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Angiotensin 2 causes the following effects. Angiotensin II receptor antagonists

The role of the hormone angiotensin for the functioning of the cardiovascular system is ambiguous and largely depends on the receptors with which it interacts. Its best known effect is on type 1 receptors, which cause vasoconstriction, an increase in blood pressure, and promote the synthesis of the hormone aldosterone, which affects the amount of salts in the blood and the volume of circulating blood.

The formation of angiotensin (angiotonin, hypertensin) occurs through complex transformations. The precursor to the hormone is the protein angiotensinogen, most of which is produced by the liver. This protein belongs to serpins, most of which inhibit (inhibit) enzymes that cleave the peptide bond between amino acids in proteins. But unlike many of them, angiotensinogen does not have such an effect on other proteins.

Protein production is increased under the influence of adrenal hormones (primarily corticosteroids), estrogens, thyroid hormones of the thyroid gland, as well as angiotensin II, into which this protein is subsequently converted. Angiotensinogen does not do this right away: first, under the influence of renin, which is produced by the arterioles of the renal glomeruli in response to a decrease in intrarenal pressure, angiotensinogen is transformed into the first, inactive form of the hormone.

It is then influenced by the angiotensin converting enzyme (ACE), which is formed in the lungs and splits off the last two amino acids from it. The result is an active octapeptide consisting of eight amino acids, known as angiotonin II, which, when interacting with receptors, affects the cardiovascular, nervous systems, adrenal glands and kidneys.

At the same time, hypertensin not only has a vasoconstrictor effect and stimulates the production of aldosterone, but also in large quantities in one of the parts of the brain, the hypothalamus, increases the synthesis of vasopressin, which affects the excretion of water by the kidneys and promotes the feeling of thirst.

Hormone receptors

Several types of angiotonin II receptors have now been discovered. The best studied receptors are the AT1 and AT2 subtypes. Most effects on the body, both positive and negative, occur when the hormone interacts with receptors of the first subtype. They are found in many tissues, most of all in the smooth muscles of the heart, blood vessels, and kidneys.

They influence the narrowing of the small arteries of the renal glomeruli, causing an increase in pressure in them, and promote the reabsorption (reabsorption) of sodium in the renal tubules. The synthesis of vasopressin, aldosterone, endothelin-1, the work of adrenaline and norepinephrine largely depend on them, and they also take part in the release of renin.

Negative impacts include:

  • inhibition of apoptosis – apoptosis is a regulated process during which the body gets rid of unnecessary or damaged cells, including malignant ones. Angiotonin, when influencing receptors of the first type, is able to slow down their decay in the cells of the aorta and coronary vessels;
  • an increase in the amount of “bad cholesterol”, which can provoke atherosclerosis;
  • stimulation of the proliferation of smooth muscle walls of blood vessels;
  • increased risk of blood clots, which slow down blood flow through the vessels;
  • intimal hyperplasia - thickening of the inner lining of blood vessels;
  • activation of the processes of remodeling of the heart and blood vessels, which is expressed in the ability of the organ to change its structure due to pathological processes, is one of the factors of arterial hypertension.


Thus, when the renin-angiotensin system, which regulates blood pressure and volume in the body, is too active, AT1 receptors have a direct and indirect effect on increasing blood pressure. They also negatively affect the cardiovascular system, causing thickening of arterial walls, enlargement of the myocardium and other ailments.

Receptors of the second subtype are also distributed throughout the body, most of all found in the cells of the fetus, after birth their number begins to decrease. Some studies have suggested that they have a significant impact on the development and growth of embryonic cells and shape exploratory behavior.

It has been proven that the number of receptors of the second subtype can increase with damage to blood vessels and other tissues, heart failure, and heart attack. This allowed us to suggest that AT2 is involved in cell regeneration and, unlike AT1, promotes apoptosis (death of damaged cells).

Based on this, the researchers hypothesized that the effects that angiotonin has through receptors of the second subtype are directly opposite to its effect on the body through AT1 receptors. As a result of stimulation of AT2, vasodilation occurs (expansion of the lumen of arteries and other blood vessels), and the increase in the muscular walls of the heart is inhibited. The impact of these receptors on the body is only at the stage of study, so their influence has been little studied.


Also almost unknown is the body's response to type 3 receptors, which were found on the walls of neurons, as well as to AT4, which are located on endothelial cells and are responsible for the expansion and restoration of the network of blood vessels, tissue growth and healing from damage. Also, receptors of the fourth subtype were found on the walls of neurons, and, according to assumptions, are responsible for cognitive functions.

Developments of scientists in the pharmaceutical field

As a result of many years of research into the renin-angiotensin system, many drugs have been created whose action is aimed at targeting individual parts of this system. Scientists paid special attention to the negative effects of the first subtype receptors on the body, which have a great impact on the development of cardiovascular complications, and set the task of developing drugs aimed at blocking these receptors. Since it became obvious that in this way it is possible to treat arterial hypertension and prevent cardiovascular complications.

During development, it became obvious that angiotensin receptor blockers are more effective than angiotensin converting enzyme inhibitors, since they act in several directions at once and are able to penetrate the blood-brain barrier.

It separates the central nervous and circulatory systems, protecting nervous tissue from blood-borne pathogens, toxins, and immune system cells that, when malfunctioning, identify the brain as foreign tissue. It is also a barrier to some medications aimed at treating the nervous system (but allows nutrients and bioactive elements to pass through).

Angiotensin receptor blockers, having penetrated the barrier, inhibit the mediator processes that occur in the sympathetic nervous system. As a result, the release of norepinephrine is inhibited and the stimulation of adrenaline receptors located in the smooth muscles of blood vessels is reduced. This leads to an increase in the lumen of blood vessels.

Moreover, each drug has its own characteristics, for example, this effect on the body is especially pronounced in eprosartan, while the effects of other blockers on the sympathetic nervous system are contradictory.


By this method, medications block the development of the effects that the hormone has on the body through receptors of the first subtype, preventing the negative effect of angiotonin on vascular tone, promoting the reverse development of left ventricular hypertrophy and reducing too high blood pressure. Regular long-term use of inhibitors causes a decrease in cardiomyocyte hypertrophy, proliferation of vascular smooth muscle cells, mesangial cells, etc.

It should also be noted that all angiotensin receptor antagonists are characterized by a selective action, which is aimed specifically at blocking receptors of the first subtype: they affect them thousands of times more than AT2. Moreover, the difference in effect for losartan exceeds a thousand times, valsartan – twenty thousand times.

With an increased concentration of angiotensin, which is accompanied by blockade of AT1 receptors, the protective properties of the hormone begin to appear. They are expressed in the stimulation of receptors of the second subtype, which leads to an increase in the lumen of blood vessels, a slowdown in cell proliferation, etc.

Also, with an increased amount of angiotensins of the first and second types, angiotonin-(1-7) is formed, which also has vasodilatory and natriuretic effects. It affects the body through unidentified ATx receptors.

Types of medications

Angiotensin receptor antagonists are usually divided according to their chemical composition, pharmacological characteristics, and method of binding to receptors. If we talk about the chemical structure, inhibitors are usually divided into the following types:

  • biphenyl tetrazole derivatives (losartan);
  • biphenyl non-tetrazole compounds (telmisartan);
  • non-biphenyl non-tetrazole compounds (eprosartan).

As for pharmacological activity, inhibitors can be active dosage forms that are characterized by pharmacological activity (valsartan). Or be prodrugs that are activated after conversion in the liver (candesartan cilexetil). Some inhibitors contain active metabolites (metabolic products), the presence of which is characterized by a stronger and longer-lasting effect on the body.


According to the binding mechanism, drugs are divided into those that reversibly bind to receptors (losartan, eprosartan), that is, in certain situations, for example, when the amount of antigensin increases in response to a decrease in circulating blood, inhibitors can be displaced from the binding sites. There are also drugs that bind to receptors irreversibly.

Features of taking medications

The patient is prescribed angiotensin receptor inhibitors in the presence of arterial hypertension, both mild and severe forms of the disease. Their combination with thiazide diuretics can increase the effectiveness of blockers, so drugs have already been developed that contain a combination of these drugs.

Receptor antagonists are not quick-acting drugs; they act on the body smoothly, gradually, the effect lasts about a day. With regular therapy, a pronounced therapeutic effect can be seen two or even six weeks after the start of therapy. You can take them regardless of food intake; for effective treatment, once a day is enough.

The drugs have a good effect on patients regardless of gender and age, including elderly patients. The body tolerates all types of these drugs well, which makes it possible to use them to treat patients with already detected cardiovascular pathology.

AT1 receptor blockers have contraindications and warnings. They are prohibited for people with individual intolerance to the components of the drug, pregnant women and during lactation: they can cause pathological changes in the baby’s body, resulting in his death in the womb or after birth (this was established during experiments on animals). It is also not recommended to use these drugs to treat children: how safe the drugs are for them has not been determined to date.

Doctors use caution when prescribing inhibitors to people who have a low circulating blood volume or tests that show a low amount of sodium in the blood. This usually happens during diuretic therapy, if a person is on a salt-free diet, or with diarrhea. The drug should be used with caution for aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy.

It is not advisable to take the medicine for people who are on hemodialysis (a method of extrarenal blood purification for renal failure). If treatment is prescribed against the background of renal disease, constant monitoring of serum potassium and cretinine concentrations is necessary. The drug is ineffective if tests show an increased amount of aldosterone in the blood.

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Description

Angiotensin II receptor antagonists, or AT 1 receptor blockers, are one of the new groups of antihypertensive drugs. It combines drugs that modulate the functioning of the renin-angiotensin-aldosterone system (RAAS) through interaction with angiotensin receptors.

The RAAS plays an important role in the regulation of blood pressure, the pathogenesis of arterial hypertension and chronic heart failure (CHF), as well as a number of other diseases. Angiotensins (from angio- vascular and tensio- tension) - peptides formed in the body from angiotensinogen, which is a glycoprotein (alpha 2 globulin) of blood plasma synthesized in the liver. Under the influence of renin (an enzyme formed in the juxtaglomerular apparatus of the kidneys), the angiotensinogen polypeptide, which does not have pressor activity, is hydrolyzed, forming angiotensin I, a biologically inactive decapeptide that is easily subject to further transformations. Under the influence of angiotensin-converting enzyme (ACE), formed in the lungs, angiotensin I is converted into an octapeptide - angiotensin II, which is a highly active endogenous pressor compound.

Angiotensin II is the main effector peptide of the RAAS. It has a strong vasoconstrictor effect, increases peripheral vascular resistance, and causes a rapid increase in blood pressure. In addition, it stimulates the secretion of aldosterone, and in high concentrations it increases the secretion of antidiuretic hormone (increased sodium and water reabsorption, hypervolemia) and causes sympathetic activation. All these effects contribute to the development of hypertension.

Angiotensin II is rapidly metabolized (half-life - 12 minutes) with the participation of aminopeptidase A with the formation of angiotensin III and then under the influence of aminopeptidase N - angiotensin IV, which have biological activity. Angiotensin III stimulates the production of aldosterone by the adrenal glands and has positive inotropic activity. Angiotensin IV is presumably involved in the regulation of hemostasis.

It is known that in addition to the RAAS of the systemic bloodstream, the activation of which leads to short-term effects (including such as vasoconstriction, increased blood pressure, aldosterone secretion), there are local (tissue) RAAS in various organs and tissues, incl. in the heart, kidneys, brain, blood vessels. Increased activity of tissue RAAS causes long-term effects of angiotensin II, which are manifested by structural and functional changes in target organs and lead to the development of pathological processes such as myocardial hypertrophy, myofibrosis, atherosclerotic damage to cerebral vessels, kidney damage, etc.

It has now been shown that in humans, in addition to the ACE-dependent pathway for converting angiotensin I to angiotensin II, there are alternative pathways involving chymases, cathepsin G, tonin and other serine proteases. Chymases, or chymotrypsin-like proteases, are glycoproteins with a molecular weight of about 30,000. Chymases have high specificity for angiotensin I. In different organs and tissues, either ACE-dependent or alternative pathways of angiotensin II formation predominate. Thus, cardiac serine protease, its DNA and mRNA were found in human myocardial tissue. Moreover, the largest amount of this enzyme is contained in the myocardium of the left ventricle, where the chymase pathway accounts for more than 80%. Chemase-dependent formation of angiotensin II prevails in the myocardial interstitium, adventitia and vascular media, while ACE-dependent formation occurs in the blood plasma.

Angiotensin II can also be formed directly from angiotensinogen through reactions catalyzed by tissue plasminogen activator, tonin, cathepsin G, etc.

It is believed that activation of alternative pathways for the formation of angiotensin II plays an important role in the processes of cardiovascular remodeling.

The physiological effects of angiotensin II, like other biologically active angiotensins, are realized at the cellular level through specific angiotensin receptors.

To date, the existence of several subtypes of angiotensin receptors has been established: AT 1, AT 2, AT 3 and AT 4, etc.

In humans, two subtypes of membrane-bound, G-protein coupled angiotensin II receptors have been identified and most fully studied—subtypes AT 1 and AT 2.

AT 1 receptors are localized in various organs and tissues, mainly in vascular smooth muscle, heart, liver, adrenal cortex, kidneys, lungs, and in some areas of the brain.

Most of the physiological effects of angiotensin II, including unfavorable ones, are mediated by AT 1 receptors:

Arterial vasoconstriction, incl. vasoconstriction of the arterioles of the renal glomeruli (especially the efferent), increased hydraulic pressure in the renal glomeruli,

Increased sodium reabsorption in the proximal renal tubules,

Secretion of aldosterone by the adrenal cortex

Secretion of vasopressin, endothelin-1,

Renin release

Increased release of norepinephrine from sympathetic nerve endings, activation of the sympathetic-adrenal system,

Proliferation of vascular smooth muscle cells, intimal hyperplasia, cardiomyocyte hypertrophy, stimulation of vascular and cardiac remodeling processes.

In arterial hypertension against the background of excessive activation of the RAAS, the AT 1 receptor-mediated effects of angiotensin II directly or indirectly contribute to an increase in blood pressure. In addition, stimulation of these receptors is accompanied by the damaging effect of angiotensin II on the cardiovascular system, including the development of myocardial hypertrophy, thickening of arterial walls, etc.

The effects of angiotensin II, mediated by AT 2 receptors, were discovered only in recent years.

A large number of AT 2 receptors were found in fetal tissues (including the brain). In the postnatal period, the number of AT 2 receptors in human tissues decreases. Experimental studies, particularly in mice in which the gene encoding AT 2 receptors has been disrupted, suggest their involvement in growth and maturation processes, including cell proliferation and differentiation, development of embryonic tissues, and the formation of exploratory behavior.

AT 2 receptors are found in the heart, blood vessels, adrenal glands, kidneys, some areas of the brain, reproductive organs, incl. in the uterus, atretic ovarian follicles, and also in skin wounds. It has been shown that the number of AT 2 receptors can increase with tissue damage (including blood vessels), myocardial infarction, and heart failure. It is assumed that these receptors may be involved in the processes of tissue regeneration and programmed cell death (apoptosis).

Recent studies show that the cardiovascular effects of angiotensin II mediated by AT 2 receptors are opposite to the effects caused by stimulation of AT 1 receptors and are relatively weakly expressed. Stimulation of AT 2 receptors is accompanied by vasodilation, inhibition of cell growth, incl. suppression of cell proliferation (endothelial and smooth muscle cells of the vascular wall, fibroblasts, etc.), inhibition of cardiomyocyte hypertrophy.

The physiological role of angiotensin II type 2 receptors (AT 2) in humans and their relationship with cardiovascular homeostasis is currently not fully understood.

Highly selective AT 2 receptor antagonists have been synthesized (CGP 42112A, PD 123177, PD 123319), which are used in experimental studies of the RAAS.

Other angiotensin receptors and their role in humans and animals have been little studied.

Subtypes of AT 1 receptors, AT 1a and AT 1b, differing in their affinity for peptide angiotensin II agonists (these subtypes were not found in humans) were isolated from a cell culture of rat mesangium. The AT 1c receptor subtype, the physiological role of which is not yet clear, was isolated from the rat placenta.

AT 3 receptors with affinity for angiotensin II are found on neuronal membranes; their function is unknown. AT 4 receptors are found on endothelial cells. By interacting with these receptors, angiotensin IV stimulates the release of plasminogen activator inhibitor type 1 from the endothelium. AT 4 receptors are also found on the membranes of neurons, incl. in the hypothalamus, presumably in the brain, they mediate cognitive functions. In addition to angiotensin IV, angiotensin III also has tropism for AT 4 receptors.

Long-term studies of the RAAS not only revealed the importance of this system in the regulation of homeostasis, in the development of cardiovascular pathology, and the influence on the functions of target organs, among which the most important are the heart, blood vessels, kidneys and brain, but also led to the creation of drugs, purposefully acting on individual parts of the RAAS.

The scientific basis for the creation of drugs that act by blocking angiotensin receptors was the study of angiotensin II inhibitors. Experimental studies show that angiotensin II antagonists capable of blocking its formation or action and thus reducing the activity of the RAAS are inhibitors of angiotensinogen formation, inhibitors of renin synthesis, inhibitors of the formation or activity of ACE, antibodies, angiotensin receptor antagonists, including synthetic non-peptide compounds, specifically blocking AT 1 receptors, etc.

The first angiotensin II receptor blocker introduced into therapeutic practice in 1971 was saralazine, a peptide compound similar in structure to angiotensin II. Saralazin blocked the pressor effect of angiotensin II and decreased the tone of peripheral vessels, reduced the content of aldosterone in plasma, and lowered blood pressure. However, by the mid-70s, experience with the use of saralazine showed that it has partial agonist properties and in some cases gives a poorly predictable effect (in the form of excessive hypotension or hypertension). At the same time, a good hypotensive effect was manifested in conditions associated with high levels of renin, while against the background of low levels of angiotensin II or with rapid injection, blood pressure increased. Due to the presence of agonistic properties, as well as due to the complexity of synthesis and the need for parenteral administration, saralazine has not received wide practical use.

In the early 90s, the first non-peptide selective antagonist of AT 1 receptors, effective when taken orally, was synthesized - losartan, which received practical use as an antihypertensive agent.

Currently, several synthetic non-peptide selective AT 1 blockers are used or are undergoing clinical trials in world medical practice - valsartan, irbesartan, candesartan, losartan, telmisartan, eprosartan, olmesartan medoxomil, azilsartan medoxomil, zolarsartan, tazosartan (zolarsartan and tazosartan are not yet registered in Russia).

There are several classifications of angiotensin II receptor antagonists: according to chemical structure, pharmacokinetic characteristics, mechanism of binding to receptors, etc.

Based on their chemical structure, non-peptide AT 1 receptor blockers can be divided into 3 main groups:

Biphenyl tetrazole derivatives: losartan, irbesartan, candesartan, valsartan, tazosartan;

Biphenyl non-tetrazole compounds - telmisartan;

Non-biphenyl non-tetrazole compounds - eprosartan.

Based on the presence of pharmacological activity, AT 1 receptor blockers are divided into active dosage forms and prodrugs. Thus, valsartan, irbesartan, telmisartan, eprosartan themselves have pharmacological activity, while candesartan cilexetil becomes active only after metabolic transformations in the liver.

In addition, AT 1 blockers differ depending on the presence or absence of active metabolites. Losartan and tazosartan have active metabolites. For example, the active metabolite of losartan, EXP-3174, has a stronger and longer-lasting effect than losartan (the pharmacological activity of EXP-3174 is 10-40 times greater than losartan).

According to the mechanism of binding to receptors, AT 1 receptor blockers (as well as their active metabolites) are divided into competitive and non-competitive angiotensin II antagonists. Thus, losartan and eprosartan reversibly bind to AT 1 receptors and are competitive antagonists (i.e., under certain conditions, for example, with an increase in the level of angiotensin II in response to a decrease in blood volume, they can be displaced from binding sites), while valsartan, irbesartan , candesartan, telmisartan, as well as the active metabolite of losartan EXP−3174 act as non-competitive antagonists and bind irreversibly to receptors.

The pharmacological effect of drugs in this group is due to the elimination of the cardiovascular effects of angiotensin II, incl. vasopressor.

It is believed that the antihypertensive effect and other pharmacological effects of angiotensin II receptor antagonists are realized in several ways (one direct and several indirect).

The main mechanism of action of drugs in this group is associated with the blockade of AT 1 receptors. All of them are highly selective AT 1 receptor antagonists. It has been shown that their affinity for AT 1 receptors exceeds that for AT 2 receptors by thousands of times: for losartan and eprosartan more than 1 thousand times, telmisartan - more than 3 thousand, irbesartan - 8.5 thousand, the active metabolite of losartan EXP−3174 and candesartan - 10 thousand, olmesartan - 12.5 thousand, valsartan - 20 thousand times.

Blockade of AT 1 receptors prevents the development of the effects of angiotensin II mediated by these receptors, which prevents the adverse effects of angiotensin II on vascular tone and is accompanied by a decrease in high blood pressure. Long-term use of these drugs leads to a weakening of the proliferative effects of angiotensin II on vascular smooth muscle cells, mesangial cells, fibroblasts, a decrease in cardiomyocyte hypertrophy, etc.

It is known that AT 1 receptors of the cells of the juxtaglomerular apparatus of the kidneys are involved in the process of regulating the release of renin (according to the principle of negative feedback). Blockade of AT 1 receptors causes a compensatory increase in renin activity, an increase in the production of angiotensin I, angiotensin II, etc.

Under conditions of increased angiotensin II content against the background of blockade of AT 1 receptors, the protective properties of this peptide are manifested, realized through stimulation of AT 2 receptors and expressed in vasodilation, slowdown of proliferative processes, etc.

In addition, against the background of increased levels of angiotensins I and II, angiotensin-(1-7) is formed. Angiotensin-(1-7) is formed from angiotensin I under the action of neutral endopeptidase and from angiotensin II under the action of prolyl endopeptidase and is another effector peptide of the RAAS, which has a vasodilating and natriuretic effect. The effects of angiotensin-(1-7) are mediated through so-called, not yet identified, AT x receptors.

Recent studies of endothelial dysfunction in hypertension suggest that the cardiovascular effects of angiotensin receptor blockers may also be related to endothelial modulation and effects on nitric oxide (NO) production. The experimental data obtained and the results of individual clinical studies are quite contradictory. Perhaps, against the background of blockade of AT 1 receptors, endothelium-dependent synthesis and release of nitric oxide increases, which promotes vasodilation, reduced platelet aggregation and reduced cell proliferation.

Thus, specific blockade of AT 1 receptors allows for a pronounced antihypertensive and organoprotective effect. Against the background of blockade of AT 1 receptors, the adverse effects of angiotensin II (and angiotensin III, which has an affinity for angiotensin II receptors) on the cardiovascular system are inhibited and, presumably, its protective effect is manifested (by stimulating AT 2 receptors), and the effect also develops angiotensin-(1-7) by stimulating AT x receptors. All these effects contribute to vasodilation and weakening of the proliferative effect of angiotensin II on vascular and cardiac cells.

AT 1 receptor antagonists can penetrate the blood-brain barrier and inhibit the activity of mediator processes in the sympathetic nervous system. By blocking presynaptic AT 1 receptors of sympathetic neurons in the central nervous system, they inhibit the release of norepinephrine and reduce the stimulation of adrenergic receptors in vascular smooth muscle, which leads to vasodilation. Experimental studies show that this additional mechanism of vasodilating action is more characteristic of eprosartan. Data on the effect of losartan, irbesartan, valsartan, etc. on the sympathetic nervous system (which manifested itself at doses exceeding therapeutic ones) are very contradictory.

All AT 1 receptor blockers act gradually, the antihypertensive effect develops smoothly, within several hours after taking a single dose, and lasts up to 24 hours. With regular use, a pronounced therapeutic effect is usually achieved after 2-4 weeks (up to 6 weeks) of treatment.

The pharmacokinetic features of this group of drugs make their use convenient for patients. These medicines can be taken with or without food. A single dose is enough to provide a good hypotensive effect throughout the day. They are equally effective in patients of different sexes and ages, including patients over 65 years of age.

Clinical studies show that all angiotensin receptor blockers have a high antihypertensive and pronounced organoprotective effect and are well tolerated. This allows them to be used, along with other antihypertensive drugs, for the treatment of patients with cardiovascular pathology.

The main indication for the clinical use of angiotensin II receptor blockers is the treatment of arterial hypertension of varying severity. Monotherapy is possible (for mild arterial hypertension) or in combination with other antihypertensive drugs (for moderate and severe forms).

Currently, according to WHO/ISH (International Society of Hypertension) recommendations, preference is given to combination therapy. The most rational option for angiotensin II receptor antagonists is their combination with thiazide diuretics. The addition of a diuretic in low doses (for example, 12.5 mg hydrochlorothiazide) can increase the effectiveness of therapy, as confirmed by the results of randomized multicenter studies. Drugs have been created that include this combination - Gizaar (losartan + hydrochlorothiazide), Co-diovan (valsartan + hydrochlorothiazide), Coaprovel (irbesartan + hydrochlorothiazide), Atacand Plus (candesartan + hydrochlorothiazide), Micardis Plus (telmisartan + hydrochlorothiazide), etc. .

A number of multicenter studies (ELITE, ELITE II, Val-HeFT, etc.) have shown the effectiveness of the use of certain AT 1 receptor antagonists in CHF. The results of these studies are controversial, but in general they indicate high efficacy and better (compared to ACE inhibitors) tolerability.

The results of experimental as well as clinical studies indicate that blockers of AT 1 subtype receptors not only prevent the processes of cardiovascular remodeling, but also cause the reverse development of left ventricular hypertrophy (LVH). In particular, it was shown that with long-term therapy with losartan, patients showed a tendency to decrease the size of the left ventricle in systole and diastole, and an increase in myocardial contractility. Regression of LVH was noted with long-term use of valsartan and eprosartan in patients with arterial hypertension. Some AT 1 receptor blockers have been shown to improve renal function, incl. in diabetic nephropathy, as well as indicators of central hemodynamics in CHF. So far, clinical observations regarding the effect of these drugs on target organs are few, but research in this area is actively continuing.

Contraindications to the use of angiotensin AT 1 receptor blockers are individual hypersensitivity, pregnancy, and breastfeeding.

Data obtained from animal experiments indicate that drugs that have a direct effect on the RAAS can cause damage to the fetus, death of the fetus and newborn. The effect on the fetus is especially dangerous in the second and third trimesters of pregnancy, because the development of hypotension, cranial hypoplasia, anuria, renal failure and death in the fetus is possible. There are no direct indications of the development of such defects when taking AT 1 receptor blockers, however, drugs of this group should not be used during pregnancy, and if pregnancy is detected during treatment, their use should be stopped.

There is no information about the ability of AT 1 receptor blockers to penetrate into women's breast milk. However, in animal experiments it was found that they penetrate into the milk of lactating rats (in the milk of rats, significant concentrations of not only the substances themselves, but also their active metabolites are found). In this regard, AT 1 receptor blockers are not used in nursing women, and if therapy is necessary for the mother, breastfeeding is stopped.

The use of these drugs in pediatric practice should be avoided since the safety and effectiveness of their use in children have not been determined.

There are a number of limitations for therapy with AT 1 angiotensin receptor antagonists. Caution should be exercised in patients with reduced blood volume and/or hyponatremia (during treatment with diuretics, limiting salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, because Symptomatic hypotension may develop. An assessment of the risk/benefit ratio is necessary in patients with renovascular hypertension caused by bilateral renal artery stenosis or renal artery stenosis of a single kidney, because excessive inhibition of the RAAS in these cases increases the risk of severe hypotension and renal failure. Use with caution in aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. Against the background of impaired renal function, monitoring of serum potassium and creatinine levels is necessary. It is not recommended for use in patients with primary hyperaldosteronism, because in this case, drugs that inhibit the RAAS are ineffective. There is insufficient data on use in patients with severe liver disease (eg, cirrhosis).

Side effects with angiotensin II receptor antagonists that have been reported so far are usually mild, transient, and rarely warrant discontinuation of therapy. The total incidence of side effects is comparable to placebo, which is confirmed by the results of placebo-controlled studies. The most common adverse effects are headache, dizziness, general weakness, etc. Angiotensin receptor antagonists do not directly affect the metabolism of bradykinin, substance P, and other peptides and, as a result, do not cause a dry cough, which often appears during treatment with ACE inhibitors.

When taking drugs of this group, there is no effect of hypotension of the first dose, which occurs when taking ACE inhibitors, and sudden withdrawal is not accompanied by the development of rebound hypertension.

The results of multicenter placebo-controlled studies show high efficacy and good tolerability of AT 1 angiotensin II receptor antagonists. However, so far their use is limited by the lack of data on the long-term consequences of use. According to WHO/ITF experts, their use for the treatment of arterial hypertension is advisable in case of intolerance to ACE inhibitors, in particular, in the case of a history of cough caused by ACE inhibitors.

Numerous clinical studies are currently ongoing, incl. and multicenter studies devoted to the study of the effectiveness and safety of the use of angiotensin II receptor antagonists, their effect on mortality, duration and quality of life of patients and comparison with antihypertensive and other drugs in the treatment of arterial hypertension, chronic heart failure, atherosclerosis, etc.

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Which is converted from its precursor serum globulin, synthesized by the liver. Angiotensin is extremely important for the hormonal renin-angiotensin system, a system that is responsible for blood volume and pressure in the human body.

The substance angiotensinogen belongs to the class of globulins, it consists of more than 400. Its production and release into the blood is carried out by the liver constantly. Angiotensin levels can increase under the influence of angiotensin II, thyroid hormone, estrogen, and plasma corticosteroids. When blood pressure decreases, it acts as a stimulating factor for the production of renin, releasing it into the blood. This process triggers the synthesis of angiotensin.

Angiotensin I and angiotensin II

Under the influence renina The following substance is formed from angiotensinogen - angiotensin I. This substance does not carry any biological activity; its main role is to be a precursor angiotensin II. The latter hormone is already active: it ensures the synthesis of aldosterone and constricts blood vessels. This system is a target for drugs that lower, as well as for many inhibitory agents that reduce the concentration of angiotensin II.

The role of angiotensin in the body

This substance is strong vasoconstrictor . This means that it also narrows the arteries, which in turn leads to an increase in blood pressure. This activity is ensured by chemical bonds that are formed when the hormone interacts with a special receptor. Also among the functions related to the cardiovascular system, one can highlight aggregation platelets, regulation of adhesion and prothrombotic effect. This hormone is responsible for those occurring in our body. It causes an increase in secretion in neurosecretory cells in such a part of the brain as hypothalamus, as well as the secretion of adrenocorticotropic hormone in pituitary gland. This leads to the rapid release of norepinephrine. Hormone aldosterone , secreted by the adrenal glands, is released into the blood precisely thanks to angiotensin. Plays an important role in maintaining electrolyte and water balance, renal hemodynamics. Sodium retention by this substance is ensured due to its ability to act on the proximal tubules. In general, it is able to catalyze the glomerular filtration reaction by increasing renal pressure and constricting renal efferent arterioles.

To determine the level of this hormone in the blood, a routine blood test is taken, like for any other hormones. Its excess may indicate increased concentration estrogen , be observed when using oral contraceptive pills and during, after binephrectomy, Itsenko-Cushing's disease may be a symptom of the disease. A reduced level of angiotensin is observed with glucocorticoid deficiency, for example, with liver diseases and Addison's disease.

Breaks down another protein in the blood angiotensinogen (ATG) with the formation of protein angiotensin 1 (AT1), consisting of 10 amino acids (decapeptide).

Another blood enzyme APF(Angiotensin converting enzyme, Angiotensin converting enzyme (ACE), Lung converting factor E) cleaves the two tail amino acids from AT1 to form an 8 amino acid protein (octapeptide) called angiotensin 2 (AT2). Other enzymes, such as chymases, cathepsin G, tonin and other serine proteases, also have the ability to form angiotensin 2 from AT1, but to a lesser extent. The pineal gland of the brain contains a large amount of chymase, which converts AT1 into AT2. Angiotensin 2 is mainly formed from angiotensin 1 under the influence of ACE. The formation of AT2 from AT1 by chymases, cathepsin G, tonin and other serine proteases is called the alternative pathway for AT2 formation. ACE is present in the blood and in all tissues of the body, but ACE is most synthesized in the lungs. ACE is a kininase, so it breaks down kinins, which have a vasodilating effect in the body.

Angiotensin 2 exerts its effect on the body's cells through proteins on the surface of cells called angiotensin receptors (AT receptors). AT receptors come in different types: AT1 receptors, AT2 receptors, AT3 receptors, AT4 receptors and others. AT2 has the greatest affinity for AT1 receptors. Therefore, first of all, AT2 interacts with AT1 receptors. As a result of this connection, processes occur that lead to an increase in blood pressure (BP). If the level of AT2 is high, and there are no free AT1 receptors (not associated with AT2), then AT2 binds to AT2 receptors, for which it has less affinity. The connection of AT2 with AT2 receptors triggers opposite processes that lead to a decrease in blood pressure.

Angiotensin 2 (AT2) connecting to AT1 receptors:

  1. has a very strong and long-lasting vasoconstrictor effect on blood vessels (up to several hours), thereby increasing vascular resistance, and, therefore, blood pressure (BP). As a result of the connection of AT2 with AT1 receptors of blood vessel cells, chemical processes are triggered, as a result of which the smooth muscle cells of the middle layer contract, the vessels narrow (vasospasm occurs), the internal diameter of the vessel (the lumen of the vessel) decreases, and the resistance of the vessel increases. At a dose of only 0.001 mg, AT2 can increase blood pressure by more than 50 mmHg.
  2. initiates the retention of sodium and water in the body, which increases the volume of circulating blood, and, therefore, blood pressure. Angiotensin 2 acts on cells of the zona glomerulosa of the adrenal gland. As a result of this action, the cells of the zona glomerulosa of the adrenal glands begin to synthesize and release the hormone aldosterone (mineralocorticoid) into the blood. AT2 promotes the formation of aldosterone from corticosterone through its action on aldosterone synthetase. Aldosterone enhances the reabsorption (absorption) of sodium, and therefore water, from the renal tubules into the blood. This results:
    • to water retention in the body, and, therefore, to an increase in the volume of circulating blood and to the resulting increase in blood pressure;
    • Sodium retention in the body causes sodium to leak into the endothelial cells that line the inside of blood vessels. An increase in sodium concentration in a cell leads to an increase in the amount of water in the cell. Endothelial cells increase in volume (swell, “swell”). This leads to a narrowing of the lumen of the vessel. Reducing the lumen of the vessel increases its resistance. An increase in vascular resistance increases the strength of heart contractions. In addition, sodium retention increases the sensitivity of AT1 receptors to AT2. This accelerates and enhances the vasoconstrictor effect of AT2. All this leads to an increase in blood pressure
  3. stimulates the cells of the hypothalamus to synthesize and release into the blood the antidiuretic hormone vasopressin and the cells of the adenohypophysis (anterior pituitary gland) of adrenocorticotropic hormone (ACTH). Vasopressin has:
    1. vasoconstrictor effect;
    2. retains water in the body, enhancing, as a result of the expansion of intercellular pores, the reabsorption (absorption) of water from the renal tubules into the blood. This leads to an increase in the volume of circulating blood;
    3. enhances the vasoconstrictor effect of catecholamines (adrenaline, norepinephrine) and angiotensin 2.

    ACTH stimulates the synthesis of glucocorticoids by cells of the zona fasciculata of the adrenal cortex: cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-dehydrocorticosterone. Cortisol has the greatest biological effect. Cortisol does not have a vasoconstrictor effect, but enhances the vasoconstrictor effect of the hormones adrenaline and norepinephrine, synthesized by cells of the zona fasciculata of the adrenal cortex.

  4. is a kininase, therefore it breaks down kinins, which have a vasodilating effect in the body.

With an increase in the level of angiotensin 2 in the blood, a feeling of thirst and dry mouth may appear.

With a prolonged increase in AT2 blood and tissues:

  1. smooth muscle cells of blood vessels are in a state of contraction (compression) for a long time. As a result, hypertrophy (thickening) of smooth muscle cells and excessive formation of collagen fibers develop - the walls of the vessels thicken, the internal diameter of the vessels decreases. Thus, hypertrophy of the muscular layer of blood vessels, which developed under the prolonged influence of an excessive amount of AT2 in the blood on the vessels, increases the peripheral vascular resistance, and, therefore, blood pressure;
  2. the heart is forced to contract with greater force for a long time in order to pump a larger volume of blood and overcome greater resistance from spasmodic vessels. This leads first to the development of hypertrophy of the heart muscle, to an increase in its size, to an increase in the size of the heart (larger than the left ventricle), and then there is a depletion of heart muscle cells (myocardiocytes), their dystrophy (myocardial dystrophy), ending with their death and replacement with connective tissue (cardiosclerosis ), which ultimately leads to heart failure;
  3. prolonged spasm of blood vessels in combination with hypertrophy of the muscular layer of blood vessels leads to a deterioration in the blood supply to organs and tissues. Insufficient blood supply primarily affects the kidneys, brain, vision, and heart. Insufficient blood supply to the kidneys over a long period of time leads kidney cells to a state of dystrophy (exhaustion), death and replacement with connective tissue (nephrosclerosis, kidney shrinkage), and deterioration of kidney function (renal failure). Insufficient blood supply to the brain leads to deterioration in intellectual capabilities, memory, communication skills, performance, emotional disorders, sleep disorders, headaches, dizziness, tinnitus, sensory disorders and other disorders. Insufficient blood supply to the heart leads to coronary heart disease (angina pectoris, myocardial infarction). Insufficient blood supply to the retina of the eye leads to progressive impairment of visual acuity;
  4. the sensitivity of body cells to insulin decreases (cell insulin resistance) – initiation and progression of type 2 diabetes mellitus. Insulin resistance leads to an increase in insulin in the blood (hyperinsulinemia). Prolonged hyperinsulinemia causes a persistent increase in blood pressure - arterial hypertension, as it leads to:
    • to the retention of sodium and water in the body - an increase in the volume of circulating blood, an increase in vascular resistance, an increase in the force of heart contractions - an increase in blood pressure;
    • to hypertrophy of vascular smooth muscle cells - - increased blood pressure;
    • to an increased content of calcium ions inside the cell - - increased blood pressure;
    • to an increase in tone - an increase in the volume of circulating blood, an increase in the strength of heart contractions - an increase in blood pressure;

Angiotensin 2 undergoes further enzymatic cleavage by glutamyl aminopeptidase to form Angiotensin 3, consisting of 7 amino acids. Angiotensin 3 has a weaker vasoconstrictor effect than angiotensin 2, but its ability to stimulate aldosterone synthesis is stronger. Angiotensin 3 is broken down by the enzyme arginine aminopeptidase to angiotensin 4, consisting of 6 amino acids.

The main difference between Angiotensin 1 and 2 is that Angiotensin 1 is produced from angiotensinogen by the enzyme renin, whereas Angiotensin 2 is produced from angiotensin 1 by the action of angiotensin-converting enzyme (ACE).

Angiotensin is a peptide that acts on the muscles of the arteries to narrow them, thereby increasing blood pressure. There are three types of Angiotensins: Angiotensin 1, 2 and 3. Angiotensinogen is converted to Angiotensin 1 by catalysis by the enzyme renin. Angiotensin 1 is converted to Angiotensin 2 by the action of angiotensin-converting enzyme. This is a type of Angiotensin that directly affects blood vessels, causing narrowing and increased blood pressure. Angiotensin 3, on the other hand, is a metabolite of Angiotensin 2.

  1. Overview and main differences
  2. What is Angiotensin 1
  3. What is Angiotensin 2
  4. Similarities between Angiotensin 1 and 2
  5. What is the difference between Angiotensin 1 and 2
  6. Conclusion

What is Angiotensin 1?

Angiotensin 1 is a protein formed from angiotensinogen under the action of renin. It is in an inactive form and is converted to angiotensin 2 due to the splitting action of angiotensin-converting enzyme.

Angiotensin I has no direct biological activity. But it acts as a precursor molecule for angiotensin 2.

Angiotensin 2 levels are difficult to measure. Therefore, the level of angiotensin I is measured as a measure of renin activity by blocking the breakdown of angiotensin 1 through inhibition of plasma converting enzyme and proteolysis by angiotensinase.

What is Angiotensin 2?

Angiotensin 2 is a protein formed from angiotensin 1 by the action of angiotensin-converting enzyme (ACE). Thus, angiotensin 1 is a precursor to angiotensin 2.


The main function of angiotensin 2 is to constrict blood vessels to increase blood pressure. In addition to its direct effects on blood vessels, angiotensin 2 has several functions related to the kidneys, adrenal glands, and nerves. Angiotensin 2 increases the feeling of thirst and the craving for salt. In the adrenal glands, angiotensin 2 stimulates the production of aldosterone. In the kidneys, it increases sodium retention and affects how the kidneys filter blood.

Angiotensin 2 should be maintained at proper levels in the body. Too much angiotensin 2 causes excess fluid to be retained in the body. In contrast, low levels of angiotensin 2 cause potassium retention, sodium loss, decreased fluid retention, and decreased blood pressure.

What are the similarities between Angiotensin 1 and 2?

  • Angiotensin 1 is converted to angiotensin 2. Therefore, angiotensin 1 is the precursor of angiotensin 2.
  • The conversion of angiotensin 1 to 2 can be blocked by drugs that inhibit ACE.

What is the difference between Angiotensin 1 and 2?

Angiotensin 1 is a protein that acts as a precursor molecule for Angiotensin 2, while Angiotensin 2 is a protein that directly acts on blood vessels to constrict and increase blood pressure. Thus, this is the key difference between Angiotensin 1 and 2. Moreover, another significant difference between Angiotensin 1 and 2 is that Angiotensin 1 is an inactive protein whereas Angiotensin 2 is an active molecule.

In addition, renin is an enzyme that catalyzes the production of Angiotensin 1, while angiotensin-converting enzyme is an enzyme that catalyzes the synthesis of Angiotensin 2. Functionally, Angiotensin 1 is the precursor of Angiotensin 2, while Angiotensin 2 is responsible for increasing blood pressure, content in the body of water and sodium.

Conclusion - Angiotensin 1 vs 2

Angiotensin 1 and Angiotensin 2 are two types of Angiotensin, which are proteins. Angiotensin 1 has no biological activity, n o It works as a precursor molecule for the formation of Angiotensin 2. On the other hand, Angiotensin 2 is the active form that causes blood vessels to constrict. This helps maintain blood pressure and water balance in the body.