Angiotensin 2 action. Renin angiotensin system

The main difference between Angiotensin 1 and 2 is that Angiotensin 1 is produced from angiotensinogen by the action of 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 constrict them and thereby increase blood pressure. There are three types of Angiotensins: Angiotensin 1, 2 and 3. Angiotensinogen is converted to Angiotensin 1 by catalysis of 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 the blood vessels, causing constriction and an increase in 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 by 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 by inhibition of plasma converting enzyme and proteolysis by angiotensinases.

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 the precursor of angiotensin 2.

The main function of angiotensin 2 is to constrict blood vessels to increase blood pressure. In addition to acting directly on the 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 II 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 the proper level in the body. Too much angiotensin 2 causes excess fluid retention in the body. Conversely, low angiotensin 2 levels 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 a 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 major 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 the enzyme that catalyzes the production of Angiotensin 1, while angiotensin converting enzyme is the 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 body of water and sodium.

Conclusion - Angiotensin 1 vs 2

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

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 most well-known effect is on type 1 receptors, which cause vasoconstriction, an increase in blood pressure, 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 of the hormone is the angiotensinogen protein, 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, and angiotensin II, into which this protein is subsequently converted. Angiotensinogen does this not immediately: 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.

Then it is affected by angiotensin converting enzyme (ACE), which is formed in the lungs and splits off the last two amino acids from it. The result is an eight-amino acid active octapeptide 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 vasoconstrictive 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 contributes to the feeling of thirst.

Hormone receptors

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

They affect 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 noradrenaline largely depend on them, they also take part in the release of renin.

The 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 influenced by type 1 receptors, 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 growth of smooth muscle walls of blood vessels;
• an increase in the risk of blood clots, which slow down the flow of blood 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.

So, with too active activity of the renin-angiotensin system, which regulates the pressure and volume of blood in the body, AT1 receptors have a direct and indirect effect on increasing blood pressure. They also negatively affect the cardiovascular system, causing thickening of the walls of the arteries, an increase in myocardium and other ailments.

Receptors of the second subtype are also distributed throughout the body, most of all are 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 infarction. This allowed us to suggest that AT2 are involved in cell regeneration and, unlike AT1, promote apoptosis (the death of damaged cells).

Based on this, the researchers suggested that the effects that angiotonin has through the receptors of the second subtype are directly opposite to its effects on the body through the AT1 receptors. As a result of AT2 stimulation, vasodilation occurs (expansion of the lumen of the 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 effect is little studied.

It is also almost unknown how the body reacts 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 in case of damage. Also, receptors of the fourth subspecies were found on the walls of neurons, and according to the assumptions are responsible for cognitive functions.

Developments of scientists in the medical field

As a result of many years of research into the renin-angiotensin system, many drugs have been created, the action of which is aimed at a targeted effect on certain parts of this system. Scientists paid special attention to the negative impact on the body of receptors of the first subtype, which have a great influence 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.

In the course of development, it became clear that angiotensin receptor blockers are more effective than angiotensin converting enzyme inhibitors, since they act in several directions at once and are able to seep through the blood-brain barrier.

It separates the central nervous and circulatory systems, protecting the nervous tissue from pathogens, toxins, and immune system cells in the blood, which, due to failures, identify the brain as a foreign tissue. It is also a barrier to some drugs aimed at the therapy of the nervous system (but skips nutrients and bioactive elements).

Angiotensin receptor blockers, having penetrated the barrier, slow down 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, which are located in vascular smooth muscles, decreases. This leads to an increase in the lumen of the blood vessels.

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

In this way, drugs block the development of the effects that the hormone has on the body through the receptors of the first subtype, preventing the negative effect of angiotonin on vascular tone, contributing to the regression of left ventricular hypertrophy and reducing too high blood pressure. Regular long-term intake 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 precisely at blocking the receptors of the first subtype: they act on them thousands of times stronger than on AT2. Moreover, the difference in influence for losartan exceeds a thousand times, for 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, slowing down cell growth, etc.

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

Types of drugs

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

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

With regard to 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 (metabolites), the presence of which is characterized by a stronger and longer effect on the body.

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

Features of taking drugs

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

Receptor antagonists are not fast-acting drugs, they act on the body smoothly, gradually, the effect lasts for 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 the meal, for effective treatment it is enough once a day.

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 for the treatment of children: how safe the drugs are for them has not yet been determined.

With caution, doctors prescribe inhibitors to people who have a low blood volume, or tests show a low amount of sodium in the blood. This usually happens with diuretic therapy, if a person is on a salt-free diet, with diarrhea. With caution, you need to use the drug for aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy.

It is undesirable to take the medicine for people who are on hemodialysis (a method of extrarenal blood purification for kidney failure). If treatment is prescribed against the background of renal disease, constant monitoring of the concentration of potassium and serum creptin is necessary. The drug is ineffective if the tests showed an increased amount of aldosterone in the blood.

Both prevention and treatment of cardiovascular diseases require a responsible and serious approach. This kind of problem is becoming more and more common among people today. Therefore, many tend to treat them somewhat lightly. Such people often either completely ignore the need to undergo treatment, or take drugs without a doctor's prescription (on the advice of friends). However, it is important to remember that the fact that a drug helped another does not guarantee that it will help you too. To form a treatment regimen, sufficient knowledge and skills are required that only specialists have. It is also possible to prescribe any drugs, only taking into account the individual characteristics of the patient's body, the severity of the disease, the features of its course and anamnesis. In addition, today there are many effective medicines that only specialists can select and prescribe. For example, this applies to sartans - a special group of drugs (they are also called angiotensin 2 receptor blockers). What are these drugs? How do angiotensin 2 receptor blockers work? Contraindications to the use of substances refer to which groups of patients? In what cases would it be appropriate to use them? What drugs are included in this group of substances? The answers to all these and some other questions will be discussed in detail in this article.

Sartans

The group of substances under consideration is also called as follows: angiotensin 2 receptor blockers. The drugs belonging to this group of drugs were produced due to a thorough study of the causes of diseases of the cardiovascular system. Today, their use in cardiology is becoming more common.

Angiotensin 2 receptor blockers: mechanism of action

Before you start using prescribed medications, it is important to understand exactly how they work. How do angiotensin 2 receptor blockers affect the human body? The drugs of this group bind to receptors, thus blocking a significant increase in blood pressure. This helps to effectively prevent hypertension. Angiotensin 2 receptor blockers are the most effective substances in this regard. Specialists pay due attention to them.

Angiotensin 2 receptor blockers: classification

There are several types of sartans that differ in their chemical structure. It is possible to choose an angiotensin II receptor blocker that is suitable for the patient. The drugs listed below are important to research and discuss the appropriateness of their use with your doctor.

So, there are four groups of sartans:

• Biphenyl derivatives of tetrazole.
• Non-biphenyl derivatives of tetrazole.
• Non-biphenyl netetrazole.
• non-cyclic compounds.

Thus, there are several types of substances into which angiotensin 2 receptor blockers are divided. The drugs (list of the main ones) are presented below:

• "Losartan".
• "Eprosartan".
• "Irbesartan".
• Telmisartan.
• "Valsartan".
• "Candesartan".

Indications for use

You can take substances of this group only as prescribed by your doctor. There are several cases in which it would be reasonable to use angiotensin II receptor blockers. The clinical aspects of the use of drugs in this group are as follows:

• Hypertension. It is this disease that is considered the main indication for the use of sartans. This is due to the fact that angiotensin 2 receptor blockers do not have a negative effect on metabolism, do not provoke erectile dysfunction, and do not impair bronchial patency. The effect of the drug begins two to four weeks after the start of treatment.
• Heart failure. Angiotensin 2 receptor blockers inhibit the action of the renin-angiotensin-aldosterone system, whose activity provokes the development of the disease.
• Nephropathy. Due to diabetes mellitus and arterial hypertension, serious disorders in the functioning of the kidneys occur. Angiotensin II receptor blockers protect these internal organs and prevent too much protein from being excreted in the urine.

"Losartan"

An effective substance that is part of the sartans group. "Losartan" is an angiotensin 2 receptor blocker antagonist. Its difference from other drugs is a significant increase in exercise tolerance in people suffering from heart failure. The effect of the substance becomes maximum after six hours from the moment of taking the medicine. The desired effect is achieved after three to six weeks of using the drug.

The main indications for the use of the drug in question are as follows:

• heart failure;
• arterial hypertension;
• reducing the risk of stroke in those patients who have prerequisites for this.

It is forbidden to use "Losartan" during the period of bearing a child and during breastfeeding, as well as in case of individual sensitivity to individual components of the drug.

Angiotensin 2 receptor blockers, to which the drug in question belongs, can cause certain side effects, such as dizziness, insomnia, sleep disturbance, taste, vision, tremor, depression, memory disorder, pharyngitis, cough, bronchitis, rhinitis, nausea, gastritis, toothache, diarrhea, anorexia, vomiting, cramps, arthritis, pain in the shoulder, back, legs, palpitations, anemia, impaired renal function, impotence, decreased libido, erythema, alopecia, rash, pruritus, edema, fever, gout, hyperkalemia .

The drug should be taken once a day, regardless of food intake, in doses prescribed by the attending physician.

"Valsartan"

This drug effectively reduces myocardial hypertrophy, which occurs due to the development of arterial hypertension. There is no withdrawal syndrome after stopping the use of the drug, although it is caused by some angiotensin 2 receptor blockers (the description of the sartans group helps to find out which drugs this property belongs to).

The main indications for taking the substance in question are the following conditions: myocardial infarction, primary or secondary hypertension, congestive heart failure.

Tablets are taken orally. They should be swallowed without chewing. The dose of the drug is prescribed by the attending physician. But the maximum amount of a substance that can be taken during the day is six hundred and forty milligrams.

Sometimes angiotensin 2 receptor blockers can also have a negative effect on the body. Side effects that Valsartan can cause: decreased libido, itching, dizziness, neutropenia, loss of consciousness, sinusitis, insomnia, myalgia, diarrhea, anemia, cough, back pain , vertigo, nausea, vasculitis, edema, rhinitis. If any of the above reactions occur, you should immediately contact a specialist.

"Candesartan"

The drug in question is made in the form of tablets for oral administration. It should be taken once or twice a day at the same time regardless of the meal. You should carefully follow the recommendations of experts. It is important not to stop taking the drug even when you feel better. Otherwise, it may neutralize the effectiveness of the drug.

When using it, you should be careful for those patients who suffer from diabetes, kidney failure or are carrying a child. All these conditions must be reported to specialists.

"Telmisartan"

The drug in question is absorbed from the gastrointestinal tract in a fairly short time. It can be taken with or without food. The main indication for use is arterial hypertension. The half-life of the drug is more than twenty hours. The drug is excreted through the intestine almost unchanged.

It is forbidden to take the drug in question during pregnancy or breastfeeding.

The drug can cause the following side effects: insomnia, dizziness, nausea, diarrhea, depression, abdominal pain, pharyngitis, rash, cough, myalgia, urinary tract infections, low blood pressure, chest pain, palpitations, anemia.

"Eprosartan"

The drug in question should be taken once a day. The recommended amount of the drug for a single use is six hundred milligrams. The maximum effect is achieved after two to three weeks of use. "Eprosartan" can be both part of complex therapy and the main component of monotherapy.

In no case should the drug in question be used during lactation or pregnancy.

What adverse reactions can occur when using "Eprosartan"? Among them are the following: weakness, diarrhea, dizziness, headache, rhinitis, cough, shortness of breath, swelling, chest pain.

"Irbesartan"

The drug in question is taken orally. It is absorbed from the gastrointestinal tract in a short time. The maximum concentration of the substance in the blood occurs after one and a half to two hours. Eating does not affect the effectiveness of the drug.

If the patient is prescribed hemodialysis, this does not affect the mechanism of action of Irbesartan. This substance is not excreted from the human body by hemodialysis. Similarly, the drug can be safely taken by patients suffering from mild to moderate cirrhosis of the liver.

The drug should be swallowed without chewing. Its use does not need to be combined with food intake. The optimal initial dosage is one hundred and fifty milligrams per day. Elderly patients are advised to start treatment with seventy milligrams. During treatment, your doctor may decide to change the dosage (for example, to increase it, provided there is insufficient therapeutic effect on the body). In this case, the patient may be prescribed a dose of three hundred milligrams of the drug or, in principle, replace the main drug. For example, for the treatment of those suffering from type 2 diabetes mellitus and arterial hypertension, the dosage should be gradually changed from one hundred and fifty milligrams per day to three hundred milligrams (this is the amount of the drug that is most effective for combating nephropathy).

There are certain features of the use of the drug in question. So, patients suffering from a violation of water and electrolyte balance, before starting treatment, it is necessary to eliminate some of its manifestations (hyponatremia).

If a person has impaired kidney function, then his treatment regimen may be the same as if there were no such problem. The same applies to mild to moderate hepatic dysfunction. At the same time, with simultaneous hemodialysis, the initial amount of the drug should be halved compared to the usual amount and be seventy-five milligrams per day.

"Irbesartan" is strictly contraindicated for use by women who are carrying a child, as it directly affects the development of the fetus. If pregnancy occurs at the time of therapy, the latter should be immediately canceled. It is recommended to switch to the use of alternative drugs even before the start of pregnancy planning. The drug in question is forbidden to be used during breastfeeding, since there is no information as to whether this substance penetrates into breast milk.

Summing up

Maintaining one's health is the personal responsibility of each person. And the older you get, the more effort you have to put in. However, the pharmaceutical industry provides invaluable assistance in this, constantly working to create better and more effective drugs. Including actively used in the fight against cardiovascular diseases and the angiotensin 2 receptor blockers discussed in this article. The drugs, the list of which was given and discussed in detail in this article, should be used and applied as prescribed by the attending physician, who is well acquainted with the current the state of health of the patient, and only under his constant control. Among such drugs, Losartan, Eprosartan, Irbesartan, Telmisartan, Valsartan and Candesartan are distinguished. The drugs in question are prescribed only in the following cases: in the presence of hypertension, nephropathy and heart failure.

If you want to start self-medication, it is important to remember the danger that is associated with this. Firstly, when using the drugs in question, it is important to strictly observe the dosage and from time to time adjust it depending on the current condition of the patient. Only a professional can carry out all these procedures in the right way. Since only the attending physician can, on the basis of the examination and the results of the tests, prescribe the appropriate dosages and accurately formulate a treatment regimen. After all, therapy will be effective only if the patient adheres to the recommendations of the doctor.

On the other hand, it is important to do everything possible to improve your own physical condition by following the rules of a healthy lifestyle. Such patients need to correctly adjust the sleep and wakefulness regimen, maintain and adjust their eating habits (after all, poor-quality nutrition that does not provide the body with a sufficient amount of essential nutrients will not make it possible to recover in a normal rhythm).

Choose quality medicines. Take care of yourself and your loved ones. Be healthy!

It remains to investigate the effect of only two chemicals in the blood, which can be suspected of being able to play the role of humoral sources of hypertension. These are angiotensin II and vasopressin.

In recent years, angiotensin II, without the necessary justification, has been made a kind of scarecrow. It is believed that this substance directly leads to the onset of hypertension. Scientists do not take into account that vasoconstriction does not determine the development of hypertension. Such an erroneous view leads experts to even neglect the fact that anti-giotensin drugs have the most harmful side effects.

“Angiotensin is endowed with physiological properties. The most pronounced of them are cardiostimulating and vasoconstrictor actions, exceeding the effect of noradrenaline by more than 50 times” (A.D. Nozdrachev).

This is an important warning. It is necessary to be extremely careful about any changes in the concentration of angiotensin II in the blood. Of course, this does not mean that with the appearance of negligible amounts of excess angiotensin II in the blood, blood pressure will rise to 500 mm Hg. Art., and heart rate - up to 350 contractions per minute.

We find very important information about angiotensin II in the book by M. D. Mashkovsky "Medicines". The author reports that angiotensin II constricts blood vessels, especially precapillary arterioles, and causes a strong and rapid increase in blood pressure (by the strength of the pressor action, angiotensin II is about 40 times more active than norepinephrine).

“Under the influence of angiotensin II, the vessels of the skin and the area innervated by the celiac nerve narrow especially strongly. Blood circulation in skeletal muscles and coronary vessels does not change significantly. The drug does not have a direct effect on the heart and does not cause arrhythmias in therapeutic doses.

"The drug does not have a direct effect on the heart." This makes it possible to deny the cardiostimulatory effect of angiotensin II on the systolic output of the heart, and, consequently, on the pulse pressure.

Above, in Chapter 10, A. D. Nozdrachev's words were quoted that angiotensin II does not cause the release of blood from the depot, and this is explained by the presence of angiotensin-sensitive receptors only in precapillary arterioles. However, there is no pulse pressure of blood in the arterioles, there is only a minimum arterial pressure. This finally excludes the effect of angiotensin II on pulse arterial pressure and systolic output of the heart, that is, on the development of hypertension..

We will consider possible cases of maintaining pulse pressure in arterioles separately.

The reference to the vasoconstrictor (vasoconstrictor) effect of angiotensin II is certainly true.

A. D. Nozdrachev:

“The strongest vasoconstrictive effect of angiotensin is manifested in the internal organs and skin, and the vessels of the skeletal muscles, brain, and heart are less sensitive; they almost do not react to the vessels of the lungs.

Yes, the chemical vasoconstrictor action of angiotensin is impressive (50 times stronger than norepinephrine!). However, this does not give any reason to declare angiotensin II to be the culprit in the development of hypertension. An increase in the concentration of angiotensin II in the blood only affects the value of the minimum blood pressure, and, as will be shown below, in the direction of its decrease!

The possibility of the influence of angiotensin II on the development of hypertension seems to be excluded. It would be possible to stop at this, if not for the question: how does antiangiotensin drugs briefly reduce blood pressure in hypertensive patients?

To answer this question, it is necessary to touch upon a whole layer of phenomena that have not found an explanation in medicine.

The pronounced effect of angiotensin II on the cardiovascular system cannot be a direct vasoconstriction, it manifests itself by affecting the kidneys!

A. D. Nozdrachev:

“Its (angiotensin P. - M. Zh.) effect on the kidneys is especially pronounced, which is expressed in a decrease in renal hemodynamics, a violation of glomerular filtration and an indirect effect of aldosterone as a regulator of tubular filtration and water-electrolyte balance. Pronounced ganglion-stimulating effects were noted.

... Angiotensin II affects vascular tone, the rate of Na reabsorption by tubular cells, it is an important physiological stimulator of aldosterone secretion by cells of the adrenal cortex. Angiotensin II is very rapidly inactivated in the blood by angiotensinases.

I emphasize that angiotensin II, unlike adrenaline, does not cause the release of blood from the depot. But its main feature, the meaning of existence is a decrease in blood flow in the kidneys!

Angiotensin II becomes an extremely active octopeptide only after two transformations of the completely harmless serum angiotensinogen beta-globulin. The first of these conversions requires the renal proteolytic enzyme renin, which converts angiotensinogen to inactive angiotensin I. Another enzyme, peptidase, converts angiotensin I to angiotensin II.

So, for the production of angiotensin II, renal renin is required. This gave grounds to talk about the renin-angiotensin system. The renal enzyme renin plays a very important role in it.

“Many different factors have been described that affect the rate of renin secretion. One of the stimuli is an increase in the concentration of NaCl in the distal tubule.

Another important stimulus is the stimulation of stretch receptors localized in the wall of the afferent (bringing. - M. Zh.) arteriole. A decrease in its blood supply activates the release of renin. The homeostatic significance of both reactions is obvious - the decrease in glomerular filtration caused by renin secretion will lead to the preservation of circulating volume and prevent the loss of excess sodium salts by the kidney ”(A.D. Nozdrachev).

What is the mechanism of action of angiotensin II on vascular tone and minimal blood pressure in hypertension?

Any increase in blood pressure inevitably automatically causes an increase in blood supply to the afferent (bringing) arterioles of the kidneys, as a result, the secretion of renin by the kidneys decreases. This causes a decrease in the concentration of angiotensin in the blood. The reninangiotensin system in this case lowers the minimum blood pressure!

To increase the concentration of angiotensin II in the blood, a preliminary increase in the secretion of renin by the kidneys is necessary. This is possible only with a decrease in blood pressure in the arterioles. At the same time, an increase in the concentration of angiotensin II will reduce glomerular filtration in the kidneys and preserve the circulating blood volume, which will lead to the restoration of blood pressure in the arterioles of the kidneys and reduce the concentration of renin, and then angiotensin in the blood.

Thus, The reninangiotensin system is designed to control the excretory function of the kidneys, ensure their ability to rid the body of excess water and sodium and, at the same time, maintain the necessary amount of these vital substances in the body. The activity of the reninangiotensin system is not aimed at increasing blood pressure.

According to the pressor effect on blood vessels under experimental conditions, angiotensin II is 50 times greater than the main regulator of vascular tone - norepinephrine. Such a powerful "club", which tones the blood vessels, could do a lot of trouble in a living organism. But evolution protected man: on the way of converting angiotensinogen to angiotensin II, nature put a double barrier in the form of renin and peptidase enzymes. The concentration of angiotensin II in the blood is especially carefully controlled by a rigid negative feedback of the concentration of renin with blood pressure.

So, the renin-angiotensin system does not even affect the minimum blood pressure, not to mention the pulse difference. Nevertheless, this system is almost always involved in the development of hypertension!

Researchers have not yet found a correct explanation for this phenomenon. The most paradoxical fact is the increased concentration of renin and angiotensin II in almost all hypertensive patients. It would seem that elevated blood pressure should lead to a decrease in the concentration of angiotensin and renin II in the blood. We will consider this completely puzzling problem in a separate chapter.

One hundred percent misunderstanding of the essence of the processes, of course, is accompanied by erroneous and primitive actions. Antiangiotensin drugs have been developed. These drugs reduce the level of angiotensin II in the blood, that is, they cause additional pathology without affecting the cause of hypertension. Artificially increases the hemodynamics of the kidneys and increases the excretion of urine.

The harm is such that surgery is often required to restore kidney function.

It must be remembered that the action anti-angiotensin drugs (saralazine, captopril, capoten, tetrotide and the like) similar to the action of the worst diuretics.

It is known that diuretics reduce pulse pressure for a short time. But what is the mechanism of this action? And this question turned out to be a mystery for modern medicine. Later we will return to it, but for now we can say that the use of diuretics has nothing to do with the cure of hypertension. If a jug of wine is heavy, no one punches holes in it. The use of diuretics for hypertension is tantamount to punching holes in a jug. In the time of Catherine II, blood was opened, now diuretics are used or, due to monstrous incompetence, leeches are used.

It remains to consider the hypertensive role of vasopressin. An increased amount of this hormone in the blood enhances the reabsorption of water from urine that has entered the collecting ducts of the kidneys. The volume of urine decreases, the concentration of salts in the urine increases. At the same time, salts are excreted with a relatively small amount of urine, the body gets rid of salts, while maintaining the required amount of water. With the intake of excess water, the secretion of vasopressin (antidiuretic hormone) decreases, diuresis increases and the body is freed from excess water.

For more information about vasopressin, we turn to authoritative sources.

"Clinical Endocrinology" (edited by N. T. Starkova, 1991):

“Vasopressin and oxytocin accumulate in the posterior pituitary gland. The hormones under consideration exhibit a variety of biological effects: they stimulate the transport of water and salts through membranes, have a vasopressor effect, increase contractions of the smooth muscles of the uterus during childbirth, and increase the secretion of the mammary glands.

It should be noted that vasopressin has a higher antidiuretic activity than oxytocin, and the latter has a stronger effect on the uterus and mammary gland. The main regulator of vasopressin secretion is water intake.

"Biological Chemistry" (M. V. Ermolaev, 1989):

“The regulation of water-salt metabolism is carried out under the control of the nervous system and other factors, including hormones. Thus, vasopressin (hormone of the posterior pituitary gland) has an antidiuretic effect, that is, it promotes the reabsorption of water in the kidneys. Therefore, in the clinic it is often called antidiuretic hormone (ADH).

The secretion of vasopressin is controlled by the magnitude of osmotic pressure, the increase of which enhances the production of the hormone. As a result, water reabsorption in the kidneys increases, the concentration of osmotically active substances in the blood decreases, and blood pressure normalizes. In this case, a small amount of highly concentrated urine is excreted.

“Antidiuretic hormone (vasopressin) and oxytocin are synthesized in the nuclei of the hypothalamus, enter the posterior pituitary via nerve fibers and are deposited here. Deficiency of antidiuretic hormone or hypofunction of the posterior lobe leads to the so-called diabetes insipidus. At the same time, there is a release of very large quantities of urine that does not contain sugar, and intense thirst. The introduction of the hormone to patients normalizes urine output. The mechanism of action of antidiuretic hormone is to increase the reabsorption of water by the walls of the collecting ducts of the kidneys. Oxytocin stimulates uterine smooth muscle contraction at the end of pregnancy.”

"Bioorganic Chemistry" (N. Tyukavkina, Yu. Baukov, 1991):

“In 1933, V. Du Vignot established the structure of two hormones - oxytocin and vasopressin, secreted by the posterior pituitary gland. Oxytocin is found in females. Vasopressin is found in both female and male organisms. It regulates mineral metabolism and fluid balance (antidiuretic hormone). It has been established that vasopressin is one of the most powerful memory stimulants.

So, the main regulator of vasopressin secretion is water intake. In this case, vasopressin acts in the body in the same direction as angiotensin II. The combined action of angiotensin II and vasopressin is sometimes considered as the influence of the pressor macrosystem, which supposedly can participate in the development of hypertension. Such a macrosystem is not directly related to an increase in pulse blood pressure and the development of hypertension. It is regrettable that this error occurs in the work of Academician I. K. Shkhvatsabay (“Hypertension Markers”, 1982). Another misconception: he believes that antidiuretic hormone and vasopressin are two different hormones. We read in his article:

“The excretory function of the kidneys, their ability to rid the body of water and sodium, depends on the renin-angiotensin system. The vasopressor system, through the antidiuretic hormone, slows down the excretion of water, sodium and vasopressin by the kidneys, which stimulates the reduction of the lumen of peripheral vessels. The activity of all these and some other links of neurohormonal regulation, which together make up the so-called pressor macrosystem, is aimed at increasing blood pressure.

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 ACE(Angiotensin Converting Enzyme, Angiotensin Convertin Enzyme (ACE), Lung Converting Factor E) cleaves two tail amino acids from AT1 to form an 8 amino acid protein (octapeptide) called angiotensin 2 (AT2). The ability to form angiotensin 2 from AT1 is also possessed by other enzymes - chymases, cathepsin G, tonin and other serine proteases, but to a lesser extent. The epiphysis of the brain contains a large amount of chymase, which converts AT1 to AT2. Basically, angiotensin 2 is formed from angiotensin 1 under the influence of ACE. The formation of AT2 from AT1 with the help of chymases, cathepsin G, tonin and other serine proteases is called an alternative pathway for the formation of AT2. 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, therefore it breaks down kinins, which in the body have a vasodilating effect.

Angiotensin 2 exerts its action on body cells through proteins on the cell surface called angiotensin receptors (AT receptors). There are different types of AT receptors: AT1 receptors, AT2 receptors, AT3 receptors, AT4 receptors, and others. AT2 has the highest affinity for AT1 receptors. Therefore, AT2 first binds to AT1 receptors. As a result of this compound, 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) binding to AT1 receptors:

1. It has a very strong and prolonged vasoconstrictive effect on the 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 membrane contract, the vessels constrict (vasospasm occurs), the inner diameter of the vessel (vessel lumen) decreases, and the resistance of the vessel increases. At a dose as low as 0.001 mg, AT2 can increase blood pressure by more than 50 mm Hg.
2. initiates the retention of sodium and water in the body, which increases the volume of circulating blood, and, hence, blood pressure. Angiotensin 2 acts on the cells of the adrenal glomerulus. As a result of this action, the cells of the glomerular zone of the adrenal glands begin to synthesize and secrete 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 in:
   • 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;
   • the delay in the body of sodium leads to the fact that sodium penetrates into the endothelial cells that cover the blood vessels from the inside. An increase in the concentration of sodium in the cell leads to an increase in the amount of water in the cell. Endothelial cells increase in volume (swell, “swell”). This leads to narrowing of the lumen of the vessel. Reducing the lumen of the vessel increases its resistance. An increase in vascular resistance increases the force of heart contractions. In addition, sodium retention increases the sensitivity of AT1 receptors to AT2. This accelerates and enhances the vasoconstrictor action of AT2. All of 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) adrenocorticotropic hormone (ACTH). Vasopressin provides:
   1. vasoconstrictor action;
   2. retains water in the body, increasing the reabsorption (absorption) of water from the renal tubules into the blood as a result of the expansion of intercellular pores. This leads to an increase in the volume of circulating blood;
   3. enhances the vasoconstrictive effect of catecholamines (adrenaline, norepinephrine) and angiotensin II.

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

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

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

With a prolonged increase in the blood and tissues of AT2:

1. smooth muscle cells of blood vessels for a long time are in a state of contraction (compression). As a result, hypertrophy (thickening) of smooth muscle cells and excessive formation of collagen fibers develop - the walls of the vessels thicken, the inner diameter of the vessels decreases. Thus, hypertrophy of the muscular layer of blood vessels, which has developed under the prolonged influence of an excessive amount of AT2 in the blood on the vessels, increases the peripheral resistance of the vessels, 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 the greater resistance of 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 in their death and replacement with connective tissue (cardiosclerosis). ), which eventually 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. From insufficient blood supply, the kidneys, brain, eyesight, and heart suffer first of all. Insufficient blood supply to the kidneys for a long time leads the kidney cells to a state of dystrophy (exhaustion), death and replacement with connective tissue (nephrosclerosis, wrinkling of the kidney), deterioration of kidney function (renal failure). Insufficient blood supply to the brain leads to a 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 - to coronary heart disease (angina pectoris, myocardial infarction). Insufficient blood supply to the retina of the eye - to a progressive impairment of visual acuity;
4. the sensitivity of body cells to insulin decreases (insulin resistance of cells) - the initiation of the onset 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 strength 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 - - an increase in 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, which consists of 7 amino acids. Angiotensin 3 has a weaker vasoconstrictive effect than angiotensin 2, and the ability to stimulate aldosterone synthesis is stronger. Angiotensin 3 is broken down by the enzyme arginine aminopeptidase to angiotensin 4, which consists of 6 amino acids.