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, which is easily subjected to further transformations. Under the action of angiotensin-converting enzyme (ACE), which is formed in the lungs, angiotensin I is converted into an octapeptide - angiotensin II, which is a highly active endogenous pressor compound. nine0267

Angiotensin II is the main effector peptide of the RAAS. It has a strong vasoconstrictor effect, increases OPSS, 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 reabsorption of sodium and water, hypervolemia) and causes sympathetic activation. All these effects contribute to the development of hypertension.

Angiotensin II is rapidly metabolized (half-life - 12 min) 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, has a positive inotropic activity. Angiotensin IV is thought to be involved in the regulation of hemostasis. nine0267

It is known that in addition to the RAAS of the systemic circulation, 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 such pathological processes 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 of 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 a high specificity for angiotensin I. In various organs and tissues, either ACE-dependent or alternative pathways for the formation of angiotensin II predominate. Thus, cardiac serine protease, its DNA and mRNA were found in human myocardial tissue. The largest amount of this enzyme is found in the myocardium of the left ventricle, where the chymase pathway accounts for more than 80%. Chymase-dependent formation of angiotensin II prevails in the myocardial interstitium, adventitia, and vascular media, while ACE-dependent formation occurs in blood plasma. nine0267

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

The physiological effects of angiotensin II, like other biologically active angiotensins, are realized at the cellular level through specific angiotensin receptors. nine0267

To date, the existence of several subtypes of angiotensin receptors has been established: AT ₁ , AT ₂ , AT ₃ and AT ₄ and others. - angiotensin II receptor protein - 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. nine0267

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

- arterial vasoconstriction, incl. vasoconstriction of arterioles of the renal glomeruli (especially 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 heart remodeling processes.

In arterial hypertension against the background of excessive activation of the RAAS, the effects of angiotensin II directly or indirectly mediated by the AT ₁ receptors contribute to an increase in blood pressure. In addition, stimulation of these receptors is accompanied by a 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, have been 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, in particular in mice in which the gene encoding AT ₂ receptors was destroyed, suggest their participation in the processes of growth and maturation, including cell proliferation and differentiation, development of embryonic tissues, and the formation of exploratory behavior. nine0267

AT ₂ - receptors are found in the heart, blood vessels, adrenal glands, kidneys, some areas of the brain, reproductive organs, incl. in the uterus, atrezirovannyh ovarian follicles, as well as 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 suggested that these receptors may be involved in the processes of tissue regeneration and programmed cell death (apoptosis). nine0267

Recent studies show that the cardiovascular effects of angiotensin II, mediated by AT ₂ receptors, are opposite to those caused by excitation 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. nine0267

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

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

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

AT 9 subtypes isolated from rat mesangium cell culture0269 1 receptors - AT _1a and AT _1b , differing in affinity for angiotensin II peptide agonists (these subtypes were not found in humans). AT _1c , a subtype of receptors, whose physiological role is not yet clear, has been isolated from rat placenta.

AT ₃ - receptors with affinity for angiotensin II, found on the membranes of neurons, their function is unknown. AT ₄ receptors are found on endothelial cells. Interacting with these receptors, angiotensin IV stimulates the release of a type 1 plasminogen activator inhibitor 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. The affinity for AT ₄ receptors has, in addition to angiotensin IV, also angiotensin III.

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, influencing 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 medicinal funds purposefully acting on individual parts of the RAAS. nine0267

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 that can block its formation or action and thus reduce the activity of the RAAS are inhibitors of the formation of angiotensinogen, 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 action of angiotensin II and lowered the tone of peripheral vessels, reduced the content of aldosterone in plasma, lowered blood pressure. However, by the mid-1970s, the experience of using saralazine showed that it has the properties of a partial agonist and in some cases gives an unpredictable effect (in the form of excessive hypotension or hypertension). At the same time, a good hypotensive effect was manifested in conditions associated with a high level of renin, while against the background of a low level of angiotensin II or with a rapid injection of blood pressure increased. Due to the presence of agonistic properties, as well as due to the complexity of the synthesis and the need for parenteral administration, saralazine has not received wide practical application. nine0267

In the early 1990s, the first non-peptide selective AT ₁ receptor antagonist, effective when taken orally, losartan was synthesized, which received practical application as an antihypertensive agent.

Currently, several synthetic non-peptide selective AT ₁ -blockers - valsartan, irbesartan, candesartan, losartan, telmisartan, eprosartan, olmesartan medoxomil, azilsartan medoxomil, zolarsartan, tazosartan (zolarsartan and tazosartan not yet registered in Russia). nine0267

There are several classifications of angiotensin II receptor antagonists: by chemical structure, pharmacokinetic features, mechanism of binding to receptors, etc. : losartan, irbesartan, candesartan, valsartan, tazosartan;

- biphenyl netetrazole compounds - telmisartan;

- non-biphenyl netetrazole compounds - eprosartan. nine0267

According to 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 and azilsartan medoxomil are prodrugs.

In addition, AT ₁ -blockers differ depending on the presence or absence of active metabolites. Active metabolites are found in losartan and tazosartan. For example, the active metabolite of losartan, EXP-3174, has a stronger and longer-lasting effect than losartan (in terms of pharmacological activity, EXP-3174 exceeds losartan by 10-40 times). nine0267

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 BCC, 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 to receptors irreversibly. nine0267

The pharmacological action of this group of drugs 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 AT9 antagonists.0269 1 -receptors. It has been shown that their affinity for AT ₁ exceeds that for AT ₂ receptors thousands of times: for losartan and eprosartan more than 1 thousand times, for telmisartan - more than 3 thousand, for irbesartan - 8.5 thousand. , the active metabolite of losartan EXP-3174 and candesartan - 10 thousand times, olmesartan - 12.5 thousand times, 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 effect of angiotensin II on vascular tone and is accompanied by a decrease in elevated blood pressure. Long-term use of these drugs leads to a weakening of the proliferative effects of angiotensin II in relation to vascular smooth muscle cells, mesangial cells, fibroblasts, a decrease in cardiomyocyte hypertrophy, etc.

It is known that AT ₁ receptors of cells of the juxtaglomerular apparatus of the kidneys are involved in the regulation of renin release (by 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.

nine0269 2 -receptors and expressed in vasodilation, slowing down of proliferative processes, etc.

In addition, against the background of an increased level 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 RAAS effector peptide that has a vasodilatory and natriuretic effect. The effects of angiotensin-(1-7) are mediated through the 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 obtained experimental data and the results of individual clinical studies are rather contradictory. Perhaps, against the background of the blockade of AT ₁ receptors, endothelium-dependent synthesis and release of nitric oxide increase, which contributes to vasodilation, a decrease in platelet aggregation and a decrease in cell proliferation. nine0267

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

Antagonists of AT ₁ receptors can penetrate the blood-brain barrier and inhibit the activity of mediator processes in the sympathetic nervous system. By blocking the presynaptic AT ₁ receptors of sympathetic neurons in the CNS, they inhibit the release of norepinephrine and reduce the stimulation of adrenoreceptors in vascular smooth muscles, which leads to vasodilation. Experimental studies show that this additional mechanism of vasodilatory 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. nine0267

All AT receptor blockers ₁ act gradually, the antihypertensive effect develops smoothly, within a few 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) treatment.

The pharmacokinetics of this group of drugs make them convenient for use by patients. These medicines can be taken with or without food. A single dose is enough to provide a good hypotensive effect during the day. They are equally effective in patients of different sex and age, including patients over 65 years of age. nine0267

Clinical studies show that all angiotensin receptor blockers have a high antihypertensive and pronounced organoprotective effect, good tolerance. 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. Possible monotherapy (for mild arterial hypertension) or in combination with other antihypertensive drugs (for moderate and severe forms). nine0267

Combination therapy is currently preferred according to WHO/ISH (International Society of Hypertension) recommendations. The most rational for angiotensin II receptor antagonists is their combination with thiazide diuretics. The addition of a low-dose diuretic (eg, 12.5 mg hydrochlorothiazide) can improve the effectiveness of therapy, as evidenced by the results of randomized multicenter trials. Preparations have been created that include this combination - Gizaar (losartan + hydrochlorothiazide), Co-diovan (valsartan + hydrochlorothiazide), Coaprovel (irbesartan + hydrochlorothiazide), Atakand Plus (candesartan + hydrochlorothiazide), Micardis Plus (telmisartan + hydrochlorothiazide), etc. . nine0267

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

The results of experimental and clinical studies indicate that ₁ -subtype AT receptor blockers not only prevent the processes of cardiovascular remodeling, but also cause the regression of left ventricular hypertrophy (LVH). In particular, it was shown that during long-term therapy with losartan, patients showed a tendency to a decrease in the size of the left ventricle in systole and diastole, an increase in myocardial contractility. LVH regression has been noted with long-term use of valsartan and eprosartan in patients with arterial hypertension. Some AT 9 receptor blockers0269 1 has been found to improve renal function, incl. with 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 ongoing.

Contraindications to the use of angiotensin AT ₁ receptor blockers are individual hypersensitivity, pregnancy, breast-feeding.

Animal data suggest that drugs that act directly on the RAAS can cause fetal harm, fetal and neonatal death. Especially dangerous is the effect on the fetus in the II and III trimesters of pregnancy, because. possible development of hypotension, hypoplasia of the skull, anuria, renal failure and death in the fetus. Direct indications for the development of such defects when taking AT 9 blockers0269 1 -receptors are absent, however, the funds of this group should not be used during pregnancy, and if pregnancy is detected during the treatment period, they must be discontinued.

There is no information on the ability of AT ₁ receptor blockers to penetrate into breast milk of women. However, in experiments on animals, it has been established that they penetrate into the milk of lactating rats (in the milk of rats, significant concentrations are found not only of the substances themselves, but also of their active metabolites). In this regard, AT 9 blockers0269 1 receptors are not used in lactating women, and if therapy is necessary for the mother, breastfeeding is stopped.

Pediatric use of these drugs should be avoided because their safety and efficacy in children have not been established.

There are a number of limitations for therapy with angiotensin receptor antagonists AT ₁ . Caution should be exercised in patients with reduced BCC and / or hyponatremia (during treatment with diuretics, limiting salt intake with diet, diarrhea, vomiting), as well as in patients on hemodialysis, tk. possible development of symptomatic hypotension. An assessment of the risk / benefit ratio is necessary in patients with renovascular hypertension due to 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. Caution should be used in aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. Against the background of impaired renal function, it is necessary to monitor the levels of potassium and serum creatinine. Not recommended for patients with primary hyperaldosteronism, tk. in this case, drugs that inhibit the RAAS are ineffective. There are no sufficient data on the use in patients with severe liver disease (eg, cirrhosis). nine0267

Side effects reported so far from angiotensin II receptor antagonists are usually mild, transient, and rarely warrant discontinuation of therapy. The overall frequency of side effects is comparable to placebo, as evidenced by the results of placebo-controlled studies.

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