New and promising drugs that block the renin-angiotensin-aldosterone system. Renin-angiotensin-aldosterone system (raas.) Different fractions of the raas and their effects

For citation: Leonova M.V. New and promising drugs that block the renin-angiotensin-aldosterone system // RMJ. Medical review. 2013. No. 17. S. 886

The role of the renin-angiotensin-aldosterone system (RAAS) in the development of arterial hypertension (AH) and other cardiovascular diseases is currently considered to be dominant. In the cardiovascular continuum, hypertension is among the risk factors, and the main pathophysiological mechanism of damage to the cardiovascular system is angiotensin II (ATII). ATII is a key component of the RAAS - an effector that implements vasoconstriction, sodium retention, activation of the sympathetic nervous system, cell proliferation and hypertrophy, development of oxidative stress and inflammation of the vascular wall.

At present, two classes of drugs that block the RAAS have already been developed and widely used clinically - ACE inhibitors and ATII receptor blockers. The pharmacological and clinical effects of these classes differ. ACE is a zinc metalloproteinase peptidase that metabolizes ATI, AT1-7, bradykinin, substance P, and many other peptides. The mechanism of action of ACE inhibitors is mainly associated with the prevention of the formation of ATII, which promotes vasodilation, natriuresis and eliminates the pro-inflammatory, proliferative and other effects of ATII. In addition, ACE inhibitors prevent the degradation of bradykinin and increase its level. Bradykinin is a powerful vasodilator, it potentiates natriuresis, and most importantly, it has cardioprotective (prevents hypertrophy, reduces ischemic damage to the myocardium, improves coronary blood supply) and vasoprotective action, improving endothelial function. At the same time, a high level of bradykinin is the cause of the development of angioedema, which is one of the serious disadvantages of ACE inhibitors, which significantly increase the level of kinins.
ACE inhibitors are not always able to completely block the formation of ATII in tissues. It has now been established that other enzymes that are not associated with ACE, primarily endopeptidases, which are not affected by ACE inhibitors, can also participate in its transformation in tissues. As a result, ACE inhibitors cannot completely eliminate the effects of ATII, which may be the reason for their lack of effectiveness.
The solution to this problem was facilitated by the discovery of ATII receptors and the first class of drugs that selectively block AT1 receptors. Through AT1 receptors, the unfavorable effects of ATII are realized: vasoconstriction, secretion of aldosterone, vasopressin, norepinephrine, fluid retention, proliferation of smooth muscle cells and cardiomyocytes, activation of the SAS, as well as the negative feedback mechanism - the formation of renin. AT2 receptors perform "beneficial" functions, such as vasodilation, repair and regeneration processes, antiproliferative action, differentiation and development of embryonic tissues. The clinical effects of ATII receptor blockers are mediated through the elimination of the "harmful" effects of ATII at the level of AT1 receptors, which provides a more complete blocking of the adverse effects of ATII and an increase in the effect of ATII on AT2 receptors, which complements the vasodilating and antiproliferative effects. ATII receptor blockers have a specific effect on the RAAS without interfering with the kinin system. The lack of influence on the activity of the kinin system, on the one hand, reduces the severity of undesirable effects (cough, angioedema), but, on the other hand, deprives ATII receptor blockers of an important anti-ischemic and vasoprotective effect, which distinguishes them from ACE inhibitors. For this reason, the indications for the use of ATII receptor blockers in the majority repeat the indications for the appointment of ACE inhibitors, making them alternative drugs.
Despite the introduction of RAAS blockers into the widespread practice of treating hypertension, problems of improving outcomes and prognosis remain. These include: the possibility of improving blood pressure control in the population, the effectiveness of the treatment of resistant hypertension, the possibility of further reducing the risk of cardiovascular disease.
The search for new ways to influence the RAAS is actively ongoing; other closely interacting systems are being studied and drugs with multiple mechanisms of action are being developed, such as ACE and neutral endopeptidase (NEP) inhibitors, endothelin-converting enzyme (EPF) and NEP inhibitors, ACE/NEP/EPF inhibitors.
Vasopeptidase inhibitors
In addition to the well-known ACE, vasopeptidases include 2 other zinc metalloproteinases - neprilysin (neutral endopeptidase, NEP) and endothelin-converting enzyme, which can also be targets for pharmacological effects.
Neprilysin is an enzyme produced by the vascular endothelium and is involved in the degradation of natriuretic peptide, as well as bradykinin.
The natriuretic peptide system is represented by three different isoforms: atrial natriuretic peptide (A-type), brain natriuretic peptide (B-type), which are synthesized in the atrium and myocardium, and endothelial C-peptide, which are endogenous RAAS inhibitors in their biological functions. and endothelin-1 (Table 1). The cardiovascular and renal effects of natriuretic peptide are to reduce blood pressure through the effect on vascular tone and water and electrolyte balance, as well as in antiproliferative and antifibrotic effects on target organs. Most recently, the natriuretic peptide system is involved in metabolic regulation of lipid oxidation, adipocyte formation and differentiation, adiponectin activation, insulin secretion, and carbohydrate tolerance, which may confer protection against the development of the metabolic syndrome.
To date, it has become known that the development of cardiovascular diseases is associated with dysregulation of the natriuretic peptide system. So, in hypertension, there is a deficiency of natriuretic peptide, leading to salt sensitivity and impaired natriuresis; in chronic heart failure (CHF), against the background of deficiency, an abnormal functioning of the hormones of the natriuretic peptide system is observed.
Therefore, NEP inhibitors can be used to potentiate the natriuretic peptide system in order to achieve additional hypotensive and protective cardiorenal effects. Inhibition of neprilysin leads to potentiation of the natriuretic, diuretic and vasodilatory effects of endogenous natriuretic peptide and, as a result, to a decrease in blood pressure. However, NEP is also involved in the degradation of other vasoactive peptides, in particular ATI, ATII, and endothelin-1. Therefore, the balance of effects on vascular tone of NEP inhibitors is variable and depends on the predominance of constrictor and dilating effects. With prolonged use, the antihypertensive effect of neprilysin inhibitors is weakly expressed due to compensatory activation of the formation of ATII and endothelin-1.
In this regard, the combination of the effects of ACE inhibitors and NEP inhibitors can significantly potentiate hemodynamic and antiproliferative effects as a result of a complementary mechanism of action, which led to the creation of drugs with a dual mechanism of action, united under the name - vasopeptidase inhibitors (Table 2, Fig. 1) .
Known inhibitors of vasopeptidases are characterized by varying degrees of selectivity for NEP/ACE: omapatrilat - 8.9:0.5; fazidoprilat - 5.1:9.8; sampatrilat - 8.0:1.2. As a result, vasopeptidase inhibitors received much greater opportunities to achieve a hypotensive effect, regardless of the activity of the RAAS and the level of sodium retention, and in organ protection (regression of hypertrophy, albuminuria, vascular stiffness). The most studied in clinical studies was omapatrilat, which showed a higher antihypertensive efficacy compared to ACE inhibitors, and in patients with CHF led to an increase in ejection fraction and improved clinical outcomes (IMPRESS, OVERTURE studies), but without advantages over ACE inhibitors.
However, in large clinical trials with the use of omapatrilat, a higher incidence of angioedema was found in comparison with ACE inhibitors. It is known that the incidence of angioedema when using ACE inhibitors is from 0.1 to 0.5% in the population, of which 20% of cases are life-threatening, which is associated with a multiple increase in the concentrations of bradykinin and its metabolites. The results of a large multicenter study OCTAVE (n=25,302), which was specifically designed to study the incidence of angioedema, showed that the incidence of this side effect during treatment with omapatrilat exceeds that in the enalapril group - 2.17% vs. 0.68% (relative risk 3.4). This was explained by the increased effect on the level of kinins during synergistic inhibition of ACE and NEP, associated with the inhibition of aminopeptidase P, which is involved in the degradation of bradykinin.
A novel dual ACE/NEP blocking vasopeptidase inhibitor, ilepatril, has a higher affinity for ACE than NEP. When studying the pharmacodynamic effects of ilepatril on the effect on the activity of the RAAS and natriuretic peptide in healthy volunteers, it was found that the drug dose-dependently (at doses of 5 and 25 mg) and significantly (more than 88%) suppresses ACE in plasma for more than 48 hours, regardless of salt sensitivity . At the same time, the drug significantly increased plasma renin activity for 48 hours and reduced the level of aldosterone. These results showed a pronounced and longer suppression of the RAAS, in contrast to the ACE inhibitor ramipril at a dose of 10 mg, which was explained by a more significant tissue effect of ilepatril on ACE and a greater affinity for ACE, and a comparable degree of blockade of the RAAS compared with the combination of irbesartan 150 mg + 10 mg ramipril. In contrast to the effect on the RAAS, the effect of ilepatril on the natriuretic peptide was manifested by a transient increase in the level of its excretion in the period 4-8 hours after a dose of 25 mg, which indicates a lower and weaker affinity for NEP and distinguishes it from omapatrilat. Moreover, in terms of the level of electrolyte excretion, the drug does not have an additional natriuretic effect compared to ramipril or irbesartan, as well as other vasopeptidase inhibitors. The maximum hypotensive effect develops 6-12 hours after taking the drug, and the decrease in mean blood pressure is 5±5 and 10±4 mm Hg. at low and high salt sensitivity, respectively. According to the pharmacokinetic characteristics, ilepatril is a prodrug with an active metabolite, which is rapidly formed with a maximum concentration in 1-1.5 hours and is slowly eliminated. Phase III clinical trials are currently underway.
An alternative route to dual suppression of RAAS and NEP is represented by a combination of blockade of ATII receptors and NEP (Fig. 2) . ATII receptor blockers do not affect the metabolism of kinins, unlike ACE inhibitors, therefore they potentially have a lower risk of developing angioedema. Currently, the first drug, an ATII receptor blocker with the effect of inhibiting NEP in a ratio of 1: 1, LCZ696, is undergoing phase III clinical trials. The combined drug molecule contains valsartan and an NEP inhibitor (AHU377) in the form of a prodrug. In a large study in patients with hypertension (n=1328), LCZ696 at doses of 200-400 mg showed an advantage in the hypotensive effect over valsartan at doses of 160-320 mg in the form of an additional decrease in blood pressure by 5/3 and 6/3 mmHg. . . The hypotensive effect of LCZ696 was accompanied by a more pronounced decrease in pulse pressure: by 2.25 and 3.32 mm Hg. at doses of 200 and 400 mg, respectively, which is currently regarded as a positive prognostic factor for the effect on vascular wall stiffness and cardiovascular outcomes. At the same time, the study of neurohumoral biomarkers during treatment with LCZ696 showed an increase in the level of natriuretic peptide with a comparable degree of increase in the level of renin and aldosterone in comparison with valsartan. Tolerability in patients with hypertension was good, and no cases of angioedema were noted. The PARAMOUMT trial has now been completed in 685 patients with CHF and unimpaired EF. The results of the study showed that LCZ696 reduces the level of NT-proBNP faster and more pronounced (the primary endpoint is a marker of increased natriuretic peptide activity and poor prognosis in CHF) compared to valsartan, and also reduces the size of the left atrium, which indicates a regression of its remodeling . A study in patients with CHF and reduced EF is ongoing (the PARADIGM-HF study).
Endothelin system inhibitors
The endothelin system plays an important role in the regulation of vascular tone and regional blood flow. Among the three known isoforms, endothelin-1 is the most active. In addition to the known vasoconstrictor effects, endothelin stimulates the proliferation and synthesis of the intercellular matrix, and also, due to a direct effect on the tone of the renal vessels, is involved in the regulation of water and electrolyte homeostasis. The effects of endothelin are realized through interaction with specific A-type and B-type receptors, the functions of which are mutually opposite: vasoconstriction occurs through the A-type receptors, and vasodilation occurs through the B-type. In recent years, it has been established that B-type receptors play an important role in the clearance of endothelin-1, i.e. blockade of these receptors disrupts the receptor-dependent clearance of endothelin-1 and increases its concentration. In addition, B-type receptors are involved in the regulation of the renal effects of endothelin-1 and the maintenance of water and electrolyte homeostasis, which is important.
Currently, the role of endothelin has been proven in the development of a number of diseases, incl. AH, CHF, pulmonary hypertension, chronic kidney disease; shows a close relationship between the level of endothelin and metabolic syndrome, endothelial dysfunction and atherogenesis. Since the 1990s a search is underway for endothelin receptor antagonists suitable for clinical use; 10 drugs are already known (“sentans”) with varying degrees of selectivity for the A / B-type receptors. The first non-selective endothelin receptor antagonist - bosentan - in a clinical study in patients with hypertension showed hypotensive efficacy comparable to that of the ACE inhibitor enalapril. Further studies on the efficacy of endothelin antagonists in hypertension have shown their clinical relevance in the treatment of resistant hypertension and at high cardiovascular risk. These data were obtained in two large clinical trials DORADO (n=379) and DORADO-AC (n=849), in which darusentan was added to triple combination therapy in patients with resistant hypertension. In the DORADO study, patients with resistant hypertension were associated with chronic kidney disease and proteinuria, and as a result of the addition of darusentan, not only a significant decrease in blood pressure was observed, but also a decrease in protein excretion. The antiproteinuric effect of endothelin receptor antagonists was subsequently confirmed in a study in patients with diabetic nephropathy using avocentan. However, in the DORADO-AC study, there was no advantage in additional BP reduction over comparators and placebo, which was the reason for the termination of further studies. In addition, in 4 large studies of endothelin antagonists (bosentan, darusentan, enrasentan) in patients with CHF, conflicting results were obtained, which was explained by an increase in the concentration of endothelin-1. Further study of endothelin receptor antagonists was suspended due to adverse effects associated with fluid retention (peripheral edema, volume overload). The development of these effects is associated with the effect of endothelin antagonists on B-type receptors, which has changed the search for drugs that affect the endothelin system through other pathways; and endothelin receptor antagonists currently have only one indication, the treatment of pulmonary hypertension.
Taking into account the high importance of the endothelin system in the regulation of vascular tone, a search is underway for another mechanism of action through vasopeptidase - EPF, which is involved in the formation of active endothelin-1 (Fig. 3) . The blocking of ACE and the combination with the inhibition of NEP can effectively suppress the formation of endothelin-1 and potentiate the effects of the natriuretic peptide. The advantages of a dual mechanism of action are, on the one hand, in preventing the disadvantages of NEP inhibitors associated with possible vasoconstriction mediated by endothelin activation, on the other hand, the natriuretic activity of NEP inhibitors makes it possible to compensate for fluid retention associated with non-selective blockade of endothelin receptors. Daglutril is a dual inhibitor of NEP and EPF, which is in phase II clinical trials. Studies have shown pronounced cardioprotective effects of the drug due to a decrease in heart and vascular remodeling, regression of hypertrophy and fibrosis.
Direct renin inhibitors
It is known that ACE inhibitors and ATII receptor blockers increase renin activity by a feedback mechanism, which is the reason for the escaping of the effectiveness of RAAS blockers. Renin represents the very first step in the RAAS cascade; it is produced by the juxtaglomerular cells of the kidneys. Renin through angiotensinogen promotes the formation of ATII, vasoconstriction and secretion of aldosterone, and also regulates feedback mechanisms. Therefore, renin inhibition makes it possible to achieve a more complete blockade of the RAAS system. The search for renin inhibitors has been going on since the 1970s; for a long time, it was not possible to obtain an oral form of renin inhibitors due to their low bioavailability in the gastrointestinal tract (less than 2%). The first direct renin inhibitor suitable for oral administration, aliskiren, was registered in 2007. Aliskiren has a low bioavailability (2.6%), a long half-life (24-40 hours), an extrarenal elimination route. The pharmacodynamics of aliskiren is associated with an 80% decrease in the level of ATII. In clinical studies in patients with hypertension, aliskiren at doses of 150-300 mg / day led to a decrease in SBP by 8.7-13 and 14.1-15.8 mm Hg. respectively, and DBP - by 7.8-10.3 and 10.3-12.3 mm Hg. . The hypotensive effect of aliskiren was observed in different subgroups of patients, including patients with metabolic syndrome, obesity; in terms of severity, it was comparable to the effect of ACE inhibitors, ATII receptor blockers, and an additive effect was noted in combination with valsartan, hydrochlorothiazide, and amlodipine. A number of clinical studies have shown organoprotective effects of the drug: antiproteinuric effect in patients with diabetic nephropathy (AVOID study, n=599), regression of left ventricular hypertrophy in patients with hypertension (ALLAY study, n=465) . Thus, in the AVOID study, after 3 months of treatment with losartan at a dose of 100 mg/day and reaching the target level of blood pressure (<130/80 мм рт.ст.) при компенсированном уровне гликемии (гликированный гемоглобин 8%) больных рандомизировали к приему алискирена в дозах 150-300 мг/сут или плацебо. Отмечено достоверное снижение индекса альбумин/креатинин в моче (первичная конечная точка) на 11% через 3 мес. и на 20% - через 6 мес. в сравнении с группой плацебо. В ночное время экскреция альбумина на фоне приема алискирена снизилась на 18%, а доля пациентов со снижением экскреции альбумина на 50% и более была вдвое большей (24,7% пациентов в группе алискирена против 12,5% в группе плацебо) . Причем нефропротективный эффект алискирена не был связан со снижением АД. Одним из объяснений выявленного нефропротективного эффекта у алискирена авторы считают полученные ранее в экспериментальных исследованиях на моделях диабета данные о способности препарата снижать количество рениновых и прорениновых рецепторов в почках, а также уменьшать профибротические процессы и апоптоз подоцитов, что обеспечивает более выраженный эффект в сравнении с эффектом ингибиторов АПФ . В исследовании ALLAY у пациентов с АГ и увеличением толщины миокарда ЛЖ (более 1,3 см по данным ЭхоКГ) применение алискирена ассоциировалось с одинаковой степенью регресса ИММЛЖ в сравнении с лозартаном и комбинацией алискирена с лозартаном: −5,7±10,6 , −5,4±10,8, −7,9±9,6 г/м2 соответственно. У части пациентов (n=136) проводилось изучение динамики нейрогормонов РААС, и было выявлено достоверное и значительное снижение уровня альдостерона и активности ренина плазмы на фоне применения алискирена или комбинации алискирена с лозартаном, тогда как на фоне применения монотерапии лозартаном эффект влияния на альдостерон отсутствовал, а на активность ренина - был противоположным, что объясняет значимость подавления альдостерона в достижении регресса ГЛЖ.
In addition, a series of clinical studies of aliskiren in the treatment of other cardiovascular diseases with an assessment of the impact on the prognosis of patients is being conducted: the ALOFT (n=320), ASTRONAUT (n=1639), ATMOSPHERE (n=7000) studies in patients with CHF, the ALTITUDE study in patients with diabetes mellitus and high cardiovascular risk, the ASPIRE study in patients with postinfarction remodeling.
Conclusion
To solve the problems of preventing cardiovascular diseases, the creation of new drugs with a complex multiple mechanism of action continues, which allows for a more complete blockade of the RAAS through a cascade of mechanisms of hemodynamic and neurohumoral regulation. The potential effects of such drugs allow not only to provide an additional antihypertensive effect, but also to achieve control of blood pressure levels in high-risk patients, including resistant hypertension. Drugs with a multiple mechanism of action show advantages in a more pronounced organoprotective effect, which will prevent further damage to the cardiovascular system. Studying the benefits of new drugs that block the RAAS requires further research and evaluation of their impact on the prognosis of patients with hypertension and other cardiovascular diseases.

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Which is formed in special cells of the juxtaglomerular apparatus of the kidney (JUGA). The secretion of renin is stimulated by a decrease in the volume of circulating blood, a decrease in blood pressure, b 2 -agonists, prostaglandins E 2, I 2, potassium ions. An increase in renin activity in the blood causes the formation of angiotensin I - a 10-amino acid peptide that is cleaved from angiotensinogen. Angiotensin I under the action of angiotensin-converting enzyme (ACE) in the lungs and in the blood plasma is converted into angiotensin II.

It causes the synthesis of the hormone aldosterone in the glomerular zone of the adrenal cortex. Aldosterone enters the bloodstream, is transported to the kidney and acts through its receptors on the distal tubules of the renal medulla. The total biological effect of aldosterone is the retention of NaCl, water. As a result, the volume of fluid circulating in the circulatory system is restored, including an increase in renal blood flow. This closes the negative feedback and renin synthesis stops. In addition, aldosterone causes loss of Mg 2+ , K + , H + with urine. Normally, this system maintains blood pressure (Fig. 25).

Rice. 25. Renin-angiotensin-aldoster system

Too much aldosterone - aldosteronism , is primary and secondary. Primary aldosteronism can be caused by hypertrophy of the glomerular zone of the adrenal glands, endocrine epithology, tumor (aldosteronoma). Secondary aldosteronism is observed in liver diseases (aldosterone is not neutralized and not excreted), or in diseases of the cardiovascular system, as a result of which the blood supply to the kidney worsens.

The result is the same - hypertension, and in the chronic process, aldosterone causes proliferation, hypertrophy and fibrosis of blood vessels and myocardium (remodeling), which leads to chronic heart failure. If it is associated with an excess of aldosterone, aldosterone receptor blockers are prescribed. For example, spironolactone, eplerenone are potassium-sparing diuretics, they promote the excretion of sodium and water.

Hypoaldosteronism is a lack of aldosterone that occurs with certain diseases. The causes of primary hypoaldosteronism can be tuberculosis, autoimmune inflammation of the adrenal glands, tumor metastases, and abrupt withdrawal of steroids. As a rule, this is insufficiency of the entire adrenal cortex. Acute failure can be caused by glomerular necrosis, hemorrhage, or acute infection. In children, a fulminant form can be observed in many infectious diseases (flu, meningitis), when a child can die in one day.

With insufficiency of the glomerular zone, the reabsorption of sodium and water decreases, the volume of circulating plasma decreases; increases the reabsorption of K + , H + . As a result, blood pressure drops sharply, electrolyte balance and acid-base balance are disturbed, the condition is life-threatening. Treatment: intravenous saline and aldosterone agonists (fludrocortisone).

The key link in the RAAS is angiotensin II, which:

Acts on the glomerular zone and increases the secretion of aldosterone;

Acts on the kidney and causes retention of Na + , Cl - and water;

Acts on sympathetic neurons and causes the release of norepinephrine, a powerful vasoconstrictor;

Causes vasoconstriction - constricts blood vessels (tens of times more active than norepinephrine);

Stimulates salt appetite and thirst.

Thus, this system brings blood pressure to normal when it decreases. Excess angiotensin II affects the heart, as well as an excess of CA and thromboxanes, causes myocardial hypertrophy and fibrosis, contributes to hypertension and chronic heart failure.

With an increase in blood pressure, three hormones begin to work mainly: NUP (natriuretic peptides), dopamine, adrenomedullin. Their effects are opposite to those of aldosterone and AT II. NUP cause the excretion of Na + , Cl - , H 2 O, vasodilation, increase vascular permeability and reduce the formation of renin.

Adrenomedullin acts in the same way as NUP: it is the excretion of Na +, Cl -, H 2 O, vasodilation. Dopamine is synthesized by the proximal tubules of the kidneys and acts as a paracrine hormone. Its effects: excretion of Na + and H 2 O. Dopamine reduces the synthesis of aldosterone, the action of angiotensin II and aldosterone, causes vasodilation and an increase in renal blood flow. Together, these effects lead to a decrease in blood pressure.

The level of blood pressure depends on many factors: the work of the heart, the tone of peripheral vessels and their elasticity, as well as on the volume of the electrolyte composition and viscosity of the circulating blood. All this is controlled by the nervous and humoral system. Hypertension in the process of chronicization and stabilization is associated with late (nuclear) effects of hormones. In this case, vascular remodeling, their hypertrophy and proliferation, vascular and myocardial fibrosis occur.

Currently, effective antihypertensive drugs are inhibitors of vasopeptidase ACE and neutral endopeptidase. Neutral endopeptidase is involved in the destruction of bradykinin, NUP, adrenomedullin. All three peptides are vasodilators, reduce blood pressure. For example, ACE inhibitors (perindo-, enalopril) reduce blood pressure by reducing the formation of AT II and delaying the breakdown of bradykinin.

Neutral endopeptidase inhibitors (omapatrilat), which are both ACE inhibitors and neutral endopeptidase inhibitors, have been discovered. They not only reduce the formation of AT II, ​​but also prevent the breakdown of hormones that reduce blood pressure - adrenomedullin, NUP, bradykinin. ACE inhibitors do not completely turn off the RAAS. A more complete shutdown of this system can be achieved with angiotensin II receptor blockers (losartan, eprosartan).

Aldosterone in humans is the main representative of mineralocorticoid hormones derived from cholesterol.

Synthesis

It is carried out in the glomerular zone of the adrenal cortex. Formed from cholesterol, progesterone undergoes sequential oxidation on its way to aldosterone. 21-hydroxylase, 11-hydroxylase and 18-hydroxylase. Ultimately, aldosterone is formed.

Scheme of the synthesis of steroid hormones (complete scheme)

Regulation of synthesis and secretion

Activate:

• angiotensin II released during activation of the renin-angiotensin system,
• increased concentration potassium ions in the blood (associated with membrane depolarization, opening of calcium channels and activation of adenylate cyclase).

Activation of the renin-angiotensin system

1. There are two starting points to activate this system:

• pressure reduction in the afferent arterioles of the kidneys, which is determined baroreceptors cells of the juxtaglomerular apparatus. The reason for this may be any violation of the renal blood flow - atherosclerosis of the renal arteries, increased blood viscosity, dehydration, blood loss, etc.
• decrease in the concentration of Na + ions in the primary urine in the distal tubules of the kidneys, which is determined by the osmoreceptors of the cells of the juxtaglomerular apparatus. Occurs as a result of a salt-free diet, with prolonged use of diuretics.

The secretion of renin (basic) is maintained by the sympathetic nervous system, constant and independent of renal blood flow.

1. When performing one or both items of the cell juxtaglomerular apparatus are activated and from them the enzyme is secreted into the blood plasma renin.
2. There is a substrate for renin in plasma - a protein of the α2-globulin fraction angiotensinogen. As a result of proteolysis, a decapeptide called angiotensin I. Further, angiotensin I with the participation angiotensin converting enzyme(ACE) turns into angiotensin II.
3. The main targets of angiotensin II are smooth myocytes. blood vessels And glomerular cortex adrenal glands:

• stimulation of blood vessels causes their spasm and recovery blood pressure.
• secreted from the adrenal glands after stimulation aldosterone acting on the distal tubules of the kidneys.

When exposed to aldosterone, the tubules of the kidneys increase reabsorption Na + ions, following sodium moves water. As a result, the pressure in the circulatory system is restored and the concentration of sodium ions increases in the blood plasma and, therefore, in the primary urine, which reduces the activity of the RAAS.

Activation of the renin-angiotensin-aldosterone system

Mechanism of action

Cytosolic.

Targets and effects

It affects the salivary glands, the distal tubules and the collecting ducts of the kidneys. Enhances in the kidneys reabsorption of sodium ions and loss of potassium ions through the following effects:

• increases the amount of Na +, K + -ATPase on the basement membrane of epithelial cells,
• stimulates the synthesis of mitochondrial proteins and an increase in the amount of energy produced in the cell for the operation of Na +, K + -ATPase,
• stimulates the formation of Na-channels on the apical membrane of renal epithelial cells.

Pathology

hyperfunction

Conn syndrome(primary aldosteronism) - occurs with adenomas of the glomerular zone. It is characterized by a triad of signs: hypertension, hypernatremia, alkalosis.

Secondary hyperaldosteronism - hyperplasia and hyperfunction of juxtaglomerular cells and excessive secretion of renin and angiotensin II. There is an increase in blood pressure and the appearance of edema.

prof. Kruglov Sergei Vladimirovich (left), Kutenko Vladimir Sergeevich (right)

Page editor: Kutenko Vladimir Sergeevich

Kudinov Vladimir Ivanovich

Kudinov Vladimir Ivanovich, Candidate of Medical Sciences, Associate Professor of the Rostov State Medical University, Chairman of the Association of Endocrinologists of the Rostov Region, Endocrinologist of the highest category

Dzherieva Irina Sarkisovna

Dzherieva Irina Sarkisovna Doctor of Medical Sciences, Associate Professor, Endocrinologist

CHAPTER 6. RENIN-ANGIOTENSIN SYSTEM

T. A. KOCHEN, M. W. ROI

(T. A. KOTCHEN,M. W.ROY)

In 1898 Tigerstedt et al. pointed out that the kidneys secrete a pressor substance, which later received the name "renin". It was found that the same substance through the formation of angiotensin stimulates the secretion of aldosterone by the adrenal glands. The advent of methods for biological, and later, radioimmunological determination of renin activity, largely contributed to the elucidation of the role of renin and aldosterone in the regulation of blood pressure both in normal conditions and in hypertension. In addition, since renin is produced in the afferent arterioles of the kidneys, the influence of renin and angiotensin on the glomerular filtration rate in normal conditions and when it decreases in conditions of renal pathology has been widely studied. This chapter presents current knowledge on the regulation of renin secretion, the interaction of renin with its substrate, resulting in the formation of angiotensin, and the role of the renin-angiotensin system in the regulation of blood pressure and GFR.

RENIN SECRETION

Renin is formed in that part of the afferent arterioles of the kidneys, which is adjacent to the initial segment of the distal convoluted tubules - the macula densa. The juxtaglomerular apparatus includes the renin-producing segment of the afferent arteriole and the macula densa. Renin-like enzymes - isorenins - are also formed in a number of other tissues, for example: in the pregnant uterus, brain, adrenal cortex, walls of large arteries and veins, and in the submandibular glands. However, evidence that these enzymes are identical to renal renin is often lacking, and there is no evidence that isorenins are involved in blood pressure regulation. After bilateral nephrectomy, plasma renin levels drop sharply or even become undetectable.

RENAL BARORECEPTOR

Renin secretion by the kidney is controlled by at least two independent structures: the renal baroreceptor and the macula densa. With an increase in pressure in the afferent arteriole or the tension of its walls, renin secretion is inhibited, while with a reduced tension of the walls of the arteriole, it increases. The most compelling evidence for the existence of a baroreceptor mechanism has come from an experimental model in which there is no glomerular filtration and hence no tubular fluid flow. The kidney, deprived of its filtration function, retains the ability to secrete renin in response to bloodletting and narrowing of the aorta (above the origin of the renal arteries). Infusion into the renal artery of papaverine, which dilates the renal arterioles, blocks the renin response in the denervated and non-filtering kidney to bleed and narrow the vena cava in the chest cavity. This indicates the reaction of vascular receptors specifically to changes in the tension of the walls of arterioles.

DENSE SPOT

The secretion of renin also depends on the composition of the fluid in the tubules at the level of the dense spot; infusion into the renal artery of sodium chloride and potassium chloride inhibits the secretion of renin while maintaining the filtration function of the kidney. Increasing the volume of filtered liquid with sodium chloride inhibits renin secretion more strongly than the same increase in volume with dextran, which is apparently due to the effect of sodium chloride on the hard spot. It is assumed that the decrease in plasma renin activity (PRA) with the introduction of sodium depends on the simultaneous presence of chloride. When administered with other anions, sodium does not reduce the ARP. ARP also decreases with the introduction of potassium chloride, choline chloride, lysine chloride and HCl, but not potassium bicarbonate, lysine glutamate or H 2 SO 4 . The main signal is, apparently, the transport of sodium chloride through the wall of the tubule, and not its entry into the filtrate; renin secretion is inversely related to chloride transport in the thick portion of the ascending limb of the loop of Henle. The secretion of renin is inhibited not only by sodium chloride, but also by its bromide, the transport of which, to a greater extent than other halogens, resembles the transport of chloride. Bromide transport competitively inhibits chloride transport across the wall of the thick portion of the ascending limb of the loop of Henle, and bromide can be actively reabsorbed under conditions of low chloride clearance. In the light of data on active chloride transport in the ascending limb of the loop of Henle, these results can be interpreted in support of the hypothesis that renin secretion is inhibited by active chloride transport in the macula densa. Inhibition of renin secretion by sodium bromide may reflect the inability of the receptor localized in the area of ​​the dense spot to distinguish between bromide and chloride. This hypothesis is also consistent with direct data from micropuncture experiments, in which a decrease in ARP during NaCl infusion was accompanied by an increase in chloride reabsorption in the loop of Henle. Both potassium depletion and diuretics acting at the level of the loop of Henle can stimulate renin secretion by inhibiting chloride transport in the thick part of the ascending loop of this loop.

Based on the results of a number of studies with retrograde microperfusion and determination of renin content in the juxtaglomerular apparatus of a single nephron, Thurau also concluded that transport of chloride through the macula serves as the main signal for the "activation" of renin. In apparent contradiction to in vivo observations, Thurau found that the JGA renin of a single nephron is "activated" not by a decrease but by an increase in sodium chloride transport. However, renin activation in the JGA of a single nephron may not reflect changes in renin secretion by the whole kidney. Indeed, Thurau believes that the increase in JGA renin activity reflects the activation of preformed renin rather than an increase in its secretion. On the other hand, it can be assumed that an increase in the content of renin in JGA reflects an acute inhibition of the secretion of this substance.

NERVOUS SYSTEM

Renin secretion is modulated by the CNS primarily through the sympathetic nervous system. Nerve terminals are present in the juxtaglomerular apparatus, and renin secretion is increased by electrical stimulation of the renal nerves, infusion of catecholamines, and increased activity of the sympathetic nervous system through a variety of techniques (eg, induction of hypoglycemia, stimulation of cardiopulmonary mechanoreceptors, occlusion of the carotid arteries, nonhypotensive bloodletting, cervical vagotomy or vagus nerve cooling). Based mainly on the results of experiments with the use of adrenergic antagonists and agonists, it can be concluded that the neural influences on renin secretion are mediated by β-adrenergic receptors (more specifically β 1 receptors) and that β-adrenergic stimulation of renin secretion can be carried out through the activation of adenylate cyclase and the accumulation of cyclic adenosine monophosphate. Data obtained from in vitro renal sections and from studies in isolated perfused kidneys indicate that activation of renal α-adrenergic receptors inhibits renin secretion. However, the results of studying the role of α-adrenergic receptors in the regulation of renin secretion in vivo are contradictory. In addition to renal adenoreceptors, atrial and cardiopulmonary stretch receptors are involved in the regulation of renin secretion; afferent signals from these receptors pass through the vagus nerve, and efferent signals through the sympathetic nerves of the kidneys. In a healthy person, immersion in water or "ascent" in a pressure chamber suppresses renin secretion, possibly due to an increase in central blood volume. Like the secretion of adrenocorticotropic hormone (ACTH), there is a diurnal periodicity in the secretion of renin, indicating the presence of influences of some as yet unidentified factors of the central nervous system.

PROSTAGLANDINS

Prostaglandins also modulate renin secretion. Arachidonic acid, PGE 2 , 13,14-dihydro-PGE 2 (a metabolite of PGE 2), and prostacyclin stimulate renin production by renal cortical sections in vitro and by filtering and non-filtering kidneys in vivo. The dependence of prostaglandin stimulation of renin secretion on cAMP formation remains unclear. Indomethacin and other prostaglandin synthetase inhibitors impair basal renin secretion and its response to low dietary sodium, diuretics, hydralazine, orthostatic position, phlebotomy, and aortic constriction. Data on the inhibition of the renin response to catecholamine infusion by indomethacin are contradictory. Inhibition of prostaglandin synthesis reduces the increase in ARP observed in dogs and with a decrease in the level of potassium in the body, as well as in patients with Bartter's syndrome. The decrease in renin secretion under the influence of inhibitors of prostaglandin synthesis does not depend on sodium retention and is observed even in the kidney, devoid of filtration function. The suppression of renin responses under conditions of inhibition of prostaglandin synthesis to all these various stimuli is consistent with the assumption that stimulation of renin secretion through the renal baroreceptor, macula densa, and possibly the sympathetic nervous system is mediated by prostaglandins. With regard to the interaction of prostaglandins with the mechanism of regulation of renin secretion through the macula, PGE 2 has recently been shown to inhibit active chloride transport through the thick part of the ascending limb of the loop of Henle in the renal medulla. It is possible that the stimulating effect of PGE 2 on renin secretion is associated with this effect.

CALCIUM

Although there are a number of negative data, but in the experiments of most researchers, an increased extracellular calcium concentration inhibited renin secretion both in vitro and in vivo and weakened the stimulating effect of catecholamines on it. This sharply distinguishes JGA cells from other secretory cells, in which calcium stimulates hormone production. However, although high extracellular calcium concentrations inhibit the release of renin, minimal levels of this ion may be necessary for its secretion. Prolonged calcium deficiency prevents increased renin secretion by catecholamines and decreased perfusion pressure.

In vivo, calcium inhibition of renin secretion is independent of tubular fluid flow. Calcium can directly affect juxtaglomerular cells, and changes in its intracellular concentration can mediate the action of various stimuli for renin secretion. It is assumed that depolarization of the juxtaglomerular cell membrane allows calcium to penetrate into it, followed by inhibition of renin secretion, while membrane hyperpolarization reduces the intracellular calcium level and stimulates renin secretion. Potassium, for example, depolarizes juxtaglomerular cells and inhibits renin release. Such inhibition is manifested only in a medium containing calcium. Calcium ionophores also weaken the secretion of renin, which is probably due to an increase in the intracellular concentration of the ion. Under the influence of β-adrenergic stimulation, hyperpolarization of juxtaglomerular cells occurs, leading to an outflow of calcium and an increase in renin secretion. Although the hypothesis linking changes in renin secretion with calcium transport into juxtaglomerular cells is attractive, it is difficult to test it due to the methodological difficulties of determining the level of intracellular calcium and assessing its transport to the corresponding cells.

Verapamil and D-600 (methoxyverapamil) block electrical charge-dependent calcium channels (slow channels), and acute administration of these substances interferes with the inhibitory effect of potassium depolarization on renin secretion. These substances, however, do not interfere with the decrease in renin secretion caused by antidiuretic hormone or angiotensin II, although both of them show their effect only in a medium containing calcium. These data indicate the existence of both charge-dependent and charge-independent pathways for calcium penetration into juxtaglomerular cells, and calcium entering by any of these pathways causes inhibition of renin secretion.

Although the direct effect of calcium on juxtaglomerular cells is to weaken the secretion of renin, a number of systemic reactions that occur with the administration of calcium could theoretically be accompanied by stimulation of this process. These reactions include: 1) narrowing of the renal vessels; 2) inhibition of chloride uptake in the loop of Henle; 3) increased release of catecholamines from the adrenal medulla and the endings of the renal nerves. Therefore, the reactions of renin in vivo to calcium or pharmacological substances that affect its transport may depend on the severity of the systemic effects of this ion, which should mask its direct inhibitory effect on juxtaglomerular cells. It was also noted that the effect of calcium on renin secretion may depend on the anions supplied with this cation. Calcium chloride inhibits renin secretion to a greater extent than calcium gluconate. It is possible that, in addition to a direct inhibitory effect on the juxtaglomerular apparatus, experimental effects that increase the flow of chloride to the macula densa further inhibit renin secretion.

The secretion of renin depends on many other substances. Angiotensin II inhibits this process by directly affecting the juxtaglomerular apparatus. A similar effect is exerted by intravenous infusion of somatostatin, as well as infusion of ADH into the renal artery.

REACTION BETWEEN RENIN AND ITS SUBSTRATE

The molecular weight of the active renin contained in the blood is 42,000 daltons. Renin metabolism occurs mainly in the liver, and the half-life of active renin in the blood in humans is approximately 10-20 minutes, although some authors believe that it is as high as 165 minutes. In a number of conditions (for example, nephrotic syndrome or alcoholic liver disease), an increase in ARP may be determined by changes in hepatic renin metabolism, but this does not play a significant role in renovascular hypertension.

Various forms of renin have been identified in blood plasma, kidney, brain, and submandibular glands. Its enzymatic activity increases both when plasma is acidified and when it is stored for a long time at -4°C. Acid-activated renin is also present in the plasma of kidneyless people. Acid activation is considered a consequence of the transformation of renin, which has a higher mol. mass, into a smaller but more active enzyme, although acidification can increase the activity of renin without reducing its mol. masses. Trypsin, pepsin, urinary kallikrein, glandular kallikrein, Hageman factor, plasmin, cathepsin D, nerve growth factor (arginine ether peptidase), and rattlesnake venom (an enzyme that activates serine proteinases) also increase plasma renin activity. Some pharmacologically neutral protease inhibitors block the stimulatory effect of freezing and (partly) acid on renin activity. In the plasma itself, proteinase inhibitors are also present, limiting the effect of proteolytic enzymes on renin. It follows that cryo- and acid activation can be reduced to a decrease in the concentration of neutral serine protease inhibitors, usually present in plasma, and after the restoration of its alkaline pH, a protease (for example, Hageman factor, kallikrein) can be released, converting inactive renin into active. The Hageman factor in the absence of an inhibitor (after the action of an acid) is able to activate prorenin indirectly through the stimulation of the conversion of prekallikrein to kallikrein, which in turn converts prorenin to active renin. Acidification can also activate acid protease, which converts inactive renin into active.

The enzymatic activity of highly purified porcine and human renin does not increase after the addition of acid. Renin inhibitors have also been found in plasma and kidney extracts, and some authors believe that renin activation by acidification or cold exposure is due (at least in part) to denaturation of these inhibitors. It is also believed that the high molecular weight inactive renin is reversibly bound to another protein, and this bond breaks down in an acidic environment.

Despite careful study of inactive renin in vitro, its physiological significance in vivo remains unknown. There are few data on the possible activation of renin in vivo and its intensity. Plasma prorenin concentration varies, in healthy individuals it may account for more than 90-95% of the total plasma renin content. As a rule, both in persons with normal blood pressure and in those with hypertension or changes in the sodium balance, a correlation is observed between the concentrations of prorenin and active renin. In patients with diabetes, this relationship may be disrupted. Relatively high concentrations of inactive renin (or prorenin) and low concentrations of active renin are noted in the plasma and kidneys of diabetic patients and experimental diabetic animals. Plasma of patients with deficiency of coagulation factors (XII, VII, V, and especially X) also contains small amounts of active renin, which suggests a violation of the conversion of inactive to active renin.

Being in the blood, active renin cleaves the leucine-leucine bond in the molecule of its substrate α 2 -globulin, synthesized in the liver, and converts it into an angio decapeptide. tensin I. The km of this reaction is approximately 1200 ng / ml, and at a substrate concentration of about 800-1800 ng / ml (in healthy ditch humans) the rate of angiotensin production depends on both the level of the substrate and the concentration of the enzyme. Based on determinations of renin enzymatic activity, some investigators believe that renin inhibitors are present in plasma, with individual renin-inhibiting compounds identified (e.g., phospholipids, neutral lipids, and unsaturated fatty acids, synthetic polyunsaturated analogs of lipophosphatidylethanolamine, and synthetic analogs of the natural substrate of renin). In the plasma of patients with hypertension or renal insufficiency, an increased enzymatic activity of renin was found; suggest that this is due to a deficiency of renin inhibitors normally present in the blood. The presence of renin-activating factor in the plasma of hypertensive patients has also been reported. The emergence of pharmacological agents that inhibit the activity of the renin-angiotensin system has increased interest in the synthesis of renin inhibitors.

The molecular weight of the renin substrate in humans is 66,000-110,000 daltons. Its plasma concentration increases with the introduction of glucocorticoids, estrogens, angiotensin II, with bilateral nephrectomy and hypoxia. In patients with liver disease and adrenal insufficiency, plasma concentrations of the substrate are reduced. Plasma may contain various renin substrates with different affinities for the enzyme. The administration of estrogens, for example, can stimulate the production of a high molecular weight substrate with an increased affinity for renin. However, little is known about the physiological significance of shifts in renin substrate concentration. Although estrogens stimulate substrate synthesis, there is still no convincing evidence of the role of this process in the genesis of estrogen-induced hypertension.

ANGIOTENSIN METABOLISM

The angiotensin-converting enzyme cleaves histidyl leucine from the COOH-terminal portion of the angiotensin I molecule, converting it into angiotensin II octapeptide. The activity of the converting enzyme depends on the presence of chloride and divalent cations. Approximately 20-40% of this enzyme comes from the lungs in one passage of blood through them. The converting enzyme is also found in the plasma and vascular endothelium of other localizations, including the kidneys. The purified enzyme from human lungs has a pier. a mass of approximately 200,000 daltons. With sodium deficiency, hypoxia, as well as in patients with chronic obstructive pulmonary lesions, the activity of the converting enzyme may decrease. In patients with sarcoidosis, the level of this enzyme increases. However, it is widely distributed in the blood and tissues and has a very high ability to convert angiotensin I to angiotensin II. In addition, it is believed that the conversion step does not limit the rate of production of angiotensin II. Therefore, a change in the activity of the converting enzyme should not have physiological significance. The angiotensin-converting enzyme simultaneously inactivates the vasodilator bradykinin. Thus, the same enzyme promotes the formation of the pressor substance angiotensin II and inactivates depressor kinins.

Angiotensin II is eliminated from the blood by enzymatic hydrolysis. Angiotensinases (peptidases, or proteolytic enzymes) are present in both plasma and tissues. The first product of the action of aminopeptidase on angiotensin II is angiotensin III (des-asp-angiotensin II) - COOH-terminal angiotensin I hectapeptide, which has significant biological activity. Aminopeptidases also convert angiotensin I to nonapeptide des-asp-angiotensin I; however, the pressor and steroidogenic activities of this substance depend on its conversion to angiotensin III. Like the converting enzyme, angiotensinases are so widespread in the body that a change in their activity should not affect the overall activity of the renin-angiotensin-aldosterone system in a visible way.

PHYSIOLOGICAL EFFECTS OF ANGIOTENSIN

The physiological effects of renin itself are unknown. All of them are associated with the formation of angiotensin. Physiological responses to angiotensin can be determined by both the sensitivity of its target organs and its concentration in plasma, and the variability of responses is attributed to changes in the number and (or) affinity of angiotensin receptors. Adrenal and vascular angiotensin receptors are not the same. Angiotensin receptors are also found in isolated renal glomeruli, and the reactivity of glomerular receptors differs from that of renal vascular receptors.

Both angiotensin II and angiotensin III stimulate aldosterone biosynthesis in the glomerular zone of the adrenal cortex, and in its steroidogenic effect, angiotensin III is at least as good as angiotensin II. On the other hand, the pressor activity of angiotensin III is only 30-50% of that of angiotensin II. The latter is a strong vasoconstrictor, and its infusion leads to an increase in blood pressure, both due to a direct effect on vascular smooth muscle, and due to an indirect effect through the central nervous system and peripheral sympathetic nervous system. Angiotensin II in those doses that do not change blood pressure during systemic infusion, when infused into the vertebral artery leads to its increase. Sensitive to angiotensin are the area postrema and, probably, the area located in the brainstem somewhat higher. Angiotensin II also stimulates the release of catecholamines from the adrenal medulla and sympathetic nerve endings. In experimental animals, chronic systemic intra-arterial infusion of subpressor amounts of angiotensin II leads to an increase in blood pressure and sodium retention, regardless of changes in aldosterone secretion. It follows that in the mechanism of the hypertensive effect of angiotensin, its direct effect on the kidneys, accompanied by sodium retention, may also play a role. When infused in large doses, angiotensin has a natriuretic effect.

The activity of the renin-angiotensin system can be impaired in many links, and studies using pharmacological inhibitors have provided data indicating the role of this system in the regulation of blood circulation in normal conditions and in a number of diseases accompanied by hypertension. Antagonists of β-adrenergic receptors inhibit the secretion of renin. Peptides inhibiting the conversion of angiotensin I to angiotensin II were extracted from the venom of the snake Bothrops jararca and other snakes. Some of the peptides present in snake venom have been synthesized. These include, in particular, SQ20881 (teprotide). An orally active substance SQ14225 (captopril), which is an inhibitor of the converting enzyme, has also been obtained. Synthesized and analogs of angiotensin II, competing with it for binding to peripheral receptors. The most widely used angiotensin II antagonist of this kind is capcosin-1, valine-5, alanine-8-angiotensin (saralazine).

The difficulty in interpreting the results obtained with the use of these pharmacological agents is due to the fact that the hemodynamic reactions that occur after their administration may not be a specific consequence of the inhibition of the renin-giotensin system. The hypotensive response to β-adrenergic antagonists is associated not only with inhibition of renin secretion, but also with their effect on the central nervous system, as well as with a decrease in cardiac output. enzyme, so the antihypertensive effect of inhibitors of the latter may also be due to the accumulation of bradykinin with an increase in its effect. In conditions of increasing the concentration of angiotensin II in the blood, saralizin acts as its antagonist, but saralazine itself is a weak angiotensin agonist. As a consequence, the response of blood pressure to infusion of saralazine may not give a full picture of the role of the renin-angiotensin system in the maintenance of hypertension.

Nevertheless, the use of such agents made it possible to elucidate the role of angiotensin in the regulation of blood pressure and normal renal function. In humans without hypertension or in experimental animals with a normal dietary intake of sodium, these substances have little or no effect on blood pressure (regardless of body position). Against the background of sodium deficiency, they reduce pressure to a moderate degree, and the vertical posture potentiates the hypotensive reaction. This indicates the role of angiotensin in maintaining arterial pressure in orthostasis in sodium deficiency.

Similar to pressure in the absence of hypertension, in humans and animals fed a high sodium diet, the renal vessels are also relatively refractory to pharmacological blockade of individual parts of the renin-angiotensin system. Moreover, in the absence of hyperreninemia, saralazine can even increase vascular resistance in the kidneys, apparently due to its agonistic effect or activation of the sympathetic nervous system. However, under conditions of sodium restriction, both saralazine and converting enzyme inhibitors cause a dose-dependent increase in renal blood flow. The increase in the latter in response to inhibition of the converting enzyme with SQ20881 in hypertension may be more pronounced than in normal blood pressure.

In the feedback mechanism between glomerular and tubular processes in the kidney, an important role belongs to chloride transport at the level of the macula densa. This was found in studies with single nephron perfusion, in which an increased supply of solutions (in particular, chloride) to the macula densa caused a decrease in GFR in the nephron, reducing the volume of the filtered fraction and its flow to the corresponding tubular region and thereby closing the feedback loop. Controversy exists regarding the role of renin in this process. Data on the inhibition of renin secretion by chloride, as well as the results of experiments with micropuncture, which showed that chloride plays a major role in the mechanism of glomerular tubular feedback, indicate a possible connection between these phenomena.

Thurau et al. adhere to the hypothesis that renin acts as an intrarenal hormone-regulator of GFR. The authors believe that an increased level of sodium chloride in the macula densa "activates" the renin present in the juxtaglomerular apparatus, leading to intrarenal formation of angiotensin II with subsequent constriction of afferent arterioles. However, as shown by other researchers, the effect of sodium chloride in the area of ​​the macula is to inhibit rather than stimulate the secretion of renin. If this is the case, and if the renin-angiotensin system is indeed involved in the regulation of GFR by closing the feedback loop, then the main effect of angiotensin II should be directed to efferent rather than afferent arterioles. Recent studies support this possibility. Thus, the expected sequence of events might look like this: promotion; the content of sodium chloride in the area of ​​the dense spot causes a decrease in the production of renin and, accordingly, the level of intrarenal angiotensin II, as a result of which the efferent arterioles of the kidneys expand and GFR decreases.

A number of observations indicate that autoregulation is generally carried out regardless of the fluid flow in the area of ​​the dense spot and the renin-angiotensin system.

DEFINITION OF RENIN

Plasma renin activity is determined by the rate of angiotensin formation during in vitro incubation. The pH optimum for human renin is 5.5. Plasma incubation can be carried out in an acid medium to increase the sensitivity of the determinations or at pH 7.4, which is more physiological. In most laboratories, the angiotensin II formed is currently determined by radioimmunoassay rather than biological method. Appropriate inhibitors are added to the in vitro incubation medium to suppress angiotensinase and converting enzyme activity. Because speed. angiotensin formation depends not only on the concentration of the enzyme, but also on the level of the substrate renin, an excess of exogenous substrate can be added to the plasma before incubation to create conditions of zero order kinetics in relation to its concentration. With such definitions, one often speaks of the "concentration" of renin. In the past, it was not uncommon for determinations to begin with acidification to denature the endogenous substrate, followed by the addition of the exogenous substrate. However, it is now known that an acidic environment activates inactive renin, and acid supplementation is currently used to provide data on plasma total renin (active plus inactive) rather than renin "concentration". The content of inactive renin is calculated from the difference between total and active renin. To avoid the influence of differences in the concentration of the endogenous substrate, the rate of formation of angiotensin in plasma can also be determined in the absence and presence of a number of known concentrations of the renin standard. A recent collaborative study showed that, despite the variability of the methods used, the results obtained in different laboratories for high, normal and low renin levels are consistent with each other.

Although highly purified preparations of renal renin and antibodies to it have been obtained in some laboratories, attempts to directly determine the level of renin in the blood by radioimmunoassay have not yet been very successful. Normally, the concentration of renin in the blood is extremely low and does not reach the sensitivity limits of such methods. In addition, radioimmunoassay techniques may not be able to separate active from inactive renin. Nevertheless, the development of a method for the direct determination of renin in the blood (rather than its indirect determination by the rate of angiotensin formation) could greatly contribute to the study of renin secretion and the reaction between this enzyme and its substrate.

Methods for direct radioimmunological determinations of angiotensin I and angiotensin II plasma concentrations have been developed. Although a similar method has recently been proposed for the renin substrate, most laboratories continue to measure it in terms of angiotensin equivalents, i.e., the concentrations of angiotensin formed after depleting incubation of plasma with exogenous renin. The activity of the converting enzyme was previously determined by fragments of angiotensin I. Currently, most methods are based on recording the ability of the converting enzyme to cleave smaller synthetic substrates; it is possible to determine both the amount of the dipeptide separated from the tripeptide substrate and the protected N-terminal amino acid formed upon hydrolysis of the substrate molecule.

Plasma renin is affected by salt intake, body position, exercise, the menstrual cycle, and virtually all antihypertensive agents. Therefore, for appropriate determinations to provide useful clinical information, they must be carried out under standard controlled conditions. A commonly used approach is to compare ARP results with daily urinary sodium excretion, especially in settings of restricted sodium intake. In such surveys, it was found that approximately 20-25% of patients with high blood pressure have low ARP in relation to sodium excretion, and in 10-15% of these patients, ARP is increased compared to that of people with normal blood pressure. In patients with hypertension, the renin response to acute stimuli, such as furosemide, was also determined; in general, there was a good agreement between the results for various methods of classifying hypertension according to the state of the renin-angiotensin system. Over time, patients can move from one group to another. Because there is a tendency for ARP to decrease with age, and because plasma renin levels are lower in blacks than in whites, the renin classification of patients with hypertension should take into account the corresponding rates in healthy individuals according to age, sex, and race.

RENIN AND HYPERTENSION

Classification of patients with hypertension according to the level of renin is of great interest. In principle, based on this indicator, one can judge the mechanisms of hypertension, clarify the diagnosis and choose rational approaches to therapy. The initial opinion about the lower incidence of cardiovascular complications in low-renin hypertension has not been sufficiently confirmed.

Mechanisms of high-renin and low-renin hypertension

Patients with high renin hypertension are more sensitive to the hypotensive effects of pharmacological blockade of the renin-angiotensin system than patients with normorenin hypertension, which indicates the role of this system in maintaining high blood pressure in patients of the first group. Conversely, patients with low-renin hypertension are relatively resistant to pharmacological blockade of the renin-angiotensin system, but have an increased sensitivity to the hypotensive effects of diuretics, including both mineralocorticoid antagonists and thiazide preparations. In other words, patients with low renin levels react as if they had an increase in body fluid volume, although measurements of plasma and extracellular fluid volumes do not always detect their increase. Active supporters of the volume-vasoconstrictor hypothesis of increased blood pressure in patients with hypertension are Laragh et al. According to this attractive hypothesis, both normal blood pressure and most types of hypertension are maintained predominantly by an angiotensin II-dependent vasoconstrictor mechanism, by a sodium or volume-dependent mechanism, and by the interaction of volume and angiotensin effects. The form of hypertension in which agents that block the production of renin or angiotensin have a therapeutic effect is referred to as vasoconstrictor, while the form sensitive to diuretics is called volumetric. An increase in blood pressure may be due to intermediate conditions, i.e., varying degrees of vasoconstriction and volume expansion.

High-renin hypertension may be associated with damage to large or small renal vessels. There is convincing evidence of the role of increased renin secretion by the ischemic kidney in the mechanism of renovascular hypertension. Although the most pronounced increase in renin levels is observed in the acute stages of hypertension, however, based on the results of a study with pharmacological blockade of the renin-angiotensin system, it can be assumed that its activation plays an equally important role in maintaining chronically elevated blood pressure in clinical and experimental renovascular hypertension. In rats, remission of hypertension induced by removal of an ischemic kidney can be prevented by infusing renin at a rate that produces a RRP similar to that experienced prior to nephrectomy. In rats with type 1C2H hypertension, sensitivity to the pressor effects of renin and angiotensin also increases. In experimental type 1C1P hypertension (removal of the contralateral kidney), the increase in blood pressure against the background of low ARP is apparently associated with sodium intake. In this case, blockade of the renin-angiotensin system under conditions of high sodium intake has little effect on blood pressure, although it can reduce blood pressure with sodium restriction. In patients with high-renin hypertension without obvious signs of renal vascular disease (judging by the results of arteriography), Hollenberg et al. with the help of xenon technique, ischemia of the cortical layer of the kidneys was detected. It is also believed that in patients with high-renin hypertension, there is a simultaneous increase in the activity of the sympathetic nervous system and that a high level of renin serves as a marker of the neurogenic genesis of an increase in blood pressure. This point of view is consistent with the increased sensitivity of patients with high-renin hypertension to the hypotensive effect of β-adrenergic blockade.

Various schemes have been proposed to explain the reduced ARP in low-renin hypertension, and this disease is probably not a separate nosological form. A small percentage of patients with low renin levels have elevated aldosterone secretion and primary aldosteronism. In the majority of patients in this group, the rate of aldosterone production is normal or reduced; with few exceptions, there is no convincing evidence that the increase in blood pressure in these cases is due to aldosterone or some other adrenal mineralocorticoid. However, several cases of hypertension have been described in children with hypokalemia and low renin levels, in which the secretion of some as yet unidentified mineralocorticoid is actually increased. In addition to the increase in fluid volume, other mechanisms have been suggested for the decrease in ARP in patients with low-renin hypertension. These include autonomic neuropathy, an increase in the concentration of a renin inhibitor in the blood, and impaired renin production due to nephrosclerosis. Several population-based studies have found an inverse correlation between blood pressure and ARP; as recently shown, in young people with relatively high blood pressure persisting for more than 6 years, physical activity increases the RDA to a lesser extent than in controls with lower BP. Such data suggest that a decrease in renin levels is an adequate physiological response to an increase in blood pressure and that in patients with "normorenin" hypertension this response is insufficient, i.e., the level of renin remains inappropriately high.

In many hypertensive patients, renin and aldosterone responses are altered, although the correlation of such changes with an increase in blood pressure has not been established. Patients with low molecular weight hypertension respond to angiotensin II with a greater increase in pressure and aldosterone secretion than those in the control group. Elevated adrenal and pressor responses were also observed in patients with normorenin hypertension who received a diet with a normal sodium content, indicating an increase in the affinity of vascular and adrenal (in the glomerular zone) receptors for angiotensin II. Suppression of the secretion of renin and aldosterone under the influence of sodium chloride load in patients with hypertension is less pronounced. They also have a weakened effect of converting enzyme inhibitors on renin secretion.

In patients with primary aldosteronism, aldosterone secretion does not depend on the renin-angiotensin system, and the sodium-retaining effect of mineralocorticoids causes a decrease in renin secretion. In these patients, low renin levels are relatively insensitive to stimulation, and high aldosterone levels are not reduced by salt loading. In secondary aldosteronism, increased secretion of aldosterone is due to increased production of renin and, consequently, angiotensin. Thus, in contrast to patients with primary aldosteronism, in secondary aldosteronism, ARP is increased. Secondary aldosteronism is not always accompanied by an increase in blood pressure, such as in congestive heart failure, ascites, or Bartter's syndrome.

Diagnosis of hypertension usually does not require the determination of ARP. Because 20–25% of hypertensive patients have reduced ARP, these measurements are too nonspecific to be a useful diagnostic test in routine screening for primary aldosteronism. A more reliable indicator in mineralocorticoid hypertension may be serum potassium levels; detection in persons with high blood pressure of unprovoked hypokalemia (not associated with taking diuretics) makes it possible to suspect primary aldosteronism with a high probability. Patients with renovascular hypertension often also have an increase in ARP, but other, more sensitive and specific diagnostic tests (eg, rapid series of intravenous pyelograms, renal arteriography) may be used if warranted by the clinical situation.

In hypertensive patients with radiologically established renal artery stenosis, the determination of ARP in the blood of the renal vein may be useful to resolve the issue of the functional significance of occlusive changes in the vessel. The sensitivity of this indicator increases if the determination of ARP in the blood of the renal vein is performed in orthostasis, against the background of vasodilation or sodium restriction. If the ARP in the venous outflow from the ischemic kidney is more than 1.5 times higher than that in the venous blood of the contralateral kidney, then this serves as a fairly reliable guarantee that the surgical restoration of the vascularization of the organ in people with normal renal function will lead to a decrease in blood pressure. The probability of successful surgical treatment of hypertension increases if the ratio of ARP in the venous outflow from the non-ischemic (contralateral) kidney and in the blood of the inferior vena cava under the mouth of the renal veins is 1.0. This indicates that the production of renin by the contralateral kidney is inhibited by angiotensin, which is formed under the influence of increased secretion of renin by the ischemic kidney. In patients with unilateral lesions of the renal parenchyma in the absence of renovascular disorders, the ratio between the renin content in the blood of both renal veins can also serve as a prognostic sign of the hypotensive effect of unilateral nephrectomy. However, experience in this regard is not as great as in patients with renovascular hypertension, and the evidence for the prognostic value of the results of the determination of renin in the renal veins in such cases is less convincing.

Another example of high-renin hypertension is malignant hypertension. This syndrome usually occurs with severe secondary aldosteronism, and a number of researchers consider increased secretion of renin to be the cause of malignant hypertension. In rats with type 1C2H hypertension, the onset of malignant hypertension coincides with an increase in natriuresis and renin secretion; in response to ingestion of salt water or infusion of antiserum to angiotensin II, blood pressure decreases and signs of malignant hypertension are weakened. Based on such observations Mohring; came to the conclusion that with a critical increase in blood pressure, sodium loss activates the renin-angiotensin system and this, in turn, contributes to the transition of hypertension to a malignant phase. However, in another experimental model of malignant hypertension induced in rats by ligation of the aorta over the origin of the left renal artery, Rojo-Ortega et al. have recently shown that the administration of sodium chloride with partial suppression of renin secretion not only does not have a beneficial effect, but, on the contrary, worsens the course of hypertension and the condition of the arteries. On the other hand, it is possible that severe hypertension in combination with necrotizing vasculitis leads to renal ischemia and secondary stimulates renin secretion. Whatever the initial process in malignant hypertension, a vicious circle is eventually created: severe hypertension - renal ischemia - stimulation of renin secretion - angiotensin II formation - severe hypertension. According to this scheme, the short feedback loop, due to which angiotensin II directly inhibits renin secretion, in this case does not function or its effect is not manifested due to the greater strength of the renin secretion stimulus. To break this vicious circle, a twofold therapeutic approach is possible: 1) suppression of the activity of the renin-angiotensin system or 2) the use of powerful antihypertensive agents that primarily act outside this system.

Elevated renin levels may cause hypertension in a relatively small percentage of patients with end-stage renal disease. In the vast majority of these patients, the magnitude of blood pressure is determined mainly by the state of sodium balance, however, in about 10% of them, it is not possible to achieve a sufficient reduction in blood pressure using dialysis and changing the sodium content in the diet. Hypertension usually reaches a severe degree, and ARP is markedly increased. Intensive dialysis may lead to a further increase in pressure or to transient hypotension, but severe hypertension soon returns. Elevated blood pressure in these patients decreases under conditions of blockade of angiotensin action by saralazine, and an increased level of renin in plasma and a hypotensive response to saralazine are, apparently, signs indicating the need for bilateral nephrectomy. In other cases, lowering blood pressure can be achieved with captopril or high doses of propranolol. Therefore, the question of the need for bilateral nephrectomy for the treatment of high-renin hypertension should only be raised in patients with end-stage irreversible renal disease. In patients with less severe renal insufficiency, hypertension is amenable to treatment with inhibitors of the converting enzyme even in the absence of an increase in ARP; this indicates that the normal level of renin may not correspond to the degree of sodium retention. Data on excessively high concentrations of renin and angiotensin II in relation to the level of exchangeable sodium in the body of patients with uremia are consistent with this assumption.

In 1967, Robertson described a patient whose hypertension disappeared after removal of a benign hemangiopericyterm of the renal cortex containing a large amount of renin. Subsequently, several more patients with renin-producing tumors were reported; all of them had pronounced secondary aldosteronism, hypokalemia, and elevated levels of renin in the blood flowing from the affected kidney, compared with the contralateral one, against the background of the absence of changes in the renal vessels. Wilms' tumor of the kidney can also produce renin; after removal of the tumor, blood pressure usually returns to normal.

Based on data on a decrease in blood pressure with pharmacological suppression of the activity of the renin-angiotensin system, the role of renin in the occurrence of hypertension is also seen in cases of obstructive uropathy, aortic coarctation, and Cushing's disease. In Cushing's disease, an increase in ARP is associated with an increase in the level of the renin substrate under the influence of glucocorticoids. Reactive hyperreninemia in response to sodium restriction and/or diuretics may impair the antihypertensive effect of these therapies in hypertensive patients.

RENIN AND ACUTE RENAL FAILURE

Plasma levels of renin and angiotensin in acute renal failure in humans often increase, and soon after the elimination of such insufficiency are normalized. A number of data indicate the possible involvement of the renin-angiotensin system in the pathogenesis of acute renal failure caused experimentally by glycerol and mercury chloride. Measures leading to a decrease in both ARP and the content of renin in the kidneys themselves (chronic loads of sodium or potassium chloride) prevent the development of renal failure under the influence of these substances. It has been shown that reduction (renin immunization) or acute suppression (acute sodium chloride load) of ARP alone, without simultaneous reduction of renin content in the kidneys themselves, has no protective effect. Thus, if the functional changes characteristic of renal failure caused by glycerol or mercuric chloride are associated with the renin-angiotensin system, then, apparently, only with intrarenal (and not contained in the blood) renin.

In glycerol-induced acute renal failure accompanied by myoglobinuria, saralazine and SQ20881 increase renal blood flow, but not glomerular filtration rate. Similarly, despite an increase in renal blood flow with saline infusion 48 hours after administration of mercuric chloride, glomerular filtration rate is not restored. Therefore, the initial disruption of the filtration process is irreversible.

Chronic sodium bicarbonate loading does not reduce either ARP or intrarenal renin content; unlike sodium chloride, sodium bicarbonate has a relatively weak protective effect in acute renal failure caused by mercuric chloride, despite the fact that loading with both sodium salts causes similar reactions in animals: a positive balance of sodium, an increase in plasma volume, and excretion of solutes. Sodium chloride (but not bicarbonate) loading reduces intrarenal renin levels and alters the course of these nephrotoxic forms of experimental renal failure, highlighting the importance of renin suppression rather than sodium loading per se in the protective effect. In apparent contradiction to these results, Thiel et al. found that rats that maintained a high urinary flow rate after administration of mercuric chloride also did not develop renal failure, regardless of changes in the level of renin in the renal cortex or plasma.

It is believed that the role of intrarenal renin in the pathogenesis of acute renal failure is to change the tubular-glomerular balance. In various types of experimental acute renal failure, the level of renin in a single nephron increases, probably due to impaired transport of sodium chloride at the level of the macula densa. This assumption is consistent with a decrease in GFR under the influence of renin activation in a single nephron.

In contrast to its effect in nephrotoxic forms of acute renal failure, chronic salt loading does not protect animals from norepinephrine-induced acute renal failure. If the starting point in the pathogenesis of filtration failure is the narrowing of the afferent arteriole, then one can understand the similarity of the effects of noradrenaline and angiotensin, as well as the fact that each of these vasoactive substances is able to initiate a cascade of reactions leading to renal failure.

BARTER SYNDROME

People with Bartter syndrome

Bartter syndrome is another example of secondary aldosteronism without hypertension. This syndrome is characterized by hypokalemic alkalosis, renal potassium loss, juxtaglomerular apparatus hyperplasia, vascular insensitivity to administered angiotensin, and elevated ARP and aldosterone secretion in the absence of hypertension, edema, or ascites. At first, it was believed that severe secondary aldosteronism was associated either with sodium loss through the kidneys or with vascular insensitivity to angiotensin II. However, some patients with this syndrome retain the ability to adequately retain sodium in the body, and their insensitivity to angiotensin may be secondary to its increased concentration in the blood. In patients with Bartter's syndrome, urinary excretion of PGE is increased, and pharmacological blockade of prostaglandin biosynthesis reduces the loss of potassium through the kidneys and the severity of secondary aldosteronism. In dogs with a low potassium content in the body, Galves et al. identified many of the necessary biochemical abnormalities characteristic of Bartter's syndrome, including increased ARP, increased PGE excretion, and vascular insensitivity to angiotensin. Indomethacin reduced both ARP and urinary PGE excretion and restored angiotensin sensitivity. Patients with Bartter's syndrome have impaired free water clearance, indicating altered chloride transport in the ascending limb of the loop of Henle. Restoring the level of potassium in the body does not lead to the elimination of this defect. In the muscles and erythrocytes of patients with Bartter's syndrome, there was also a violation of transport processes catalyzed by Na, K-ATPase. This suggests the presence of a more generalized defect in the transport system in such patients. Recent experimental evidence suggests that chloride transport in the ascending limb of the loop of Henle is inhibited by prostaglandins in the renal medulla; increased renal production of prostaglandins could also be involved in the mechanism of impaired chloride transport in patients with Bartter's syndrome. However, after the administration of indomethacin or ibuprofen, despite the inhibition of prostaglandin synthesis in the kidneys, the reduced free water clearance persists.

A specific defect in chloride transport in the ascending loop of Henle causes stimulation of renin secretion and, consequently, aldosterone production. This single defect could "trigger" a whole cascade of reactions leading to the development of Bartter's syndrome. Disruption of active transport in the ascending knee could not only stimulate renin secretion, but also increase the flow of sodium and potassium into the distal tubule. Increased intake of sodium in the distal nephron can, in addition to aldosteronism, be the direct cause of potassium loss in the urine. Potassium deficiency through stimulation of PGE production could exacerbate impaired chloride transport in the loop of Henle. Therefore, the inhibition of PGE synthesis should lead to only a partial weakening of the symptoms of the syndrome. If the putative defect in sodium reabsorption in the proximal tubule does exist, then it could also mediate an acceleration of sodium to potassium exchange in the more distal nephron.

HYPORENINEMIC HYPOALDOSTERONISM

As is known, selective hypoaldosteronism is observed in patients with interstitial nephritis and in diabetic patients with nephropathy. Against the background of hyperkalemia, hyperchloremia, and metabolic acidosis, they have weakened reactions of renin and aldosterone to provocative stimuli and a normal cortisol response to ACTH. Hyperkalemia sharply distinguishes such patients from patients with low-renin hypertension, in whom the potassium content in the blood remains normal. Hyperkalemia responds to mineralocorticoid therapy.

Low renin levels in diabetic patients are attributed to autonomic neuropathy, nephrosclerosis, and impaired conversion of inactive to active renin. In diabetes with hyporeninemic hypoaldosteronism, signs of an enzymatic defect in the adrenal glands are also found, leading to disruption of aldosterone biosynthesis. Recently, a diabetic patient has also been described with high renin levels but poor aldosterone secretion due to adrenal insensitivity to angiotensin II.

CONCLUSION

Renin secretion appears to be regulated by a number of different mechanisms, and their interaction remains unclear. The sequence of reactions leading to the production of agiotensin II and aldosterone turned out to be more complex than previously thought. Plasma contains inactive renin, or prorenin, and possibly inhibitors of the reaction between renin and its substrate. Potentially, all these compounds can strongly influence the overall activity of renin. The proposed pharmacological tests with the suppression of the activity of the renin-angiotensin system made it possible to obtain convincing evidence of the importance of angiotensin II in the pathogenesis of hypertension that accompanies various diseases. The involvement of the renin-aldosterone system in the mechanisms of increase and decrease in blood pressure remains an area of ​​intensive research aimed at elucidating the pathogenesis of hypertension. Data on the role of renin in the regulation of GFR are contradictory. The existence of syndromes characterized by excess and deficiency of renin in the absence of hypertension indicates an important role of the renin-aldosterone system in the regulation of electrolyte metabolism.

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Aldosterone in humans is the main representative of mineralocorticoid hormones derived from cholesterol.

Synthesis

It is carried out in the glomerular zone of the adrenal cortex. Formed from cholesterol, progesterone undergoes sequential oxidation on its way to aldosterone. 21-hydroxylase, 11-hydroxylase and 18-hydroxylase. Ultimately, aldosterone is formed.

Scheme of the synthesis of steroid hormones (complete scheme)

Regulation of synthesis and secretion

Activate:

• angiotensin II released during activation of the renin-angiotensin system,
• increased concentration potassium ions in the blood (associated with membrane depolarization, opening of calcium channels and activation of adenylate cyclase).

Activation of the renin-angiotensin system

1. There are two starting points to activate this system:

• pressure reduction in the afferent arterioles of the kidneys, which is determined baroreceptors cells of the juxtaglomerular apparatus. The reason for this may be any violation of the renal blood flow - atherosclerosis of the renal arteries, increased blood viscosity, dehydration, blood loss, etc.
• decrease in the concentration of Na + ions in the primary urine in the distal tubules of the kidneys, which is determined by the osmoreceptors of the cells of the juxtaglomerular apparatus. Occurs as a result of a salt-free diet, with prolonged use of diuretics.

The secretion of renin (basic) is maintained by the sympathetic nervous system, constant and independent of renal blood flow.

1. When performing one or both items of the cell juxtaglomerular apparatus are activated and from them the enzyme is secreted into the blood plasma renin.
2. There is a substrate for renin in plasma - a protein of the α2-globulin fraction angiotensinogen. As a result of proteolysis, a decapeptide called angiotensin I. Further, angiotensin I with the participation angiotensin converting enzyme(ACE) turns into angiotensin II.
3. The main targets of angiotensin II are smooth myocytes. blood vessels And glomerular cortex adrenal glands:

• stimulation of blood vessels causes their spasm and recovery blood pressure.
• secreted from the adrenal glands after stimulation aldosterone acting on the distal tubules of the kidneys.

When exposed to aldosterone, the tubules of the kidneys increase reabsorption Na + ions, following sodium moves water. As a result, the pressure in the circulatory system is restored and the concentration of sodium ions increases in the blood plasma and, therefore, in the primary urine, which reduces the activity of the RAAS.

Activation of the renin-angiotensin-aldosterone system

Mechanism of action

Cytosolic.

Targets and effects

It affects the salivary glands, the distal tubules and the collecting ducts of the kidneys. Enhances in the kidneys reabsorption of sodium ions and loss of potassium ions through the following effects:

• increases the amount of Na +, K + -ATPase on the basement membrane of epithelial cells,
• stimulates the synthesis of mitochondrial proteins and an increase in the amount of energy produced in the cell for the operation of Na +, K + -ATPase,
• stimulates the formation of Na-channels on the apical membrane of renal epithelial cells.

Pathology

hyperfunction

Conn syndrome(primary aldosteronism) - occurs with adenomas of the glomerular zone. It is characterized by a triad of signs: hypertension, hypernatremia, alkalosis.

Secondary hyperaldosteronism - hyperplasia and hyperfunction of juxtaglomerular cells and excessive secretion of renin and angiotensin II. There is an increase in blood pressure and the appearance of edema.