2 receptor antagonists);

3. cytoprotective substances: free radical scavengers superoxide dismutase and probucol, a lazaroid inhibitor of free radical production;

4. lipid-lowering drugs.

ACE inhibitors.

The effect of ACE inhibitors on endothelial function has been most extensively studied. The great importance of the endothelium in the development of cardiovascular diseases follows from the fact that the main part of ACE is located on the membrane of endothelial cells. 90% of the total volume of the renin-angiotensin-aldosterone system (RAAS) is in organs and tissues (10% in plasma), therefore, hyperactivation of the RAAS is an indispensable condition for endothelial dysfunction.

The participation of ACE in the regulation of vascular tone is realized through the synthesis of a powerful vasoconstrictor angiotensin II (AII), which has an effect through stimulation of the AT1 receptors of vascular smooth muscle cells. In addition, ATII stimulates the release of endothelin-1. At the same time, oxidative stress processes are stimulated, numerous growth factors and mitogens are synthesized (bFGF - fibroblast growth factor, PDGF - platelet growth factor, TGF-b1 - transforming growth factor beta, etc.), under the influence of which the structure of the vascular wall changes.

Another mechanism, more associated with endothelial dysfunction itself, is associated with the property of ACE to accelerate the degradation of bradykinin. Second messengers of bradykinin are NO, prostaglandins, prostacyclin, tissue plasminogen activator, endothelial hyperpolarization factor. An increase in the activity of ACE located on the surface of endothelial cells catalyzes the breakdown of bradykinin with the development of its relative deficiency. The lack of adequate stimulation of bradykinin B2 receptors in endothelial cells leads to a decrease in the synthesis of endothelial relaxation factor (EGF) - NO and an increase in the tone of vascular smooth muscle cells.

Comparison of the effect of ACE inhibitors on the endothelium with other antihypertensive drugs shows that a simple normalization of pressure to restore endothelial function is not enough. Many studies have shown that ACE inhibitors can attenuate the atherosclerosis process even in conditions of stable blood pressure and lipid profile. The best "success" in this direction have ACE inhibitors, which have the highest affinity for tissue (endothelial) RAAS.

Among the known ACE inhibitors, quinaprilat (the active metabolite of quinapril) has the highest affinity for tissue RAAS, which, in terms of tissue affinity, is 2 times higher than perindoprilat, 3 times ramiprilat, and 15 times enalaprilat. The mechanism of the positive effect of quinapril on endothelial dysfunction is associated not only with its modulating effect on bradykinin metabolism and improvement in the function of B2 receptors, but also with the ability of this drug to restore the normal activity of endothelial muscarinic (M) receptors, which leads to mediated arterial dilatation due to a receptor-dependent increase in synthesis of EGF-NO. Currently, there is evidence that quinapril has a direct modulating effect on the synthesis of EGF-NO.

The ability to improve endothelial function is also demonstrated by other ACE inhibitors with high affinity for tissue RAAS, in particular perindopril, ramipril, and less often enalapril.

Thus, taking ACE inhibitors eliminates vasoconstrictor effects, prevents or slows down the remodeling of the walls of blood vessels and the heart. Noticeable morphofunctional changes in the endothelium should be expected after about 3-6 months of taking ACE inhibitors.

lipid-lowering drugs.

Currently, the most popular theory is that atherosclerosis is considered as a reaction to damage to the vascular wall (primarily the endothelium). Hypercholesterolemia is the most important damaging factor.

The richest lipoprotein (LP) particles are low-density lipoproteins (LDL), which carry about 70% of plasma cholesterol (Cholesterol).

On the surface of the endothelium are specialized receptors for various macromolecules, in particular, for LDL. It has been shown that hypercholesterolemia changes the structure of the endothelium: the content of cholesterol and the ratio of cholesterol/phospholipids in the membrane of endothelial cells increase, which leads to a violation of the barrier function of the endothelium and an increase in its permeability to LDL. As a result, excessive LDL infiltration occurs. During the passage through the endothelium, LDL undergoes oxidation, and mainly oxidized forms of LDL penetrate into the intima, which themselves have a damaging effect on the structural elements of both the endothelium and the intima. As a result of modification (oxidation) of LDL with the help of "scavenger receptors", there is a massive uncontrolled accumulation of cholesterol in the vascular wall with the formation of foam cells - monocytes, which penetrate the endothelium, accumulate in the subendothelial space and acquire the properties of macrophages that capture lipids. The role of macrophages is far from exhausted by this. They secrete biologically active compounds, including chemotaxins, mitogens, and growth factors, which stimulate the migration of smooth muscle cells and fibroblasts from the media to the intima, their proliferation, replication, and connective tissue synthesis.

Peroxide-modified LDL is the most atherogenic. They have a direct cytotoxic effect, causing damage to the endothelium, stimulate the adhesion of monocytes on its surface, interact with blood coagulation factors, activating the expression of thromboplastin and an inhibitor of plasminogen activation.

Peroxide-modified LDL play a direct role in the development of endothelial dysfunction, inhibiting the production of the endothelial relaxation factor - NO and causing an increase in the production of endothelin - a potential vasoconstrictor.

On the early stages atherosclerosis is represented by the so-called lipid strips, which contain foam cells rich in cholesterol and its esters. Subsequently, connective tissue develops around the lipid accumulation zone and a fibrous atherosclerotic plaque is formed.

According to the currently accepted concept, the clinical and prognostic significance of coronary atherosclerosis is determined by the stage of development and morphological features of atherosclerotic plaques.

In the early stages of formation, they contain a large amount of lipids and have a thin connective tissue capsule. These are the so-called vulnerable, or yellow, plaques. The thin connective tissue membrane of yellow plaques can be damaged both due to the influence of hemodynamic factors (pressure drops in the vessel, compression and stretching of the wall), and as a result of the fact that macrophages and mast cells contained near the membrane produce proteinases that can destroy the protective interstitial matrix . Erosion or rupture of the connective tissue capsule of yellow plaques occurs at the edge of the plaque near the intact segment of the coronary artery. Violation of the integrity of the fibrous capsule leads to the contact of detritus and lipids contained in the plaque with platelets and to the immediate formation of a thrombus. The release of vasoactive substances by platelets can lead to spasm of the coronary artery. As a result, an acute coronary syndrome develops - unstable angina pectoris or small-focal myocardial infarction (with parietal thrombosis of the coronary artery), large-focal myocardial infarction (with occlusive coronary artery). Sudden death may be another manifestation of atherosclerotic plaque rupture.

In the later stages of development, fibrous plaques are dense, rigid formations that have a strong connective tissue capsule and contain relatively few lipids and a lot of fibrous tissue- white plaques. Such plaques are located concentrically, cause hemodynamically significant (by 75% or more) narrowing of the coronary artery and, thus, are the morphological substrate of stable exertional angina.

The possibility of rupture of the dense fibrous capsule of the white plaque is not excluded, but is much less likely than that of the yellow plaque.

In connection with the importance that is currently attached to vulnerable (yellow) plaques in the genesis of acute coronary syndrome, the prevention of their formation is considered as the main goal of lipid-lowering therapy in primary and especially in secondary prevention of coronary artery disease. Statin therapy can stabilize an atherosclerotic plaque, that is, strengthen its capsule and reduce the likelihood of rupture.

The experience of using various lipid-lowering drugs shows that in many cases a favorable effect of treating patients is observed already in the first weeks, when there can be no talk of regression of atherosclerotic lesions. The positive effect of lipid-lowering drugs in early periods their use is primarily due to the fact that a decrease in the level of LDL cholesterol in the blood leads to an improvement in the function of the endothelium, a decrease in the number of adhesive molecules, normalization of the blood coagulation system, and restoration of NO formation suppressed in hypercholesterolemia.

In hypercholesterolemia, the formation of NO is suppressed and the arterial response to the action of vasodilators such as acetylcholine is perverted. Reducing the level of cholesterol in the blood allows you to restore the ability of arteries to dilate when exposed to biologically active substances. Another reason for the beneficial effect of lipid-lowering therapy is the improvement of oxygen diffusion through the capillary wall with a reduced level of cholesterol and LDL.

Naturally, for 1.5-2 months of treatment with lipid-lowering agents, atherosclerotic plaques cannot decrease in size. The functional class of angina primarily depends on the tendency of the arteries to spasm, on the initial vascular tone, which is primarily determined by the oxygenation of smooth muscle cells. The relationship between the concentration of blood lipids and oxygenation of the endothelium of the vascular wall has been proven by a number of studies.

In the presence of hyperlipidemia, a kind of dynamic barrier of lipoproteins is created between the blood and the endothelial cover of the vessel, which, located along the periphery of the blood flow, serve as an obstacle to oxygen from erythrocytes to the vascular endothelium and beyond. If this obstacle to oxygen diffusion is significant, the vascular tone will increase, and the readiness for regional vascular spasm will increase.

A particularly important result of lipid-lowering therapy is the reduction in mortality from cardiovascular diseases and overall mortality. It has been established in many fundamental research on primary and secondary prevention of atherosclerosis and coronary artery disease, in which cholesterol-lowering therapy for about 5 years led to a decrease in mortality from cardiovascular diseases by 30-42% and overall mortality by 22-30%.

Antioxidants.

There is ample evidence that free radicals, lipid peroxidation, and oxidative modification of LDL play a role in the initiation of the atherosclerotic process. Oxidized LDL is highly toxic to cells and may be responsible for damage to the endothelial layer and death of smooth muscle cells.

Peroxide-modified LDL retard the formation or inactivate NO. In hypercholesterolemia and developing atherosclerosis, when the production of superoxide radical by endothelial cells and macrophages is increased, conditions are created for direct interaction of NO with superoxide radical to form peroxynitrate (ONNN-), which also has a strong oxidizing potential. At the same time, switching NO to the formation of peroxynitrate deprives it of the opportunity to show a protective effect on the endothelium.

Numerous experimental and clinical studies have shown that antioxidants inhibit the modification of LDL, reduce their entry into the arterial wall, and thus prevent the development of atherosclerosis.

A decrease in the concentration of lipids in the blood also entails a decrease in the products of lipid peroxidation, which have a damaging effect on the endothelium. Not surprisingly, the combined use of cholesterol-lowering drugs from the group of GMC-CoA reductase inhibitors and antioxidants (probucol) has a more pronounced protective effect on the endothelium than these drugs alone.

There is evidence that macrophages, precursors of stumpy cells, do not phagocytize native, unchanged LDL, but only engulf modified LDL, after which they transform into foam cells. It is they, subjected to LDL peroxidation, captured by macrophages, that play a leading role in the development of endothelial dysfunction and the progression of atherosclerosis.

Antioxidants protect LDL from peroxidation, and thus from intense uptake of LDL by macrophages, thus reducing the formation of foam cells, endothelial damage, and the possibility of lipid infiltration in the intima.

Free peroxide radicals inactivate NO-synthetase. This effect underlies the positive effect of antioxidants on the tone-regulating function of the endothelium.

One of the best known antioxidants is vitamin E - alpha-tocopherol. A number of studies have been conducted that demonstrate that vitamin E at a dose of 400-800-1000 IU per day (100 IU corresponds to 100 mg of tocopherol) reduces the sensitivity of LDL to oxidation and protects against the development of endothelial dysfunction and the progression of atherosclerosis - IHD.

In large doses (1 g per day), ascorbic acid, vitamin C, also has an antioxidant effect, which also significantly reduces the sensitivity of LDL to oxidation.

A similar effect on LDL has beta-carotene - provitamin A, so that beta-carotene, like vitamins C and E, inhibits the oxidation of LDL and can be considered as one of the means of preventing atherosclerosis.

Simultaneous long-term use of vitamins C and E for preventive purposes reduces the risk of death from coronary artery disease by 53%.

Of particular note are the antioxidant properties of probucol. Probucol is a weak lipid-lowering drug. The effect of probucol is not associated with a decrease in blood lipid levels. In the blood, it binds to lipoproteins, including LDL, protecting them from peroxide modification and thus exhibiting an antioxidant effect. Probucol is dosed at 0.5 2 times a day. After treatment for 4-6 months, it is necessary to take a break in the reception for several months.

Among the antioxidants, a well-known drug, preductal (trimetazidine, Servier, France), stands apart. The use of preductal is based on its ability to reduce cell damage caused by free radicals.

It is now clear that atherosclerosis is a process that is characterized by fundamental patterns inherent in any inflammation: exposure to a damaging factor (oxidized LDL), cell infiltration, phagocytosis, and connective tissue formation.

It is now known that trimetazidine significantly reduces the production of malondialdehyde and diene conjugates. In addition, it maximally prevents the deficiency of intracellular glutathione (a natural intracellular “capturer” of free radicals) and increases the ratio of reduced / oxidized glutathione. These data indicate that, against the background of trimetazidine, the increase in the oxidative activity of cells occurs to a lesser extent.

The action of trimetazidine also extends to platelet aggregation. This effect is due to the inhibition of the arachidonic acid cascade and thereby a decrease in the production of thromboxane A2. In the future, this is manifested in a decrease in platelet aggregation caused by collagen.

Data have also been obtained, according to which trimetazidine prevents the activation of neutrophils.

Hormone replacement therapy in women (HRT).

HRT in women after menopause is currently considered as one of the important areas in the prevention and treatment of coronary artery disease and arterial hypertension.

The available data on the vasoprotective effect of estrogens indicate that under the influence of estrogen, the synthesis of prostacyclin increases, the adhesive properties of platelets, macrophages and leukocytes, cholesterol, and LDL decrease.

According to the HERZ placebo-controlled study, HRT increases basal NO levels and thereby lowers blood pressure.

Promising directions in the treatment of endothelial dysfunction.

Great hopes are placed on the activation of the L-arginine/NO/guanylate cyclase system by exogenous factors. Nitrosothiol, sodium nitroprusside, L-arginine, protoporphyrin X, disulfide, etc. can be used as activators.

The use of the drug bosentan, which is a blocker of endothelin receptors, is promising.

We also received encouraging results from experimental and clinical trials of recombinant genes encoding the synthesis of endothelial growth factors VEGF and bFGF. A single transendocardial injection of DNA of these genes into the zone of hibernating myocardium in a number of patients with IHD caused a significant increase in perfusion, left ventricular ejection fraction after 3-6 months, reduced the frequency of angina attacks, and increased exercise tolerance. A noticeable clinical effect was obtained with the introduction of these drugs into ischemic tissues of patients. obliterating atherosclerosis arteries of the lower extremities.

Of the drugs, special attention should be paid to the drug nebivolol (Nebilet, Berlin-Chemie, Germany) - a representative of the third generation of highly selective b-blockers. This agent has a modulating effect on the release of NO by the vascular endothelium, followed by physiological vasodilation. This induces endothelium-dependent relaxation. coronary arteries. Pre- and afterload, end-diastolic pressure in the left ventricle are mildly reduced, diastolic dysfunction of the heart is eliminated.

Normalization of endothelial function is achieved in some cases as a result of correction of risk factors and non-drug methods of treatment (weight loss with initial obesity, salt load, smoking cessation, alcohol abuse, elimination of various intoxications, including infectious genesis, increased physical activity, physiotherapy and balneological procedures, etc.).

For the treatment of patients with homozygous and heterozygous familial hypercholesterolemia, resistant to dietary therapy and lipid-lowering drugs, LDL apheresis is used. The essence of the method lies in the extraction of apo-B-containing drugs from the blood using extracorporeal binding with immunosorbents or dextrancellulose. Immediately after this procedure, the level of LDL cholesterol is reduced by 70-80%. The effect of the intervention is temporary, in connection with which regular lifelong repeated sessions are required at intervals of 2 weeks-1 month. Due to the complexity and high cost of this method of treatment, it can be used in a very limited circle of patients.

Thus, the existing arsenal medicines and non-drug methods of treatment already today allows for a number of diseases to effectively correct endothelial dysfunction.

Assessment and correction of endothelial dysfunction today is a new and most promising direction in the development of cardiology.

Keywords

vascular endothelium / ENDOTHELIAL DYSFUNCTION/ NITRIC OXIDE / OXIDATIVE STRESS/ VASCULAR ENDOTHELIUM / ENDOTHELIAL DYSFUNCTION / NITRIC OXIDE / OXIDATIVE STRESS

annotation scientific article on clinical medicine, author of scientific work - Melnikova Yulia Sergeevna, Makarova Tamara Petrovna

The vascular endothelium is a unique "endocrine tree" that lines absolutely all organs of the vascular system of the body. Endothelial cells create a barrier between blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a large number of various biologically active substances. The strategic location of the endothelium allows it to be sensitive to changes in the hemodynamic system, signals carried by the blood, and signals from the underlying tissues. A balanced release of biologically active substances contributes to the maintenance of homeostasis. To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the occurrence and development of various pathological conditions. This is due not only to its participation in the regulation of vascular tone, but also to its direct influence on the processes of atherogenesis, thrombosis, and protection of the integrity of the vascular wall. endothelial dysfunction considered as a pathological condition of the endothelium, which is based on a violation of the synthesis of endothelial factors. As a result, the endothelium is not able to provide hemorheological balance of blood, which leads to dysfunction of organs and systems. Endothelial dysfunction a key link in the pathogenesis of many diseases and their complications. At present, the role of endothelial dysfunction in the development of such chronic diseases as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory bowel disease, etc. has been proven. The review provides data on the functions and dysfunction of the vascular endothelium. Forms Considered endothelial dysfunction. Modern concept introduced endothelial dysfunction as a central link in the pathogenesis of many chronic diseases. Endothelial dysfunction precedes the development of clinical manifestations of diseases, therefore, it seems promising to study the state of the endothelium in the early stages of the development of diseases, which is of great diagnostic and prognostic value.

Endothelial dysfunction as the key link of chronic diseases pathogenesis

Endothelium is the unique "endocrine tree" lining absolutely all cardiovascular system organs of the body. Endothelial cells form a barrier between the blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a wide range of biologically active substances. The strategic location of the endothelium allows it to be sensitive to haemodynamic changes as well as to the signals carried by the blood and signals of underlying tissues. Balanced release of biologically active substances contributes to homeostasis maintenance. The data concerning the multiple mechanisms of endothelium participation in the origin and development of various pathological conditions is accumulated so far. This is not only due to its participation in vascular tone regulation, but also due to the direct influence on atherogenesis, thrombus formation, and protection of the vascular wall integrity. Endothelial dysfunction is considered as a pathological condition of the endothelium based on impaired synthesis of endothelial factors. As a result, endothelium is unable to provide the haemorheological balance of the blood, resulting in disorders of different organs and systems functions. Endothelial dysfunction is a key link in the pathogenesis of many diseases and their complications. The role of endothelial dysfunction in the development of chronic diseases such as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory bowel disease, and others has been proven recently. The provides review data on the functions of vascular endothelium and its dysfunction. Types of endothelial dysfunction are described. Modern concept of endothelial dysfunction as the key link of pathogenesis of many chronic diseases is presented. Endothelial dysfunction precedes the development of clinical manifestations of diseases, so the study of the endothelium condition at early stages of the diseases is promising and could be of great diagnostic and prognostic value.

The text of the scientific work on the topic "Endothelial dysfunction as a central link in the pathogenesis of chronic diseases"

child, lead to increased shortness of breath, tachycardia, cyanosis, the appearance of hypoxic attacks and attacks of paroxysmal tachycardia.

3. Parents of a child with chronic heart failure should have all the useful information about this problem and actively contribute to achieving optimal results in treatment, improving the prognosis, and increasing the life expectancy of children.

financial support/conflict of interest to be disclosed.

LITERATURE

1. Baranov A.A., Tutelyan A.V. National program for optimizing the feeding of children in the first year of life in the Russian Federation.-M .: The Union of Pediatricians of Russia, 2011. - S. 28-29.

2. Burakovsky V.I., Bockeria L.A. Cardiovascular surgery. - M.: Medicine, 1989. - S. 240-257.

3. Skvortsova V.A., Borovik T.E., Bakanov M.I. Eating disorders in children of early age and the possibility of their correction. - Q. modern pediatrician. - 2011. - V. 10, No. 4. -FROM. 119-120.

4. Feldt R.H., Driscoll DJ., Offord K.P. et al. Protein-losing enteropathy after the Fontan operation // J. Thorac. Cardiovasc. Surg. - 1996. - Vol. 112, No. 3. - P. 672-680.

5. Johnson J.N., DriscollD.J., O "Leary P.W. Protein-losing enteropathy and the Fontan operation // Nutr. Clin. Pract. - 2012. - Vol. 27. - P. 375.

6. Mertens M, Hagler D.J., Sauer U. et al. Protein-losing enteropathy after the Fontan operation: An international multicenter study // J. Thorac. Cardiovasc. Surg. - 1998. - Vol. 115. - P. 1063-1073.

7. Monteiro F.P.M, de Araujo T.L., Veníaos M. et al. Nutritional status of children with congenital heart disease // Rev. Latin-Am. Enfermagem. - 2012. - Vol. 20, No. 6. - P. 1024-1032.

8. Rychik J., Gui-Yang S. Relation of mesenteric vascular resistance after Fontan operation and proteinlosing enteropathy // Am. J. Cardiology. - 2002. - Vol. 90.-P. 672-674.

9. Thacker D, Patel A, Dodds K. et al. Use of oral Budesonide in the management of protein-losing enteropathy after the Fontan operation // Ann. Thorac. Surg. - 2010. - Vol. 89.-P. 837-842.

ENDOTHELIAL DYSFUNCTION AS A CENTRAL LINK IN THE PATHOGENESIS OF CHRONIC DISEASES

Yulia Sergeevna Melnikova *, Tamara Petrovna Makarova Kazan State Medical University, Kazan, Russia

Abstract DOI: 10.17750/KMJ2015-659

The vascular endothelium is a unique "endocrine tree" that lines absolutely all organs of the vascular system of the body. Endothelial cells create a barrier between blood and tissues, perform a number of important regulatory functions, synthesizing and releasing a large number of various biologically active substances. The strategic location of the endothelium allows it to be sensitive to changes in the hemodynamic system, signals carried by the blood, and signals from the underlying tissues. A balanced release of biologically active substances contributes to the maintenance of homeostasis. To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the occurrence and development of various pathological conditions. This is due not only to its participation in the regulation of vascular tone, but also to its direct influence on the processes of atherogenesis, thrombosis, and protection of the integrity of the vascular wall. Endothelial dysfunction is considered as a pathological condition of the endothelium, which is based on a violation of the synthesis of endothelial factors. As a result, the endothelium is not able to provide hemorheological balance of blood, which leads to dysfunction of organs and systems. Endothelial dysfunction is a key link in the pathogenesis of many diseases and their complications. At present, the role of endothelial dysfunction in the development of such chronic diseases as atherosclerosis, arterial hypertension, chronic heart failure, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, inflammatory bowel disease, etc. has been proven. The review provides data on the functions and dysfunction of the vascular endothelium. Forms of endothelial dysfunction are considered. The modern concept of endothelial dysfunction as a central link in the pathogenesis of many chronic diseases is presented. Endothelial dysfunction precedes the development of clinical manifestations of diseases; therefore, it seems promising to study the state of the endothelium in the early stages of disease development, which is of great diagnostic and prognostic value.

Key words: vascular endothelium, endothelial dysfunction, nitric oxide, oxidative stress.

ENDOTHELIAL DYSFUNCTION AS THE KEY LINK OF CHRONIC DISEASES PATHOGENESIS

Yu.S. Mel "nikova, T.P. Makarova

Kazan State Medical University, Kazan, Russia

Address for correspondence: [email protected]

Keywords: vascular endothelium, endothelial dysfunction, nitric oxide, oxidative stress.

The problem of endothelial dysfunction is currently attracting many researchers, since it is one of the predictors of morphological changes in the vascular wall in atherosclerosis, arterial hypertension, diabetes mellitus, chronic illness kidneys, etc. Endothelial dysfunction in this case, as a rule, is systemic in nature and is found not only in large vessels, but also in the microvasculature.

The vascular endothelium, by classical definition, is a single layer of flat cells of mesenchymal origin, lining the inner surface of blood and lymphatic vessels, as well as cardiac cavities. According to modern concepts, the endothelium is not just a semipermeable membrane, but an active endocrine organ, the largest in the human body. A large area of vessels, their penetration into all organs and tissues create the prerequisites for the spread of endothelial influences on all organs, tissues and cells.

Vascular endothelium has long been considered a protective layer, a membrane between the blood and the inner membranes of the vessel wall. And only at the end of the twentieth century, after the award to a group of scientists consisting of R. Furchgott, L.S. Ignorro, F. Murad in 1998 Nobel Prize in Medicine for studying the role of nitric oxide as a signaling molecule of the cardiovascular system, it became possible to explain many processes of regulation of the cardiovascular system in normal and pathological conditions. This opened up a new direction in fundamental and clinical research on the involvement of the endothelium in the pathogenesis of arterial hypertension and other cardiovascular diseases, as well as ways to effectively correct its dysfunction.

The most important functions of the endothelium are the maintenance of hemovascular homeostasis, the regulation of hemostasis, the modulation of inflammation, the regulation of vascular tone and vascular permeability. In addition, endothelium was found to have its own

naya renin-angiotensin system. The endothelium secretes mitogens, participates in angiogenesis, fluid balance, and the exchange of components of the extracellular matrix. These functions are performed by the vascular endothelium through the synthesis and release of a large number of various biologically active substances (Table 1).

The main task of the endothelium is the balanced release of biologically active substances that determine the holistic work of the circulatory system. There are two options for the secretion of biologically active substances by the endothelium - basal, or constant, and stimulated secretion, that is, the release of biologically active substances during stimulation or damage to the endothelium.

The main factors stimulating the secretory activity of the endothelium include changes in blood flow velocity, circulating and/or intraparietal neurohormones (catecholamines, vasopressin, acetylcholine, bradykinin, adenosine, histamine, etc.), platelet factors (serotonin, adenosine diphosphate, thrombin) and hypoxia. Risk factors for endothelial damage include hypercholesterolemia, hyperhomocysteinemia, elevated levels of cytokines (interleukins-1p and -8, tumor necrosis factor alpha).

By the rate of formation of various factors in the endothelium (which is largely due to their structure), as well as by the predominant direction of secretion of these substances (intracellular or extracellular), substances of endothelial origin can be divided into the following groups.

1. Factors that are constantly formed in the endothelium and released from cells in the basolateral direction or into the blood (nitric oxide, prostacyclin).

2. Factors that accumulate in the endothelium and are released from it during stimulation (von Willebrand factor, tissue plasminogen activator). These factors can enter the blood not only when the endothelium is stimulated, but also when it is activated and damaged.

Table 1

Factors synthesized in the endothelium and determining its functions

Factors affecting vascular smooth muscle tone

Vasoconstrictors Vasodilators

Endothelin Nitric Oxide

Angiotensin II Prostacycline

Thromboxane A2 Endothelin depolarization factor

Prostaglandin H2 Angiotensin I Adrenomedulin

Hemostasis factors

Prothrombogenic Antithrombogenic

Platelet Growth Factor Nitric Oxide

Tissue plasminogen activator inhibitor Tissue plasminogen activator

Willebrand factor (VW clotting factor) Prostacycline

Angiotensin IV Thrombomodulin

Endothelin I

fibronectin

Thrombospondin

Platelet activating factor (PAF)

Factors affecting growth and proliferation

Stimulants Inhibitors

Endothelin I Nitric Oxide

Angiotensin II Prostacycline

Superoxide radicals C-type natriuretic peptide

Endothelial growth factor Heparin-like growth inhibitors

Factors affecting inflammation

Pro-inflammatory Anti-inflammatory

Tumor necrosis factor alpha Nitric oxide

superoxide radicals

C-reactive protein

3. Factors, the synthesis of which practically does not occur under normal conditions, but increases sharply with the activation of the endothelium (endothelin-1, type 1 intercellular adhesion molecule - ICAM-1, type 1 vascular endothelial adhesion molecule - UCAM-1).

4. Factors synthesized and accumulated in the endothelium (tissue plasminogen activator - 1-PA) or which are membrane proteins (receptors) of the endothelium (thrombomodulin, protein C receptor).

In a physiological state, the endothelium has the ability to maintain a balance

between its multidirectional functions: the synthesis of pro- and anti-inflammatory factors, vasodilating and vasoconstrictive substances, pro- and anti-aggregants, pro- and anticoagulants, pro- and antifibrinolytics, proliferation factors and growth inhibitors. Under physiological conditions, vasodilation, the synthesis of inhibitors of aggregation, coagulation and fibrinolysis activators, anti-adhesive substances predominate. Vascular cell dysfunction disrupts this balance and predisposes vessels to vasoconstriction, leukocyte adhesion, platelet activation, mitogenesis, and inflammation.

Thus, endothelial function is a balance of opposing principles: relaxing and constrictive factors, anticoagulant and procoagulant factors, growth factors and their inhibitors.

Such causes as impaired blood flow, hypoxia, increased systemic and intrarenal pressure, hyperhomocysteinemia, and increased lipid peroxidation processes can lead to a change in the physiological balance in the body. The vascular endothelium is extremely vulnerable, but, on the other hand, researchers note its enormous compensatory capabilities in violation of physiological conditions.

Endothelial dysfunction was first described in 1990 on the vessels of the human forearm in hypertension and was defined as impaired vasodilation upon the action of specific stimuli such as acetylcholine or bradykinin. More broad understanding The term includes not only a decrease in vasodilation, but also a proinflammatory and prothrombotic state associated with endothelial dysfunction. Mechanisms involved in the reduction of vasodilatory responses in endothelial dysfunction include decreased nitric oxide synthesis, oxidative stress, and decreased hyperpolarizing factor production.

Currently, endothelial dysfunction is understood as an imbalance between the formation of vasodilating, athrombogenic, antiproliferative factors, on the one hand, and vasoconstrictive, prothrombotic and proliferative substances synthesized by the endothelium, on the other. Endothelial dysfunction can be an independent cause of circulatory disorders in the organ, since it often provokes angiospasm or vascular thrombosis. On the other hand, regional circulation disorders (ischemia, venous stasis) can also lead to endothelial dysfunction. Hemodynamic causes, age-related changes, free radical damage, dyslipoproteinemia, hypercytokinemia, hypothyroidism can contribute to the formation of endothelial dysfunction.

perhomocysteinemia, exogenous and endogenous intoxications. Endothelial dysfunction can lead to structural damage in the body: accelerated apoptosis, necrosis, de-squamation of endotheliocytes. However, functional changes in the endothelium usually precede morphological changes in the vascular wall.

There are four forms of endothelial dysfunction: vasomotor, thrombophilic, adhesive and angiogenic.

The vasomotor form of endothelial dysfunction is caused by a violation of the ratio between endothelial vasoconstrictors and vasodilators and is important in the mechanisms of both systemic increase in blood pressure and local angiospasm. Some of the vasoactive substances produced by the endothelium cannot be clearly classified as vasodilators or vasoconstrictors, due to the existence of several types of receptors for these substances. Some types of receptors mediate vasoconstrictive reactions, others - vasodilators. Sometimes activation of receptors of the same type, located on vascular endothelial and smooth muscle cells, gives opposite results. According to the principle of antagonistic regulation, the formation of vasoconstrictive substances, as a rule, is associated with stimulation of the synthesis of vasodilators.

The resulting effect (vasoconstrictor or vasodilator) of vasoactive substances depends on their concentration, as well as the type and localization of vessels, which is explained by the uneven distribution of receptors in arteries, arterioles, venules, and even in vessels of the same type in different regions.

The thrombophilic form of endothelial dysfunction is caused by a violation of the ratio of thrombogenic and athrombogenic substances formed in the endothelium and participating in hemostasis or affecting this process. Under physiological conditions, the formation of athrombogenic substances in the endothelium prevails over the formation of thrombogenic ones, which ensures the preservation of the liquid state of the blood in case of damage to the vascular wall. The thrombophilic form of endothelial dysfunction can lead to the development of vascular thrombophilia and thrombosis. A significant decrease in vascular thromboresistance occurs with atherosclerosis, arterial hypertension, diabetes mellitus, and tumor diseases.

The adhesive form of endothelial dysfunction is caused by a violation of the interaction between leukocytes and the endothelium - a constantly ongoing physiological process that is carried out with the participation of special adhesive molecules. On the luminal surface of endotheliocytes, there are P- and E-selectins, adhesion molecules (ICAM-1, 662

VCAM-1). Expression of adhesion molecules occurs under the influence of inflammatory mediators, anti-inflammatory cytokines, thrombin, and other stimuli. With the participation of P- and E-selectins, the delay and incomplete stop of leukocytes are carried out, and ICAM-1 and VCAM-1, interacting with the corresponding ligands of leukocytes, ensure their adhesion. Increased adhesiveness of the endothelium and uncontrolled adhesion of leukocytes are of great importance in the pathogenesis of inflammation in atherosclerosis and other pathological processes.

The angiogenic form of endothelial dysfunction is associated with a violation of neoangiogenesis, a process in which several stages are distinguished: an increase in endothelial permeability and destruction of the basement membrane, migration of endothelial cells, proliferation and maturation of endothelial cells, and vascular remodeling. At various stages of angiogenesis, factors formed in the endothelium play an extremely important role: vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), in addition, there are receptors on the endothelial surface that interact with angiogenesis regulators (angiopoietins, angiostatin, vasostatin, etc.), formed in other cells. Dysregulation of neoangiogenesis or stimulation of this process, out of connection with functional needs, can lead to serious consequences.

The modern understanding of endothelial dysfunction, according to Russian scientists, can be reflected in the form of three complementary processes: a shift in the balance of antagonist regulators, a violation of reciprocal interactions in feedback systems, the formation of metabolic and regulatory "vicious circles" that change functional state of endothelial cells, which leads to dysfunction of tissues and organs.

Endothelial dysfunction as a typical pathological process is a key link in the pathogenesis of many diseases and their complications.

With prolonged exposure to damaging factors on the endothelium (such as hypoxia, toxins, immune complexes, inflammatory mediators, hemodynamic overload, etc.), endothelial cells are activated and damaged, subsequently leading to a pathological response even to ordinary stimuli in the form of vasoconstriction, thrombosis - development, increased cell proliferation, hypercoagulability with intravascular fibrinogen deposition, impaired microhemorheology. The longer the pathological response to irritating stimuli persists, the faster the chronization of the process and the stabilization of irreversible phenomena occur. Thus, chronic activation of the endothelium can lead to the formation of a "vicious circle"

and endothelial dysfunction.

Decreased endothelial synthesis of nitric oxide (NO), increased levels of endothelin-1, circulating von Willebrand factor, plasminogen activator inhibitor, homocysteine, thrombomodulin, soluble molecule of vascular intercellular adhesion B1, C-reactive protein, microalbuminuria and etc. .

To date, data have been accumulated on the versatility of the mechanisms of participation of the endothelium in the emergence and development of various pathological conditions.

The main role in the development of endothelial dysfunction is played by oxidative stress, the synthesis of powerful vasoconstrictors, as well as cytokines and tumor necrosis factor, which suppress the production of nitric oxide (NO).

Oxidative (oxidative) stress is one of the most widely studied mechanisms of endothelial dysfunction. Oxidative stress is defined as an imbalance between excessive free radical production and deficient antioxidant defense mechanisms. Oxidative stress is an important pathogenetic link in the development and progression of various diseases. The participation of free radicals in the inactivation of nitric oxide and the development of endothelial dysfunction has been proven.

Oxidation is an important process for life, and hydrogen peroxide, as well as free radicals such as superoxide, hydroxyl radical and nitric oxide, are constantly formed in the body. Oxidation becomes a powerful damaging factor only with excessive formation of free radicals and / or a violation of antioxidant protection. Products of lipid peroxidation damage endothelial cells by initiating radical chain reactions in membranes. The triggering mediator of oxidative stress in the vascular bed is NADH/NADPH oxidase of the cytoplasmic membrane of macrophages, which produces superoxide anions. In addition, in the presence of hypercholesterolemia in the vascular wall, the formation of NO decreases due to the accumulation of NO-synthase inhibitors, such as L-glutamine, asymmetric dimethylarginine, as well as a decrease in the concentration of the NO-synthase cofactor - tetrahydrobiopterin.

NO is synthesized from L-arginine in the presence of a number of cofactors and oxygen by various isoforms of NO synthase (NOS): neuronal or cerebral (nNOS), inducible (iNOS), and endothelial (eNOS). For biological activity, not only the amount, but also the source of NO is important. Nitric oxide synthesized in the endothelium diffuses into vascular smooth muscle cells and stimulates soluble guanylate cyclase there. This leads to

an increase in the content of cyclic guanosine monophosphate (cGMP) in the cell, the calcium concentration in smooth muscle cells decreases, resulting in relaxation of vascular smooth muscle cells and vasodilation.

Nitric oxide is released by endothelial cells and is a chemically unstable compound that exists for several seconds. In the vessel lumen, NO is quickly inactivated by dissolved oxygen, as well as by superoxide anions and hemoglobin. These effects prevent NO from acting at a distance from its release site, making nitric oxide an important regulator of local vascular tone. Impaired or absent NO synthesis due to endothelial dysfunction cannot be compensated for by its release from healthy borderline endothelial cells. It is now known that of the large number of biologically active substances secreted by the endothelium, it is nitric oxide that regulates the activity of other mediators.

There is a correlation between markers of oxidative stress and endothelial dysfunction. Endothelial dysfunction may result from a decrease in the ability of the endothelium to synthesize, release, or inactivate NO.

Of interest is the reaction of interaction of nitric oxide with superoxide anion with the formation of peroxynitrite, which is not a vasodilator, and then peroxynitrous acid, which is converted into nitrogen dioxide and a particularly active hydroxyl radical. The result of this reaction, firstly, is a violation of endothelium-dependent vasodilation, which is accompanied by insufficient perfusion of organs, and secondly, the hydroxyl radical has a powerful damaging effect on cells and exacerbates inflammation.

Thus, the vascular endothelium is an active dynamic structure that controls many important body functions. At present, ideas about the functions of the endothelium have expanded significantly, which allows us to regard the vascular endothelium not only as a selective barrier to the penetration of various substances from the bloodstream into the interstitium, but also as a key link in the regulation of vascular tone. The main lever of influence of the endothelium is the release of a number of biologically active substances.

To date, the concept of endothelial dysfunction has been formulated as a central link in the pathogenesis of many chronic diseases. The main role in the development of endothelial dysfunction is played by oxidative stress, the synthesis of powerful vasoconstrictors that inhibit the formation of nitric oxide. Endothelial dysfunction precedes

the development of clinical manifestations of diseases, therefore, the evaluation of endothelial functions is of great diagnostic and prognostic value. Further study of the role of endothelial dysfunction in the development of diseases is necessary for the development of new therapeutic approaches.

LITERATURE

1. Bobkova I.N., Chebotareva I.V., Rameev V.V. et al. The role of endothelial dysfunction in the progression of chronic glomerulonephritis, modern possibilities for its correction. Therap. archive. - 2005. - T. 77, No. 6. - S. 92-96.

2. Bolevich S.B., Voinov V.A. Molecular mechanisms in human pathology. - M.: MIA, 2012. - 208 p.

3. Golovchenko Yu.I., Treschinskaya M.A. Review of modern ideas about endothelial dysfunction // Consil. med. Ukraine. - 2010. - No. 11. - S. 38-39.

4. BioChemMac group of companies. Markers of endothelial dysfunction / In: Catalog of BioChemMac Group of Companies. - M., 2005. - S. 49-50. "BioKhimMak" companies group. Markers for endothelial dysfunction, in Catalog Gruppy kompaniy "BioKhimMak". (Catalogue of the "BioKhimMak" companies group.) Moscow. 20 0 5:49-50. (In Russ.)]

5. Konyukh E.A., Paramonova N.S. Clinical features of the course of acute and chronic glomerulonephritis in children with endothelial dysfunction // J. GrSMU. - 2010. - No. 2 (30). - S. 149-151.

6. Kurapova M.V., Nizyamova A.R., Romasheva E.P., Davydkin I.L. Endothelial dysfunction in patients with chronic kidney disease // Izvestiya Samar. scientific center of the Russian Academy of Sciences. - 2013. - V. 15, No. 3-6. - S. 18231826.

7. Lupinskaya Z.A., Zarifyan A.G., Gurovich T.Ts. and others. Endothelium. function and dysfunction. - Bishkek: KRSU, 2008. - 373 p.

8. Margieva T.V., Sergeeva T.V. Participation of markers of endothelial dysfunction in the pathogenesis of chronic glomerulonephritis // Vopr. modern pediatrician. - 2006. - V. 5, No. 3. - S. 22-30.

9. Margieva T.V., Smirnov I.E., Timofeeva A.G. and etc.

Endothelial dysfunction in various forms of chronic glomerulonephritis in children // Ros. pediatrician. well. - 2009. - No. 2. - S. 34-38.

10. Martynov A.I., Avetyak N.G., Akatova E.V. et al. Endothelial dysfunction and methods for its determination // Ros. cardiol. well. - 2005. - No. 4 (54). - S. 94-98.

11. Mayanskaya S.D., Antonov A.R., Popova A.A., Grebyonkina I.A. Early markers of endothelial dysfunction in the dynamics of the development of arterial hypertension in young people. Kazan Med. well. - 2009. -T. 90, #1. - S. 32-37.

12. Panina I.Yu., Rumyantsev A.Sh., Menshutina M.A. Features of endothelial function in chronic kidney disease. Literature review and own data // Nephrology. - 2007. - V. 11, No. 4. - S. 28-46.

13. Petrishchev N.N. Pathogenetic significance of dysfunction // Omsk. scientific vestn. - 2005. - No. 13 (1). -FROM. 20-22.

14. Petrishchev N.N., Vlasov T.D. Physiology and pathophysiology of the endothelium. - St. Petersburg: St. Petersburg State Medical University,

2003. - 438 p.

15. Popova A.A., Mayanskaya S.D., Mayanskaya N.N. Arterial hypertension and endothelial dysfunction (part 1) // Vestn. modern wedge. honey. - 2009. -T. 2, #2. - S. 41-46.

16. Saenko Yu.V., Shutov A.M. The role of oxidative stress in the pathology of the cardiovascular system in patients with kidney disease // Nephrol. and dialysis. -

2004. - V. 6, No. 2. - S. 138-139.

17. Tugusheva F.A., Zubina I.M. Oxidative stress and its involvement in non-immune mechanisms of chronic kidney disease progression. Nephrology. - 2009. - V. 13, No. 3. - S. 42-48.

18. Chernekhovskaya N.E., Shishlo V.K., Povalyaev A.V. Correction of microcirculation in clinical practice. - M.: Binom, 2013. - 208 p.

19. Shishkin A.N., Kirilyuk D.V. Endothelial dysfunction in patients with progressive disease

kidney // Nephrology. - 2005. - V. 9, No. 2. - S. 16-22.

20. Shishkin A.N., Lyndina M.L. Endothelial dysfunction and arterial hypertension // Arterial. hypertension. - 2008. - V. 14, No. 4. - S. 315-319.

21. Annuk M., Zilmer M., Lind L. et al. Oxidative stress and endothelial function in chronic renal failure // J. Am. soc. Nephrol. - 2001. - Vol. 12. - R. 2747-2750.

22. Guzik T.J., Harrison D.G. Vascular NADPH oxidases as drug targets for novel antioxidant strategies // Drug Discovery Today. - 2006. - Vol. 11-12. - P. 524-526.

23. Higashi Y, Noma K., Yoshizumi M. et al. Endothelial function and oxidative stress in cardiovascular diseases // Circulation J. - 2009. - Vol. 3. - P. 411-415.

24. Marie I., Beny J.L. Endothelial dysfunction in murine model of systemic sclerosis // J. Invest. Dermatol. -2002. - Vol. 119, No. 6. - P. 1379-1385.

25. Schultz D, Harrison D.G. Quest for fire: seeking the source of pathogenic oxygen radicals in atherosclerosis (Editorial) // Arterioscler. Thromb. Vasc. Biol. - 2000. -Vol. 20. - P. 1412-1413.

UDC 616.12-008.331.1-053.2: 612.172: 612.181: 612.897

THE ROLE OF THE SEROTONINERGIC SYSTEM IN THE DEVELOPMENT OF DISEASES

HEART AND VESSELS IN CHILDREN

Dinara Ilgizarovna Sadykova1, Razina Ramazanovna Nigmatullina2, Gulfiya Nagimovna Aflyatumova3*

Kazan State Medical Academy, Kazan, Russia;

Kazan State Medical University, Kazan, Russia;

3Children's Republican clinical Hospital, Kazan, Russia

Abstract DOI: 10.17750/KMJ2015-665

In recent decades, the role of the serotonin system as a link in the pathogenesis of atherosclerosis and arterial hypertension has been widely discussed. Serotonin and histamine are a humoral system of regulators and modulators of physiological processes, which, under conditions of pathology, turn into factors contributing to the development of the disease. Membrane serotonin transporter has been identified on neurons, platelets, myocardium and smooth muscle cells. The higher the activity of the membrane carrier, the higher the concentration of serotonin in platelets, its release into the blood plasma increases and its negative effects on platelets and the vessel wall are realized. The 5-HT1A, 5-HT2, and 5-HT3 receptor subtypes play a key role in the central mechanisms of regulation of cardiovascular activity, while the peripheral effects of serotonin on the vascular system are mediated by the 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7. Activation of 5-HT1A receptors causes central inhibition of sympathetic influences and further bradycardia, while 5-HT2 receptors cause excitation of the sympathetic division, increased blood pressure, and tachycardia. With the development of anaerobic processes, serotonin through 5-HT2 receptors triggers the process of apoptosis of cardiomyocytes, which leads to the development and progression of heart failure. The participation of 5HT2B receptors in the regulation of heart development during embryogenesis was proven in mice mutant for this receptor: cardiomyopathy was noted with loss of ventricular mass due to a decrease in the number and size of cardiomyocytes. The participation of 5-HT4 receptors in the development of sinus tachycardia and atrial fibrillation was shown, in turn, the use of 5-HT4 receptor antagonists was effective in the treatment of this rhythm disorder. Thus, the study of the role of the serotonergic system in the development of cardiovascular diseases will reveal new links in the pathogenesis of arterial hypertension in childhood.

Keywords: serotonergic system, cardiovascular diseases, arterial hypertension,

THE ROLE OF SEROTONERGIC SYSTEM IN CARDIOVASCULAR DISEASES DEVELOPMENT IN CHILDREN

D.I. Sadykova1, R.R. Nigmatullina2, G.N. Aflyatumova3

Kazan State Medical Academy, Kazan, Russia;

2Kazan State Medical University, Kazan, Russia;

3Children's Republican Clinical Hospital, Kazan, Russia

The role of the serotonin system as a link in the pathogenesis of atherosclerosis and arterial hypertension is widely discussed during the recent decades. Serotonin and histamine are part of the humoral system of physiological processes regulators and modulators which under pathological conditions are transformed into factors contributing to the disease development. The membrane serotonin transporter has been identified on neurons, platelets, myocardium and smooth muscle cells. The higher is the activity of membrane transporter, the higher is the platelet serotonin concentration, its release into the blood plasma increases thus implementing its negative effects on platelets and wall of the vessels. 5-HT1A, 5-HT2 and 5-HT3 receptor subtypes play a key role in the central mechanisms of regulation of cardiovascular activities while peripheral effects of serotonin on the vascular system are mediated by 5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7 receptor subtypes. Activation of 5-HT1A receptors causes inhibition of central sympathetic influences and further bradycardia, while 5-HT2 receptors activation - arousal of the sympathetic division, blood pressure elevation, and tachycardia. With the development of anaerobic processes serotonin via 5-HT2 receptors triggers apoptosis of cardiomyocytes leading to the development and progression of heart failure. Participation of 5HT2B receptors in the regulation of heart development during embryogenesis

Address for correspondence: [email protected]

Currently, there is growing interest in the role of endothelial function in the pathogenesis of cardiovascular diseases.

The endothelium is a monolayer of endotheliocytes that acts as a transport barrier between the blood and the vascular wall, responding to the mechanical action of the blood flow and tension of the vascular wall, and is sensitive to various neurohumoral agents. The endothelium continuously produces a huge amount of the most important biologically active substances. In essence, it is a giant paracrine organ in human body. Its main role is determined by the maintenance of cardiovascular homeostasis by regulating the equilibrium state of the most important processes:

a) vascular tone (vasodilation/vasoconstriction);

b) hemovascular hemostasis (production of procoagulant/anticoagulant mediators);

c) cell proliferation (activation/inhibition of growth factors);

d) local inflammation (production of pro- and anti-inflammatory factors) (Table 1).

Among the abundance of biologically active substances produced by the endothelium, the most important is nitric oxide - NO. Nitric oxide is a powerful vasodilator, in addition, it is a mediator in the production of other biologically active substances in the endothelium; short-lived agent, the effects of which are manifested only locally. Nitric oxide plays a key role in cardiovascular hemostasis not only by regulating vascular tone, but also by inhibiting adhesion and aggregation of circulating platelets, preventing the proliferation of vascular smooth muscle cells, various oxidative and migratory processes of atherogenesis.

Table 1

Functions and mediators of the endothelium

	Endothelial mediators
Vasoregulatory (secretion of vasoactive mediators)	Vasodilators (NO, prostacyclin, bradykinin) Vasoconstrictors (endothelin-1, thromboxane A2, angiotensin II, endoperoxides)
Participation in hemostasis (secretion of coagulation factors and fibrinolysis)	Procoagulants (thrombin, plasminogen activator inhibitor) Anticoagulants (NO, prostacyclin, thrombomodulin, tissue plasminogen activator)
Regulation of proliferation	secretion of endothelial growth factor, platelet-derived growth factor, fibroblast growth factor) Secretion of heparin-like growth inhibitors, NO
Regulation of inflammation	Secretion of adhesion factors, selectins Production of superoxide radicals
Enzymatic activity	Secretion of protein kinase C, an angiotensin-converting enzyme

Currently, endothelial dysfunction is defined as an imbalance of opposing mediators, the emergence of "vicious circles" that disrupt cardiovascular homeostasis. All major factors are associated with endothelial dysfunction. cardiovascular factors risk: smoking, hypercholesterolemia, hypertension and diabetes mellitus. Disturbances in the function of the endothelium, apparently, occupy one of the first places in the development of many cardiovascular diseases - hypertension, coronary artery disease, chronic heart failure, chronic renal failure. Endothelial dysfunction is the earliest stage in the development of atherosclerosis. Numerous prospective studies have shown the relationship between endothelial dysfunction and the development of adverse cardiovascular complications in patients with coronary artery disease, hypertension, and peripheral atherosclerosis. That is why the concept of the endothelium as a target organ for the prevention and treatment of cardiovascular diseases has now been formulated.

In patients with hypertension, endothelial dysfunction is manifested primarily by impaired endothelium-dependent vasodilation (EDVD) in the arteries of various regions, including the skin, muscles, renal and coronary arteries, and the microvasculature. The mechanism of development of endothelial dysfunction in AH is based on hemodynamic and oxidative stress, which damages endotheliocytes and destroys the nitric oxide system.

Diagnosis of endothelial dysfunction

Methods for studying the function of the endothelium of peripheral arteries are based on assessing the ability of the endothelium to produce NO in response to pharmacological (acetylcholine, methacholine, bradykinin, histamine) or physical (changes in blood flow) stimuli, direct determination of the level of NO and other NO-dependent mediators, as well as on the assessment of " surrogate" indicators of endothelial function. The following methods are used for this:

veno-occlusive plethysmography;

coronary angiography;

Magnetic resonance imaging;

ultrasonic duplex scanning of peripheral arteries with sampling;

assessment of microalbuminuria.

The most practical non-invasive method is duplex scanning of peripheral arteries, in particular, assessment of changes in the diameter of the brachial artery before and after short-term ischemia of the limb.

Methods for correcting endothelial dysfunction

Therapy of endothelial dysfunction is aimed at restoring the balance of the factors described above, limiting the action of some endothelial mediators, compensating for the deficiency of others, and restoring their functional balance. In this regard, data on the effect of various drugs on the functional activity of the endothelium are of great interest. The presence of the ability to influence NO-dependent vasodilation has been shown for nitrates, ACE inhibitors, calcium antagonists, as well as for new b-blockers latest generation with additional vasodilating properties.

Nebivolol is the first of the b-blockers, the vasodilatory effect of which is associated with the activation of the release of NO from the vascular endothelium. In comparative clinical studies, this drug increased the vasodilating activity of the endothelium, while second-generation b-blockers (atenolol) did not affect vascular tone. When studying pharmacological properties nebivolol has been shown to be a racemic mixture of D- and L-isomers, with the D-isomer having a b-blocking effect and the L-isomer stimulating NO production.

The combination of blockade of b-adrenergic receptors and NO-dependent vasodilation provides not only the hypotensive effect of nebivolol, but also a beneficial effect on systolic and diastolic myocardial function. Early studies of the vasodilating effects of nebivolol in healthy volunteers showed that when administered acutely intravenously or intra-arterially, it causes a dose-dependent NO-mediated vasodilation of arterial and venous vessels. The vasodilating effect of nebivolol was manifested in various regions of the vascular and microcirculatory bed and was accompanied by an increase in arterial elasticity, which was also confirmed in patients with hypertension. Evidence for an NO-dependent mechanism of the vasodilating effect of nebivolol was obtained not only in experimental studies, but also in clinical settings using tests with acetylcholine, an inhibitor of the arginine / NO system. Hemodynamic unloading of the myocardium, provided by nebivolol, reduces myocardial oxygen demand, increases cardiac output in patients with diastolic myocardial dysfunction and heart failure. It is the ability to modulate the reduced production of nitric oxide, which has angioprotective and vasodilating properties, that is the basis of the anti-atherosclerotic effect of the drug.

In modern studies on the study of the vasodilating effect of nebivolol in patients with hypertension, it was shown that nebivolol at a dose of 5 mg per day compared with bisoprolol at a dose of 10 mg or atenolol at a dose of 50 mg per day causes a significant decrease in the vascular resistance index, an increase in cardiac index, an increase in microvascular blood flow in various parts of the vascular bed, in the absence of differences in the degree of reduction in blood pressure and the absence of these effects in atenolol and bisoprolol.

Thus, nebivolol has clinically significant advantages over other b-blockers. The presence of the NO-dependent vasodilating effect of nebivolol in patients with hypertension may be of great importance from the standpoint of the protective role of nitric oxide against cardiovascular risk factors and especially the development of atherosclerosis. By restoring the balance in the nitric oxide system, nebivolol can eliminate endothelial dysfunction in patients with hypertension both in the arterial and microcirculatory channels and have an organoprotective effect, which was the goal of our study.

Study of the vasoprotective action of nebivolol

The study of the vasoprotective effect of nebivolol in comparison with the ACE inhibitor quinapril was carried out in 60 patients with hypertension (mean age 56 years). The vasoprotective effect was assessed by the dynamics of the vasodilating function of the endothelium using non-invasive vasodilation tests with reactive hyperemia (endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation) and the state of the intima-media complex of the carotid artery wall in the bifurcation area.

Patients underwent a general clinical examination, assessment of office blood pressure and ABPM, duplex scanning of the carotid arteries with the determination of the thickness of the intima-media complex (ITM), assessment of endothelium-dependent vasodilation (EDVD) and endothelium-independent vasodilation (ENVD) during ultrasound examination of the brachial artery . An increase in arterial dilatation by 10% was taken as a normal EZVD, an increase of more than 15% was taken as a normal EZVD; in addition, the vasodilation index (IVD) was assessed - the ratio of the degree of increase in ENZVD to the increase in EZVD (normal index 1.5-1.9). When assessing IMT - up to 1.0 mm was taken as normal, 1.0-1.4 mm - thickening, more than 1.4 mm was regarded as the formation of an atherosclerotic plaque.

Office blood pressure data after 6 months of treatment

nebivolol and quinapril

After 6 months of treatment, the decrease in SBP/DBP during nebivolol therapy was 17/12.2 mm Hg. Art., against the background of quinapril therapy - 19.2 / 9.2 mm Hg. Art. Nebivolol showed a more pronounced decrease in DBP: according to the office measurement, DBP reached 86.8 versus 90 mm Hg. Art. (R

Analysis of the vasodilating function of the brachial artery

Initially, patients with AH showed significant disturbances in the vasodilating function of the brachial artery, mainly in the form of a decrease in EDVD: a normal EDVD in a sample with reactive hyperemia (increase in arterial diameter by more than 10%) was recorded only in one patient; 22 patients (36%) had normal baseline values of ENZVD in the nitroglycerin test (increase in arterial diameter by more than 15%), while IVD was 2.4 ± 0.2.

After 6 months of therapy, the diameter of the brachial artery at rest increased by 1.9% in the nebivolol group and by 1.55% in the quinapril group (p = 0.005), which is a manifestation of the vasodilatory effect of the drugs. Improvement in the vasodilating function of the vessels was noted to a greater extent due to EVD: the increase in the diameter of the vessel in the sample with reactive hyperemia reached 12.5 and 10.1% during therapy with nebivolol and quinapril, respectively. The severity of the effect of nebivolol on EDVD was greater both in terms of the degree of increase in EDVD (p = 0.03) and in the frequency of normalization of EDVD parameters (in 20 patients (66.6%) versus 15 patients (50%) in the quinapril group). The improvement in ENZVD was less pronounced: only 10% of patients showed an increase in vasodilation in the test with nitroglycerin in both groups (Fig. 1). The IVD at the end of treatment was 1.35 ± 0.1 in the nebivolol group and 1.43 ± 0.1 in the quinapril group.

The results of the study of the intima-madia complex of the carotid arteries

Initially normal parameters of the intima-media complex of the carotid arteries in the area of bifurcation (IMT 1.4 mm).

After 6 months of treatment, the number of patients with atherosclerotic plaques did not change; the rest showed a decrease in IMT by 0.06 mm (7.2%, p

When analyzing the correlation relationships between EDVD and ENZVD and the level of the initial "office" BP, a statistically significant negative correlation was found between the level of SBP and DBP and the degree of increase in EDVD and ENZVD. This suggests that the higher the initial level of blood pressure in hypertensive patients, the lower the ability of the vessels to normal vasodilation (Table 2). When analyzing the relationship between EDVD and ENZVD and the severity of the hypotensive effect by 6 months of therapy, a statistically significant negative correlation was revealed between the achieved level of DBP and the degree of increase in EDVD and ENZVD, indicating the role of normalization of DBP in ensuring the vasodilating function of blood vessels, and this dependence took place only in relation to nebivolol and absent for quinapril.

table 2

Correlation analysis of the relationship between blood pressure and vasodilatory function of blood vessels

Indicators	n	Spearman	p
Growth in HELV and SBP office baseline
Growth in EZVD and DBP office baseline
Growth ENZVD and SAD office initially
Growth ENZVD and DBP office initially
Growth of EZVD and SBP office after 6 months
Growth of ENZVD and CAD office after 6 months
Growth of EZVD and DBP office after 6 months
Growth of ENZVD and DBP office after 6 months

Thus, in our study, it was shown that almost all patients with AH have endothelial dysfunction in the form of a delayed and insufficient vasodilating effect in a test with reactive hyperemia, which indicates a disturbed EZVD, with a slight decrease in EZVD (in one third of patients, EZVD remained normal ), which correlated with the degree of increase in blood pressure. As a result of treatment in the nebivolol group, more pronounced changes in vasodilating vascular function were observed, and mainly EDVD, which may indicate that the drug has NO-dependent mechanisms of action. In addition, the effect on endothelial function was accompanied by a more pronounced hypothetical effect of nebivolol, especially on the level of DBP, which is additional confirmation of the vasodilating effect of this b-blocker. By normalizing endothelial function, nebivolol reduced IMT in patients with hypertension and contributed to the inhibition of the progression of atherosclerotic plaques. This effect of nebivolol was comparable to the most highly lipophilic and tissue-specific ACE inhibitor, quinapril, whose anti-atherogenic properties were shown in the large QUIET study.

Study of the nephroprotective action of nebivolol

Endothelial dysfunction is a trigger pathogenetic mechanism for the development of nephropathy in patients with AH. An increase in systemic blood pressure and a violation of intraglomerular hemodynamics, damaging the endothelium of the glomerular vessels, increases the filtration of proteins through the basement membrane, which in the early stages is manifested by microproteinuria, and in the future - by the development of hypertensive nephroangiosclerosis and chronic renal failure. The most significant mediators of the development of nephroangiosclerosis are angiotensin II and an inferior precursor of NO - abnormal dimethylarginine, which contributes to the development of a deficiency in the formation of nitric oxide. Therefore, the restoration of the function of glomerular endotheliocytes can provide a nephroprotective effect against the background of antihypertensive therapy. In this regard, we studied the possibilities of the action of nebivolol on microproteinuria in 40 patients with hypertension (mean age 49.2 years) in comparison with quinapril.

According to office measurements of blood pressure, the hypotensive effect of nebivolol and quinapril after 6 months of therapy was comparable: 138/85 and 142/86 mm Hg. st, respectively. However, the achievement of the target level of blood pressure by the end of treatment was observed in 41% of patients treated with nebivolol, and only in 24% of patients treated with quinapril, and the addition of HCT was required in 6 and 47% of cases, respectively.

Initially, microproteinuria was detected in 71% of patients with AH, and in these patients the level of blood pressure was significantly higher than in patients without microproteinuria. During treatment with nebivolol and quinapril, there was a decrease in albumin excretion to normal levels in both daily and morning portions of urine; the level of excretion of b2-microglobulin during the entire period of treatment remained elevated in both groups (Fig. 2).

Thus, both drugs effectively improved glomerular filtration and, as a result, reduced albuminuria in patients with hypertension. It is known that the mechanism of the nephroprotective action of the ACE inhibitor quinapril is the elimination of the damaging effect of angiotensin II; for nebivolol, which does not have a direct effect on angiotensin II, the nephroprotective effect is realized only through a direct vasodilating effect through the NO system.

Conclusion

Nebivolol is a representative of a new generation of b-blockers with a vasodilatory effect and belongs to the class of modern vasoactive drugs that regulate endothelial function through the NO system. Nebivolol showed pronounced organoprotective properties in patients with hypertension. Given the clinical significance of endothelial dysfunction in the development of cardiovascular disease, nebivolol may be an alternative to ACE inhibitors.

Literature
1. Vane J.R., Anggard E.E., Botting R.M. Regulatory functions of the vascular endothelium // N.Engl. J. Med. 1990. V. 323. P. 27-36.
2. Gimbrone M.A. Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis // Am. J. Cardiol. 1995. V. 75. P. 67B-70B.
3. Drexler H. Endothelial dysfunction: clinical implications // Prog. Cardiovascular Dis. 1997. V. 39. P. 287-324.
4. Heitzer T., Schlinzig T., Krohn K. et al. Endothelial dysfunction, oxidative stress and risk of cardiovascular events in patients with coronary disease // Circulation 2001. V. 104. P. 263-268.
5. Perticone F., Ceravolo R., Pujia A. et al. Prognostic significance of endothelial dysfunction in hypertensive patients // Circulation. 2001. V. 104. P. 191-196.
6. Lucher T.F., Noll G. The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator // Atherosclerosis.1995. V. 118(suppl.). S81-90.
7. Lind L, Grantsam S, Millgard J. Endothelium-dependent vasodilation in hypertension – A review // Blood Pressure. 2000. V. 9. P. 4-15.
8. Taddei S., Salvetti A. Endothelial dysfunction in essential hypertension: clinical implications // J. Hypertens. 2002. V. 20. P. 1671-1674.
9. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension // Circulation. 1993. V. 87. P. 468-474.
10. Cadrillo C, Kilcoyne CM, Quyyumi A, et al. Selective defect in nitric oxide synthesis may explain the impaired endothelium-dependent vasodilation in essential hypertension // Circulation. 1998. V. 97. P. 851-856.
11. Broeders M.A.W., Doevendans P.A., Bronsaer R., van Gorsel E. Nebivolol: A Third - Generation ß-Blocker That Augments Vascular Nitric Oxide Release Endothelial ß2-Adrenergic Receptor-Mediated Nitric Oxide Production // Circulation. 2000. V. 102. P. 677.
12. Dawes M., Brett S. E., Chowienczyk P. J. et al. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension // Br. .J Clin. Pharmacol. 1994. V. 48. P. 460-463.
13. Kubli S., Feihl F., Waeber B. Beta-blockade with nebivolol enhances the acetylcholine-induced cutaneus vasodilation. // Clin.Pharmacol.Therap. 2001. V. 69. P. 238-244.
14. Tzemos N., Lim P.O., McDonald T.M. Nebivolol reverses endothelial dysfunction in essential hypertension. A randomized, double-blind, cross-over study // Circulation. 2001. V. 104. P. 511-514.
15. Kamp O., Sieswerda G.T., Visser C.A. Favorable effects on systolic and diastolic left ventricular function of nebivolol in comparison to atenolol in patients with uncomplicated essential hypertension // Am.J.Cardiol. 2003. V. 92. P. 344-348.

16. Brett S.E., Forte P., Chowienczyk P.J. et al. Comparison of the effects of nebivolol and bisoprolol on systemic vascular resistance in patients with essential hypertension // Clin.Drug Invest. 2002. V. 22. P. 355-359.

17. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis // Lancet. 1992. V. 340. P. 1111-1115.

Chronic cerebral ischemia (CCI) is a disease with progressive multifocal diffuse brain damage, manifested by neurological disorders of varying degrees, caused by a reduction in cerebral blood flow, transient ischemic attacks or previous cerebral infarctions. The number of patients with symptoms of chronic cerebral ischemia in our country is steadily growing, amounting to at least 700 per 100,000 population.

Depending on the severity of clinical disorders, three stages of the disease are distinguished. Each of the stages in turn can be compensated, subcompensated and decompensated. In stage I, headaches, a feeling of heaviness in the head, dizziness, sleep disturbances, decreased memory and attention are observed, in the neurological status - scattered small-focal neurological symptoms, insufficient for diagnosing the outlined neurological syndrome. In stage II, complaints are similar, but more intense - memory progressively worsens, unsteadiness when walking joins, difficulties arise in professional activity; there is a distinct symptomatology of organic, neurological lesions of the brain. Stage III is characterized by a decrease in the number of complaints, which is associated with the progression of cognitive impairment and a decrease in criticism of one's condition. In the neurological status, a combination of several neurological syndromes is observed, which indicates a multifocal brain lesion.

The role of endothelial dysfunction in the pathogenesis of atherosclerosis and arterial hypertension

The main factors leading to the development of chronic cerebral ischemia are atherosclerotic vascular lesions and arterial hypertension (AH).

Risk factors for the development of cardiovascular diseases, such as hypercholesterolemia, arterial hypertension, diabetes mellitus, smoking, hyperhomocysteinemia, obesity, physical inactivity, are accompanied by impaired endothelium-dependent vasodilation.

Endothelium is a single layer of squamous cells of mesenchymal origin, lining the inner surface of the blood and lymphatic vessels, cardiac cavities. To date, numerous experimental data have been accumulated that allow us to speak about the role of the endothelium in maintaining homeostasis by maintaining the dynamic balance of a number of multidirectional processes:

vascular tone (regulation of vasodilation / vasoconstriction processes through the release of vasodilator and vasoconstrictor factors, modulation of the contractile activity of smooth muscle cells);
hemostasis processes (synthesis and inhibition of platelet aggregation factors, pro- and anticoagulants, fibrinolysis factors);
local inflammation (production of pro- and anti-inflammatory factors, regulation of vascular permeability, leukocyte adhesion processes);
anatomical structure and vascular remodeling (synthesis/inhibition of proliferation factors, growth of smooth muscle cells, angiogenesis).

The endothelium also performs transport (performs bilateral transport of substances between blood and other tissues) and receptor functions (endotheliocytes have receptors for various cytokines and adhesive proteins, express a number of compounds on the plasmolemma that ensure adhesion and transendothelial migration of leukocytes).

An increase in blood flow velocity leads to an increase in the formation of vasodilators in the endothelium and is accompanied by an increase in the formation of endothelial NO-synthase and other enzymes in the endothelium. Shear stress is of great importance in the autoregulation of blood flow. Thus, with an increase in the tone of arterial vessels, the linear velocity of blood flow increases, which is accompanied by an increase in the synthesis of endothelial vasodilators and a decrease in vascular tone.

Endothelium-dependent vasodilation (EDVD) is associated with the synthesis of mainly three main substances in the endothelium: nitric monoxide (NO), endothelial hyperpolarizing factor (EDHF), and prostacyclin. Basal NO secretion determines the maintenance of normal vascular tone at rest. A number of factors, such as acetylcholine, adenosine triphosphoric acid (ATP), bradykinin, as well as hypoxia, mechanical deformation and shear stress, cause the so-called stimulated NO secretion mediated by the second messenger system.

Normally, NO is a powerful vasodilator and also inhibits the processes of vascular wall remodeling by inhibiting the proliferation of smooth muscle cells. It prevents adhesion and aggregation of platelets, adhesion of monocytes, protects the vascular wall from pathological restructuring and the subsequent development of atherosclerosis and atherothrombosis.

With prolonged exposure to damaging factors, a gradual disruption of the functioning of the endothelium occurs. The ability of endothelial cells to release relaxing factors decreases, while the formation of vasoconstrictor factors persists or increases, i.e., a condition is formed, defined as "endothelial dysfunction". There are pathological changes in vascular tone (general vascular resistance and blood pressure), vascular structure (structural integrity of the layers of the vascular wall, manifestations of atherogenesis), immunological reactions, inflammation processes, thrombosis, fibrinolysis.

A number of authors give a narrower definition of endothelial dysfunction — a state of the endothelium in which there is insufficient NO production, since NO is involved in the regulation of almost all endothelial functions and, in addition, is the most sensitive factor to damage.

There are 4 mechanisms through which endothelial dysfunction is mediated:

1) violation of the bioavailability of NO due to:

decrease in NO synthesis with inactivation of NO synthase;
a decrease in the density on the surface of endothelial cells of muscarinic and bradykinin receptors, irritation of which normally leads to the formation of NO;
increased NO degradation - NO degradation occurs before the substance reaches its site of action (during oxidative stress);

2) increased activity of angiotensin-converting enzyme (ACE) on the surface of endothelial cells;

3) increased production of endothelin-1 and other vasoconstrictor substances by endothelial cells;

4) violation of the integrity of the endothelium (deendothelialization of the intima), as a result of which the circulating substances, directly interacting with smooth muscle cells, cause their contraction.

Endothelial dysfunction (DE) is a universal mechanism of pathogenesis of arterial hypertension (AH), atherosclerosis, cerebrovascular diseases, diabetes mellitus, coronary heart disease. Moreover, endothelial dysfunction itself contributes to the formation and progression of the pathological process, and the underlying disease often exacerbates endothelial damage.

With hypercholesterolemia, cholesterol, low-density lipoproteins (LDL) accumulate on the walls of blood vessels. Low density lipoproteins are oxidized; the consequence of this reaction is the release of oxygen radicals, which, in turn, interacting with already oxidized LDL, can further enhance the release of oxygen radicals. Such biochemical reactions create a kind of pathological vicious circle. Thus, the endothelium is under the constant influence of oxidative stress, which leads to an increased decomposition of NO by oxygen radicals and a weakening of vasodilation. As a result, DE is realized in a change in the structure of the vascular wall or vascular remodeling in the form of a thickening of the vessel media, a decrease in the lumen of the vessel and the extracellular matrix. In large vessels, the elasticity of the wall decreases, the thickness of which increases, leukocyte infiltration sets in, which, in turn, predisposes to the development and progression of atherosclerosis. Vascular remodeling leads to disruption of their function and typical complications of hypertension and atherosclerosis - myocardial infarction, ischemic stroke, renal failure.

With the predominant development of atherosclerosis, NO deficiency accelerates the development of atherosclerotic plaque from a lipid spot to a crack in the atherosclerotic plaque and the development of atherothrombosis. Hyperplasia and hypertrophy of smooth muscle cells increases the degree of vasoconstrictor response to neurohumoral regulation, increases peripheral vascular resistance and, thus, is a factor stabilizing hypertension. An increase in systemic arterial pressure is accompanied by an increase in intracapillary pressure. Increased intramural pressure stimulates the formation of free radicals, especially superoxide anion, which, by binding to nitric oxide produced by the endothelium, reduces its bioavailability and leads to the formation of peroxynitrite, which has a cytotoxic effect on the endothelial cell and activates smooth muscle cell mitogenesis, there is an increased formation of vasoconstrictors, in particular endothelin-1, thromboxane A2 and prostaglandin H2, which stimulates the growth of smooth muscle cells.

Diagnostics of the functional state of the endothelium

There are a large number of different methods for assessing the functional state of the endothelium. They can be divided into 3 main groups:

1) assessment of biochemical markers;
2) invasive instrumental methods for assessing endothelial function;
3) non-invasive instrumental methods for assessing endothelial function.

Biochemical assessment methods

Decreased synthesis or bioavailability of NO is central to the development of DE. However, the short lifetime of the molecule severely limits the use of measuring NO in serum or urine. The most selective markers of endothelial dysfunction include: von Willebrand factor (vWF), antithrombin III, desquamated endothelial cells, content of cellular and vascular adhesion molecules (E-selectin, ICAM-1, VCAM-1), thrombomodulin, protein C receptors, annexin -II, prostacyclin, tissue plasminogen activator t-PA, P-selectin, tissue coagulation pathway inhibitor (TFPI), protein S.

Invasive Assessment Methods

Invasive methods are chemical stimulation of endothelial muscarinic receptors with endothelial-stimulating drugs (acetylcholine, methacholine, substance P) and some direct vasodilators (nitroglycerin, sodium nitroprusside), which are injected into the artery and cause endothelium-independent vasodilation (ENVD). One of the first such methods was radiopaque angiography using intracoronary administration of acetylcholine.

Non-invasive diagnostic methods

Recently, there has been great interest in the use of photoplethysmography (PPG), i.e., registration of a pulse wave using an optical sensor to assess the vasomotor effect that appears during an nitric oxide occlusion test and the functional state of the endothelium. The most convenient place for the location of the PPG sensor is the finger of the hand. In the formation of the PPG signal, mainly the pulse dynamics of changes in the pulse volume of blood flow and, accordingly, the diameter of the digital arteries takes part, which is accompanied by an increase in the optical density of the measured area. The increase in optical density is determined by pulse local changes in the amount of hemoglobin. The test results are comparable to those obtained with coronary angiography with the introduction of acetylcholine. The described phenomenon underlies the functioning of the non-invasive diagnostic hardware-software complex "AngioScan-01". The device allows you to identify the earliest signs of endothelial dysfunction. The registration technology and contour analysis of the volume pulse wave make it possible to obtain clinically significant information about the state of stiffness of the elastic type arteries (aorta and its main arteries) and the tone of small resistive arteries, as well as to assess the functional state of the endothelium of large muscular and small resistive vessels (the methodology is similar to ultrasound "cuff test").

Pharmacological methods of correction of endothelial dysfunction in patients with CCI

Methods for correcting DE in CCI can be divided into two groups:

1) elimination of endothelial-aggressive factors (hyperlipidemia, hyperglycemia, insulin resistance, postmenopausal hormonal changes in women, high blood pressure, smoking, sedentary lifestyle, obesity) and, thus, modification and reduction of oxidative stress;
2) normalization of endothelial NO synthesis.

To solve these problems in clinical practice, various drugs are used.

Statins

Decrease in plasma cholesterol levels slows down the development of atherosclerosis and in some cases causes regression of atherosclerotic changes in the vessel wall. In addition, statins reduce lipoprotein oxidation and free radical damage to endotheliocytes.

NO donators and NO synthase substrates

Nitrates (organic nitrates, inorganic nitro compounds, sodium nitroprusside) are NO donators, i.e. they show their pharmachologic effect by releasing NO from them. Their use is based on vasodilating properties that promote hemodynamic unloading of the heart muscle and stimulation of endothelium-independent vasodilation of the coronary arteries. Long-term administration of NO donors can lead to inhibition of its endogenous synthesis in the endothelium. It is with this mechanism that the possibility of accelerated atherogenesis and the development of hypertension is associated with their chronic use.

L-arginine is a substrate of endothelial NO-synthase, which leads to an improvement in endothelial function. However, the experience of its use in patients with hypertension, hypercholesterolemia is only theoretical.

Calcium antagonists of the dihydropyridine series improve EDVD by increasing NO (nifedipine, amlodipine, lacidipine, pranidipine, felodipine, etc.).

ACE inhibitors and AT-II antagonists

In experiments, EVD has been improved with angiotensin-converting enzyme inhibitors and angiotensin-2 antagonists. ACE inhibitors increase the bioavailability of NO by reducing the synthesis of angiotensin-2 and increasing the level of bradykinin in the blood plasma.

Other antihypertensive drugs

Beta-blockers have vasodilating properties due to stimulation of NO synthesis in the vascular endothelium and activation of the L-arginine/NO system, as well as the ability to stimulate the activity of NO synthase in endothelial cells.

Thiazide diuretics lead to an increase in the activity of NO-synthase in endothelial cells. Indapamide exerts a direct vasodilatory effect through purported antioxidant properties, increasing the bioavailability of NO and reducing its breakdown.

Antioxidants

Considering the role of oxidative stress in the pathogenesis of endothelial dysfunction, it is expected that the administration of antioxidant therapy may become the leading strategy in its treatment. The reverse development of endothelial dysfunction in the coronary and peripheral arteries has been proven against the background of the use of glutathione, N-acetyl cysteine, vitamin C. Drugs with antioxidant and antihypoxic activity may improve endothelial function.

Thioctic Acid (TA, Alpha Lipoic Acid)

The protective role of TC in relation to endothelial cells from extra- and intracellular oxidative stress has been shown in cell culture. In the ISLAND study in patients with the metabolic syndrome, TK contributed to an increase in EVR of the brachial artery, which was accompanied by a decrease in the plasma levels of interleukin-6 and plasminogen activator-1. TA affects energy metabolism, normalizes NO synthesis, reduces oxidative stress and increases the activity of the antioxidant system, which may also explain the decrease in the degree of brain damage during ischemia-reperfusion.

Vinpocetine

Numerous studies have shown an increase in cerebral volumetric blood flow with the use of this drug. Vinpocetine is not supposed to be a classic vasodilator, but relieves existing vasospasm. It enhances the utilization of oxygen by nerve cells, inhibits the entry and intracellular release of calcium ions.

Deproteinized calf blood hemoderivat (Actovegin)

Actovegin is a highly purified hemoderivative of calf blood, consisting of more than 200 biologically active components, including amino acids, oligopeptides, biogenic amines and polyamines, sphingolipids, inositol phospholigosaccharides, metabolic products of fats and carbohydrates, free fatty acids. Actovegin increases the consumption and use of oxygen, due to which it activates energy metabolism, shifting the energy exchange of cells towards aerobic glycolysis, inhibiting the oxidation of free fatty acids. At the same time, the drug also increases the content of high-energy phosphates (ATP and ADP) in conditions of ischemia, thereby replenishing the resulting energy deficit. In addition, Actovegin also prevents the formation of free radicals and blocks the processes of apoptosis, thereby protecting cells, especially neurons, from death under conditions of hypoxia and ischemia. There is also a significant improvement in cerebral and peripheral microcirculation against the background of improved aerobic energy exchange of the vascular walls and the release of prostacyclin and nitric oxide. The resulting vasodilation and decrease in peripheral resistance are secondary to the activation of the oxygen metabolism of the vascular walls.

The results obtained by A. A. Fedorovich convincingly prove that Actovegin not only has a pronounced metabolic effect, increasing the functional activity of the microvascular endothelium, but also affects the vasomotor function of microvessels. The vasomotor effect of the drug is most likely realized through an increase in the production of NO by the microvascular endothelium, which results in a significant improvement in the functional state of the smooth muscle apparatus of the microvessels. However, a direct myotropic positive effect cannot be ruled out.

In a recent work by a group of authors, the role of Actovegin as an endothelioprotector in patients with CCI was studied. When it was used in patients, an improvement in blood flow in the carotid and vertebrobasilar systems was registered, which correlated with an improvement in neurological symptoms and was confirmed by indicators of normalization of the functional state of the endothelium.

Despite the emergence of separate scientific research However, the problem of early diagnosis of endothelial dysfunction in CCI remains insufficiently studied. At the same time, timely diagnosis and subsequent pharmacological correction of DE will significantly reduce the number of patients with cerebrovascular diseases or achieve maximum regression. clinical picture in patients with different stages of chronic cerebral ischemia.

Literature

Fedin A.I. Selected lectures on ambulatory neurology. Moscow: AST 345 LLC. 2014. 128 p.
Suslina Z. A., Rumyantseva S. A. Neurometabolic therapy of chronic cerebral ischemia. Toolkit. M.: VUNMTs MZ RF, 2005. 30 p.
Schmidt E. V., Lunev D. K., Vereshchagin N. V. Vascular diseases of the brain and spinal cord. Moscow: Medicine, 1976. 284 p.
Bonetti P. O., Lerman L. O., Lerman A. et al. endothelial dysfunction. A marker of atherosclerotic risk // Arterioscler. Thromb. Vasc. Biol. 2003 Vol. 23. P. 168-175.
Buvaltsev V.I. Endothelial dysfunction as new concept prevention and treatment of cardiovascular diseases // Intern. honey. magazine 2001. No. 3. S. 202-208.
Storozhakov G. I., Vereshchagina G. S., Malysheva N. V. Endothelial dysfunction in arterial hypertension in elderly patients // Clinical Gerontology. 2003. No. 1. S. 23-28.
Esper R. J., Nordaby R. A., Vilarino J. O. et al. Endothelial dysfunction: a comprehensive appraisal // Cardiovascular Diabetology. 2006 Vol. 5 (4). P. 1-18.
Mudau M., Genis A., Lochner A., Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis // Cardiovasc. J. Afr. 2012. Vol. 23(4). P. 222-231.
Chhabra N. Endothelial dysfunction - a predictor of atherosclerosis // Internet J. Med. update. 2009 Vol. 4(1). P. 33-41.
Buvaltsev V.I. Vasodilating function of the endothelium and possible ways of its correction in patients with arterial hypertension. Dis. … Dr. med. Sciences: 14.00.06. M., 2003. 222 p.
Novikova N. A. Endothelial dysfunction - a new target for drug exposure in cardiovascular diseases // Vrach. 2005. No. 8. S. 51-53.
Verma S., Buchanan M. R., Anderson T. J. Endothelial function testing as a biomarker of vascular disease // Circulation. 2003 Vol. 108. P. 2054-2059.
Landmesser U., Hornig B., Drexler H. endothelial function. A critical determinant in atherosclerosis? // Circulation. 2004 Vol. 109 (suppl II). P.II27-II33.
Chazov E. I., Kukharchuk V. V., Boytsov S. A. Guide to atherosclerosis and coronary heart disease. M.: Media Medica, 2007. 736 p.
Soboleva G. N., Rogoza A. N., Shumilina M. V., Buziashvili Yu. I., Karpov Yu. A. Endothelial dysfunction in arterial hypertension: vasoprotective effects of new generation β-blockers. Ross. honey. magazine 2001. V. 9, No. 18. S. 754-758.
Vorobieva E. H., Schumacher G. I., Khoreva M. A., Osipova I. V. Endothelial dysfunction is a key link in the pathogenesis of atherosclerosis // Ros. cardiol. magazine 2010. No. 2. S. 84-91.
Madhu S. V., Kant S., Srivastava S., Kant R., Sharma S. B., Bhadoria D. P. Postprandial lipaemia in patients with impaired fasting glucose, impaired glucose tolerance and diabetes mellitus // Diabetes Res. Clin. practice. 2008 Vol. 80. P. 380-385.
Petrishchev N. N. endothelial dysfunction. Causes, mechanisms, pharmacological correction. St. Petersburg: Publishing House of St. Petersburg State Medical University, 2003. 181 p.
Voronkov A.V. Endothelial dysfunction and ways of its pharmacological correction. Diss. … Dr. med. Sciences: 14.03.06. Volgograd, 2011. 237 p.
Gibbons G. H., Dzau V. J. The emerging concept of vascular remodeling // N. Engl. J. Med. 1994 Vol. 330. P. 1431-1438.
Lind L., Granstam S. O., Millgard J. Endothelium-dependent vasodilation in hypertension: a review // Blood Pressure. 2000 Vol. 9. P. 4-15.
Fegan P. G., Tooke J. E., Gooding K. M., Tullett J. M., MacLeod K. M., Shore A. C. Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy // Hypertension. 2003 Vol. 41(5). P. 1111-1117.
Parfenov A.S. Early diagnosis of cardiovascular diseases using the hardware-software complex "Angioscan-01" // Polyclinic. 2012. No. 2 (1). pp. 70-74.
Fonyakin A. V., Geraskina L. A. Statins in prevention and treatment ischemic stroke// Annals of Clinical and Experimental Neurology. 2014. No. 1. S. 49-55.
Hussein O., Schlezinger S., Rosenblat M., Keidar S., Aviram M. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL // Atherosclerosis. 1997 Vol. 128(1). P. 11-18.
Drexler H. Nitric oxide and coronary endothelial dysfunction in humans // Cardiovasc. Res. 1999 Vol. 43. P. 572-579.
Ikeda U., Maeda Y., Shimada K. Inducible nitric oxide synthase and atherosclerosis // Clin. cardiol. 1998 Vol. 21. P. 473-476.
Creager M. A., Gallagher S. J., Girerd X. J., Coleman S. M., Dzau V. J., Cooke J. P. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans // J. Clin. Invest. 1992 Vol. 90. P. 1242-1253.
Shilov A. M. The place of third-generation calcium channel blockers in the metabolic syndrome continuum // Difficult patient. 2014. No. 12 (4). pp. 20-25.
Berkels R., Egink G., Marsen T. A., Bartels H., Roesen R., Klaus W. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms // Hypertension. 2001. V. 37. No. 2. P. 240-245.
Wu C.C., Yen M.H. Nitric oxide synthase in spontaneously hypertensive rats/C.C. Wu // J. Biomed. sci. 1997 Vol. 4 (5). P. 249-255.
Young R. H., Ding Y. A., Lee Y. M., Yen M. H. Cilazapril reverses endothelium-dependent vasodilator response to acetylcholine in mesenteric artery from spontaneously hypertensive rats // Am. J. Hypertens. 1995 Vol. 8(9). P. 928-933.
Parenti A., Filippi S., Amerini S., Granger H. J., Fazzini A., Ledda F. Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol // J. Pharmacol. Exp. Ther. 2000 Vol. 292(2). P. 698-703.
Murphy M.P. Nitric oxide and cell death // Biochim. Biophys. acta. 1999 Vol. 1411. P. 401-414.
Perfilova V. N. Cardioprotective properties of structural analogues of GABA. Abstract dis. … Dr. Biol. Sciences. Volgograd, 2009. 49 p.
Ishide T., Amer A., Maher T. J., Ally A. Nitric oxide within periaqueductal gray modulates glutamatergic neurotransmission and cardiovascular responses during mechanical and thermal stimuli // Neurosci Res. 2005 Vol. 51(1). P. 93-103.
Sabharwal A. K., May J. M. Alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells // Mol. cell. Biochem. 2008. 309(1-2). P. 125-132.
Kamchatnov P. R., Abusueva B. A., Kazakov A. Yu. The use of alpha-lipoic acid in diseases of the nervous system // Journal of Neurology and Psychiatry. S. S. Korsakov. 2014. V. 114., No. 10. S. 131-135.
Karneev A. N., Solovieva E. Yu., Fedin A. I., Azizova O. A. The use of α-lipoic acid preparations as a neuroprotective therapy for chronic cerebral ischemia. Handbook of a polyclinic doctor. 2006. No. 8. S. 76-79.
Burtsev E. M., Savkov V. C., Shprakh V. V., Burtsev M. E. 10-year experience of using Cavinton in cerebrovascular disorders // Journal of Neurology and Psychiatry. S. S. Korsakov. 1992. No. 1. S. 56-61.
Suslina Z. A., Tanashyan M. M., Ionova V. G., Kistenev B. A., Maksimova M. Yu., Sharypova T. N.. Cavinton in the treatment of patients with ischemic disorders of cerebral circulation // Russian Medical Journal. 2002. No. 25. S. 1170-1174.
Molnár P., Erdö S. L. Vinpocetine is as potent as phenytoin to block voltage-gated Na+ channels in rat cortical neurons // Eur. J Pharmacol. 1995 Vol. 273(5). P. 303-306.
Vaizova O. E. Pharmacological and extracorporeal correction of vascular endothelial dysfunction in cerebral atherosclerosis. Dis. … Dr. med. Sciences: 14.00.25. Tomsk, 2006. 352 p.
Machicao F., Muresanu D. F., Hundsberger H., Pfluger M., Guekht A. Pleiotropic neuroprotective and metabolic effects of Actovegin’s mode of action // J Neurol Sci. 2012; 322(1): 222-227.
Elmlinger M. W., Kriebel M., Ziegler D. Neuroprotective and Anti-Oxidative Effects of the Hemodialysate Actovegin on Primary Rat Neurons in Vitro // Neuromolecular Med. 2011; 13(4): 266-274.
Astashkin E. I., Glazer M. G. Actovegin reduces the level of oxygen radicals in whole blood samples of patients with heart failure and inhibits the development of necrosis of transplanted human neurons of the SK-N-SH line. Reports of the Academy of Sciences. 2013: 448(2); 232-235.
Fedorovich A. A., Rogoza A. N., Kanishcheva E. M., Boytsov S. A. Dynamics of the functional activity of the microvascular endothelium during an acute pharmacological test with Actovegin // Сonsilium medicum. 2010. V. 12. No. 2. S. 36-45.
Uchkin I. G., Zudin A. M., Bagdasaryan A. G., Fedorovich A. A. Influence of pharmacotherapy of chronic obliterating diseases of the arteries of the lower extremities on the state of the microcirculatory bed. Angiology and vascular surgery. 2014. V. 20, No. 2. S. 27-36.
Fedin A. I., Rumyantseva S. A. Selected issues of basic intensive therapy for cerebrovascular accidents. Methodical instructions. Moscow: Intermedica, 2002. 256 p.
Fedin A. I., Starykh E. P., Parfenov A. S., Mironova O. P., Abdrakhmanova E. K., Starykh E. V. Pharmacological correction of endothelial dysfunction in atherosclerotic chronic cerebral ischemia // Journal of Neurology and Psychiatry. S. S. Korsakov. 2013. V. 113. No. 10. S. 45-48.

A. I. Fedin,
E. P. Starykh 1
M. V. Putilina, doctor of medical sciences, professor
E. V. Starykh,doctor of medical sciences, professor
O. P. Mironova, Candidate of Medical Sciences
K. R. Badalyan