Studies in the last decade or so have suggested that the renin-angiotension aldosterone system (RAS) plays a very important role in the development of renal disease. Once chronic, renal disease often progresses at different rates to end-stage renal failure. How to slow down or stop the diffuse progression of kidney disease has been one of the most important topics in kidney disease research. The mechanisms underlying the chronicity of renal disease and progressive decline in renal function are complex and have not been elucidated, but the deleterious effects of certain factors are well established. The role of the RAS system in kidney disease involves many aspects of the development of kidney disease, especially in recent years, a large number of clinical and experimental studies have confirmed that blocking the RAS system delays the progression of kidney disease. Therefore, the study of the relationship between the RAS system and renal diseases is an important topic in renal disease research and has received increasing attention. Zhai Wensheng, Department of Pediatrics, The First Affiliated Hospital of Henan College of Traditional Chinese Medicine
I. Composition and basic role of renin angiotensin system (RAS)
The renin-angiotensin system consists of renin, angiotensinogen, angiotensin I (AngI), angiotensin-converting enzyme (ACE), angiotensin II (AngII) and angiotensin receptor (ATR), among which AngII is the most important bioactive substance.
RAS can be divided into circulating RAS (cRAS) and local RAS (tRAS). cRAS includes angiotensinogen secreted by liver, which is cleaved by renin to form AngI. AngI is converted to active AngII by ACE and other enzymes (e.g., gastrin) in the vascular system of lung, and the latter reaches various tissues via circulation and acts by binding to ATR. The heart, blood vessels, and kidney are the major AngII producers.
The tRAS is present in the brain, adrenal glands, kidney, blood vessels (endothelial and smooth muscle), testes, uterus, sympathetic ganglia, heart and lungs. The anatomical location of localized RAS in the kidney is close to the paraglomerular apparatus and the small arterial regions of the inlet and outlet glomeruli. High concentrations of AngI and AngII in the tubular fluid were confirmed by micropuncture, and AngII concentrations in the renal cortex were 1000-fold higher than in plasma. There is evidence that tissue tRAS has a greater effect on target organs than cRAS.
The most important role of the RAS system is to maintain a stable circulatory status, and this effect is mainly through the constricting effect of Angiotensin II on systemic vasculature, which affects systemic hemodynamics.
The effects of the RAS system on renal disease are mainly through both hemodynamic-dependent and non-hemodynamic-dependent pathways. The renal local RAS is newly considered to play a more important role in the progression of renal disease, while the circulating RAS plays a complementary role in situations such as stress. Local renal RAS play a major role in the maintenance of basic renal functions, including the regulation of renal plasma flow and glomerular filtration rate through the involvement of tubuloglomerular feedback (TGF); the regulation of water metabolism by affecting renal concentration and dilution through the regulation of blood flow in the small vessels; the direct stimulation of adrenal synthesis and secretion of aldosterone, which promotes tubular sodium reabsorption and thus increases extracellular fluid It can directly stimulate the synthesis and secretion of aldosterone by the adrenal glands, promote sodium reabsorption by the renal tubules, thus increasing the extracellular fluid volume and raising blood pressure. It affects the physiopathology of the kidney by stimulating the secretion of cytokines and ECM from renal thylakoid cells and epithelial cells.
II. Production and regulation of RAS system
1. Renin
Renin is an acidic glycoprotein proteinase, which can be produced in many organs, but most of the renin in the circulation originates from the kidney, i.e., it is mainly synthesized by the paracellular cells and the dense spots located in the distal tubular junction of the ascending branches of the medullary struts, and its substrate is the angiotensinogen synthesized from the liver. Its enzymatic action on angiotensinogen is the rate-limiting step of RAS, and therefore many scholars believe that renin is the key substance in the regulation of RAS.
The secretion of renin is regulated by sympathetic nerves, pressure receptors and the amount of sodium in the body. In addition, it is also regulated by feedback from plasma angiotensin, aldosterone and ADH levels. When the levels of angiotensin, aldosterone and ADH are increased, the secretion of renin can be inhibited by feedback.
2. ACE and angiotensin
Angiotensin-converting enzyme (ACE) is a zinc-containing dicarboxypeptidase and a glycoprotein. It is widely distributed in the body, and according to its synthesis site, ACE is divided into somatic ACE and testicular ACE. somatic ACE is the most studied one, mainly exists in the lung, but it is abundant in the luminal surface of many vascular endothelial cells, renal vesicles and proximal tubular brush border. Testicular ACE is mainly distributed in the testis. The two are distinct in the regulation of gene expression, mRNA transcription, translation levels, and protein synthesis. the physiological role of ACE is to dehydrodipeptide AngI, convert it to active AngII, and inactivate bradykinin, which has a vasodilatory effect.
Angiotensin is synthesized by the liver and is converted to a 10-peptide structure, AngI, by the action of renin; AngI is generally inactive and is converted to the active AngII by ACE.
AngII is the main biologically active substance in the RAS. AngII is 40 times more potent than norepinephrine in constricting blood vessels and is one of the most potent of the known naturally occurring antihypertensive substances. Angiotensin II can bind to AngII receptors in all tissues.
AngII synthesis has multiple pathways: (1) Classical synthesis pathway: Angiotensinogen is produced by a series of protein hydrolases to produce AngI, which is converted to active AngII by ACE, and this is the main pathway of AngII production. (ii) Bypass synthesis pathway: it is believed that there are at least two types of serine proteases that do not require the action of ACE, which can independently catalyze the conversion of AngI to AngII [1]. (iii) Non-renin pathway: Tissue proteinase G and tissue-type fibrinogen activator (tPA) directly break down angiotensinogen to form AngII.
3. AngII receptors
AngII mainly acts through its specific receptors. Due to the application of selective receptor antagonists and the intervention of molecular biology methods, two main types of AngII receptors have been identified, namely type I (ATl) and type II (AT2). There are germline differences and tissue differences in their distribution. In recent years, it has been shown that ATl receptors are abundantly expressed mainly in the kidney, AT2 receptors are mainly present in the fetal kidney, AT2 receptors are greatly reduced in the adult kidney, AT2 receptors are only distributed in the larger blood vessels in the adult pre-globule, and AT2 receptors are absent in the epithelial cells of the individual kidney glomeruli. This suggests that AT2 receptors are associated with renal development. Since the vast majority of pathophysiological effects produced by AngII are mediated through its ATl receptors. Therefore, ATl receptors and their blockers have been studied more and AT2 receptor function is less understood.
AT1 receptors: The receptors that can be blocked by Losartan and DDT are AT1 receptors, which are divided into two subtypes: AT1A receptors and AT1B receptors [2]. It is mediated by AT1 receptors. AT1 receptors are also associated with tubulointerstitial lesions and are abundantly expressed on renal interstitial fibroblasts, which, when combined with AngII, stimulate the production of collagen III by interstitial cells [3].
AT2 receptors: the physiological and pathological functions mediated by AT2 receptors are not fully understood. AT2 receptors are widely and abundantly expressed in all tissues of the embryo and rapidly decrease or disappear in most tissues and organs after birth. Some recent studies have found that small amounts of AT2 receptors are also present in the renal peritoneum, renal vasculature, paraglomerular apparatus, and glomerular thylakoid cells, and that AT2 receptors are present in adult human renal tissue at 5% of the total AngII receptors in renal tissue [4].A study by Muller et al [5], on the other hand, found that AT2 receptors can also mediate some of the AngII-induced renal vasoconstrictor effects, although This constrictive effect is weak and normally counteracted by the diastolic effect of endogenous nitric oxide (NO); it can only be revealed after inhibition of endogenous NO production with an NO synthase inhibitor (LNAME). However, there are inconsistent findings, as Arima [6] et al. in an in vitro study of the small inlet arteries of the rabbit isolated kidney by microperfusion method found, however, that in antagonizing AngII-induced vasoconstriction with an AT1 receptor antagonist (CV11974), the small inlet arteries dilated instead with increasing concentrations of AngII in the perfusate, and this dilation could be counteracted by the AT2 receptor antagonist. It is suggested that AT2 receptors mediate the diastolic effect. Therefore, most scholars believe that ATl receptors and AT2 receptors have mutually antagonistic effects on vasoconstriction and cell growth, but usually ATl receptors play a dominant role. studies of AT2 receptors can help further clarify the mechanism of action of AngII and its effects on the kidney.
The presence of AT3 and AT4 receptors has also been reported. AT3 receptors are located in cultured neuroblastoma cells, and AT4 receptors bind specifically to angiotensin 3-8 (A IV) and are distributed in the coronary arteries, aorta and central nervous system. the role of AT3 and AT4 receptors is not yet clear [7].
Third, the role of AngII on the kidney and its mechanism
AngII is the main bioactive substance in the renin-angiotensin system (RAS) and plays an important role in renal damage.AngII binds to angiotensin type I receptors on renal cell membranes and can cause renal damage through both hemodynamic-dependent and non-hemodynamic-dependent pathways, both indirectly by increasing glomerular capillary intracapillary pressure and It can cause kidney damage directly by stimulating the secretion of various growth and cytokines, such as TGF-ß, from renal cells [7]. To summarize, the main effects are as follows.
(1) vasoconstrictive effect: AngII is a vasoactive substance that regulates intra-glomerular hemodynamic changes by constricting large blood vessels and small glomerular arteries and glomerular capillary network. It preferentially constricts the small glomerular outflow arteries, which increases the intra-glomerular pressure and causes glomerular injury.
(2) Contraction of thylakoid cells: AngII can also contract thylakoid cells, affecting the intra-glomerular capillary filtration barrier and causing a decrease in glomerular ultrafiltration coefficient.
(3) Effects on renal tubules: AngII affects the Na+-H+ conversion system and Na+/HC03+ co-transport in renal tubules, thus affecting the secretion of Na+ and HCO3+ in the proximal tubules, AngII not only regulates acid-base balance and the important transport system of extracellular fluid, but also promotes the amino-producing effect of renal tubular epithelium, so that NH3 is secreted more into the tubular lumen. AngII not only regulates the acid-base and sodium balance, but also regulates the hypertrophy and proliferation of this part of tubule. The hyperactivity of the RAS in and around the renal tubules may increase tubular cell hypertrophy. In addition, AngII promotes amino acid production in the renal tubular epithelium, which directly promotes renal hypertrophy, and also causes an increase in C569 by activating complement, which acts as a membrane attack complex causing renal tissue damage. In addition, AngII promotes increased sodium reabsorption in renal tubular epithelium, which increases oxygen consumption in renal tissue and causes relative oxygen deficiency in renal tissue, all of which are important mechanisms for the chronic progression of renal disease.
(4) Pro-renal growth factor effect: recent studies have found that AngII is also a pro-renal growth factor, which plays an important role in cell proliferation. It can not only directly promote the proliferation and hypertrophy of glomerular thylakoid cells, but also stimulate the secretion of growth factors and cytokines from thylakoid cells, epithelial cells and mesenchymal fibroblasts, such as TGF-ß, PDGF, CTGF, IL-6, TNFa, MCP-1, PA1, metalloproteinases
etc., leading to glomerular thylakoid cell proliferation and extracellular matrix accumulation, promoting the infiltration of inflammatory cells in the glomerular and tubular interstitium, and promoting glomerular and tubular fibrosis.
AngII stimulates the production of some cytokines, especially TGF-ß, which has attracted the interest of many scholars, and most animal models have confirmed that AngII is an important factor in inducing TGF-ß1 expression, and the administration of ACEI or ATl receptor antagonist can significantly inhibit TGF-ß1 production and delay the decline of renal function. AngII binds to ATl receptor and activates protein kinase (PKC), which in turn causes the expression of proto-oncogenes such as c-fos and c-Jun through a series of intracellular signaling systems, both of which form AP-l-like transcription factors, and it is known that AP-l-like transcription sites exist in the promoter of TGF-ß1 gene, thus inducing TGF-ß1 expression. Thus, AngII can also promote ECM accumulation through TGF-ß1 mediation. In addition, AngII can inhibit ECM degradation, and in addition to its role with TGF-ß1, AngII can directly upregulate PAI-ImRNA expression. It has been observed in experiments in animal models of glomerulosclerosis that benazepril plays an important role in downregulating TGF-ß1 expression and extracellular matrix accumulation in renal tissues by blocking intrarenal RAS.
(5) The effect of AngII on macrophages: (1) there are receptors for ArlgII on macrophages, and AngII can directly activate macrophages; (2) AngII induces the release of chemokines from monocytes/macrophages, and perfusion of AngII can cause interstitial nephritis; (3) the kinin system may be involved in this process, and ACEI can increase bradykinin and stimulate the production of prostaglandins or NO, which in turn Increased mRNA expression of kinin-releasing enzyme in the rat kidney after ACEI treatment can be antagonized by specific B2-type bradykinin receptor antagonists, and reduced degradation of kinin by peptidase can lead to reduced urinary protein excretion, suggesting that increased bradykinin levels after ACEI treatment are associated with reduced urinary protein. Therefore, it is now believed that bradykinin also plays an important role in the progression of renal disease.
IV. Gene polymorphism of RAS
All genes that make up RAS are polymorphic. Since the genetic composition of each individual is different, the response to treatment varies from person to person. Several polymorphic regions have been found in the genes encoding each component of the RAS system.
Polymorphisms in the ACE gene: This is the most studied RAS gene polymorphism. The human ACE gene is located on the long arm of chromosome 17, region 2, band 3 (17q23). the ACE-gene span (ACE-gene spans) is 2lKb and has 26 exons. the ACE
There is a 287bp insertion/deletion variant in intron 16 of the gene. Genes containing this 287bp segment are called alleles (insertion, I), while those without this segment are called deletion alleles (deletion, D). This insertion/deletion polymorphism of ACE genes was found to be closely related to circulating ACE levels and intracellular ACE activity. Plasma ACE levels are constant in the same individual, but vary considerably between individuals, and this variation depends to a large extent (50%) on the insertion/deletion polymorphism of the ACE gene. In other words, the ACE gene controls plasma ACE levels, and ACE gene polymorphisms are closely related to circulating ACE levels; among ACE genes, plasma ACE levels are highest in individuals with DD type, twice as high as in individuals with type II, and intermediate in individuals with ID type. The prognosis of renal disease is affected by the relatively poor efficacy of ACEI. The incidence of glomerulosclerosis and/or renal failure is significantly higher in patients with diabetic ACE genotype DD than in other genotypes; ACE genotype DD in children with NS is associated with partial and no effect of hormones and the development of glomerulosclerosis, and may be a marker to determine the efficacy of hormones and pathological progression in pediatric patients.
Gene polymorphism of ATl receptor: Recently, ATl receptor gene polymorphism has been studied, in which the 1166th pair of alkaline group of ATl receptor gene is adenine (A) or cytosine (C), located at the 3′ end of the gene, which is a non-coding region. the ATl receptor gene is A1166 ®C1166 polymorphism, which is expressed as AA, AC and CC genotypes. This gene polymorphism is associated with the development of hypertension and also with atherosclerosis in hypertensive patients. It was found that in healthy individuals ATl receptor gene polymorphisms are associated with renal hemodynamic effects, especially the C allele often has a lower glomerular filtration rate and lower renal blood flow; ATl receptor antagonists have hypotensive and increased glomerular filtration rate only in individuals with the C allele, i.e., those with the C allele respond better to ATl receptor antagonists [8].
V. Role of RAS blockers in the treatment of renal diseases
Among the many factors affecting the progression of renal disease, hemodynamics, renal lamina propria and infiltrating cells, growth factors, cytokines, vasoactive substances and organismal metabolites are involved in the role. In the past two decades, numerous animal experiments and clinical observations have led to the positive conclusion that lowering blood pressure and reducing urinary protein excretion are the most important measures to stop progressive kidney injury.
Before the late 1980s, it was only recognized that hypertension was a common complication of substantial renal diseases, such as primary glomerular diseases with an incidence of 20%-80%, secondary glomerular nephropathy with an incidence of 65%-70% in diabetic nephropathy, and end-stage renal disease with an incidence of 80%-90% in hypertension. Since the late 80s, some scholars such as Kasiske BL et al (Am J Med, 1988), Brazy PC, Stead WW et al (Kidney Int, 1989), Wright JP, Brown CB, El Nahas AM (Clin Nephrol, 1993) published studies one after another, which initially formed A new view that the persistence of hypertension can accelerate the deterioration of renal function in substantial renal disease, whether hypertensive renal damage or hypertension complicating substantial renal disease. Hypertension is now considered to be the 1st independent risk factor for accelerated deterioration of renal function [9].
RAS plays an important role in the development, progression and chronicity of renal disease through hemodynamic and non-hemodynamic pathways, of which the main component is AngII. numerous studies have shown that AngII is directly involved in progressive renal damage, which not only elevates intra-glomerular pressure by affecting systemic and local renal hemodynamics, but also directly promotes the production of various cytokines and cell It not only elevates intra-glomerular pressure by affecting systemic and local hemodynamics, but also directly promotes the production of various cytokines and cell proliferation/hypertrophy as well as the accumulation of matrix proteins. Recent studies have found that renin-angiotensin system inhibitors can satisfactorily lower blood pressure and reduce urinary protein excretion, thereby protecting the kidney and preventing the chronic progression of renal disease.
(I) Classification and effects of RAS blockers
Theoretically, there may be many ways to block RAS. According to the different links of blocking RAS, renin-angiotensin system inhibitors are classified into anti-angiotensinogen gene therapy, renin inhibitors, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists and so on. At present, anti-angiotensinogen gene therapy is still in animal experiments; renin inhibitors such as peptide renin inhibitors Enlkiren and Remikiren have high affinity for renal tissues and are more selective, but at present, these drugs are only in phase II clinical trials in cardiovascular diseases and are still in animal experiments in renal diseases; non-skin renin inhibitors are still in animal experiments. Currently, there are two main classes of drugs used in clinical practice: angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor 1 (ATl) antagonists.
1. ACEI
ACEI can effectively inhibit the conversion of AngI to AngII, inhibit the production of AngII, and also inhibit the degradation of bradykinin, so that bradykinin production increases. The purpose of lowering blood pressure and protecting the kidney is achieved. It has been suggested that bradykinin receptors are most important in lowering blood pressure, improving renal hemodynamics and improving cardiac function.
(1) The mechanism of hypotensive effect of ACEI: (1) reduce vasoconstriction caused by AngII; (2) inhibit the release of norepinephrine; (2) inhibit brain RAS to enhance the decompression reflex; (4) block the formation of AngII in the vasomotor center of the medulla; (5) inhibit bradykininase II and promote bradykinin accumulation; (6) stimulate the synthesis of diastolic prostaglandins and vascular endothelial diastolic factor [8].
(2) Mechanism of action of ACEI for renal protection: ACEI can delay the progression of renal damage through two effects, namely hemodynamic and non-hemodynamic effects. ACEI can block AngII production, reduce vasoconstriction, block aldosterone production, and reduce water and sodium storage, so it can reduce systemic hypertension in terms of reducing vascular resistance and blood volume, and the reduction of systemic hypertension can indirectly improve the “three highs” in the glomerulus. The reduction of systemic hypertension can indirectly improve the “three highs” in the glomerulus. ACEI can also directly dilate the small glomerular arteries, and the effect of dilating the small glomerular arteries is stronger than that of dilating the small glomerular arteries, so it can directly reduce the “three highs” in the glomerulus. ACEI can reduce the degradation of bradykinin, which has anti-proliferative and vascular tone improving effects. The dilatation of small glomerular arteries is regulated by two mechanisms, AngII receptor level and bradykinin level: the density of ATl receptors in the wall of small glomerular arteries is significantly higher than that in small glomerular arteries, so the effect of constriction of small glomerular arteries in the presence of AngII is greater, while bradykinin can directly dilate small glomerular arteries. The non-hemodynamic effect refers to the effect of reducing the accumulation of extracellular matrix (ECM) in the glomerulus. AngII can stimulate glomerular cells to secrete cytokines, growth factors and synthesize ECM. ACEI blocks the production of AngII or the effect of AngII, so it can reduce ECM production; AngII can also stimulate the production of fibrinogen activator inhibitor (PAD), so it can make ACEI blocks the production of AngII, which also promotes the degradation of ECM. Therefore, ACEI can reduce the accumulation of ECM in the glomerulus, which also slows down the progress of residual glomerulosclerosis and protects renal function.
(3) ACEI classification: At present, there are many kinds of ACEI preparations, which are only used for clinical purposes, and the mechanism of action of each is different. According to its group can be combined with zinc ions in ACE can be divided into three major categories: ① sulfhydryl SH class: Captopril as a representative (Captopril); ② carboxyl group: Enalapril (Enalapril), Benazapril as a representative (Benazapril), without the disadvantages of sulfhydryl class taste abnormalities. (2) Phosphonic acid group: Fosinopril as the representative, with dual elimination pathway of liver and kidney, suitable for patients with hepatic and renal insufficiency and senile hypertension.
(4) Variability of ACEI effects: ACEI effects vary according to individual differences, the type and stage of renal disease, as well as the type and dose of ACEI.
(5) ACEI action characteristics and precautions: ① ACEI is not selective for the action of substrates, in addition to AⅠ it also decomposes bradykinin, so the decomposition of bradykinin is reduced when using ACEI. It has been suggested that bradykinin receptor antagonists can counteract the effect of ACEI in reducing intra-glomerular pressure and urinary protein, and it is believed that bradykinin plays an important role in the renal protective effect of ACEI, which cannot be replaced by other blocking links such as AT1RA. Thus ACEI can improve insulin resistance, reverse left ventricular hypertrophy, reduce proteinuria, and delay the progression of renal disease while lowering blood pressure, but has the side effect of causing cough. ②Further studies found that the renal protective effects of ACEI analogs are mainly accomplished by regulating the biological effects produced by the binding of AngII to its receptor, i.e., by inhibiting the production of TGF-β and the synthesis of cellular matrix. ③The effect of ACEI dilates the small glomerular outflow arteries, which reduces renal blood flow and glomerular filtration rate. There is a transient self-limiting decrease in GFR at the beginning of clinical use of ACEI, which is reversible, and GFR can mostly be recovered after withdrawal of the drug, which is a manifestation of ACEI decreasing the intra-glomerular pressure. It is believed that this transient decrease in GFR is caused by the premise that ACEI reduces urinary protein and protects renal function. ④ Renal vascular malignant hypertension is prohibited. When ACEI or ATRB is used in patients with renal insufficiency, there can be an increase in blood creatinine, but if it is less than 30%, it can continue to be used and has the effect of protecting renal function. It should be contraindicated in patients with creatinine levels above 4-5 mg/L. ⑤ For patients with hypovolemia, ACEI can lead to hypotension, so such patients should be treated with active volume expansion. (6) Blood potassium should be monitored when ACEI is applied. Because ACEI inhibits the production of AngII, the production of aldosterone is also reduced, which can increase the serum potassium level, especially in patients with impaired renal function and low urine output. (7) ACEI inhibits AngII production and may inhibit hematopoiesis, which may lead to anemia. In particular, EPO dosage may be significantly increased in children with anemia of renal failure.
2. AT1 receptor antagonists
ACEI can inhibit the classical pathway of AngII formation, but not the non-renin and bypass pathway (serine protease), and renin receptor antagonists cannot block the non-renin pathway to produce AngII, therefore, the blocking effect of renin receptor antagonists and ACEI on RAS AngII receptor antagonists directly antagonize AngII at the receptor level and can inhibit AngII produced by either source or pathway, thus giving Ang receptor antagonists a greater advantage.
There are four known subtypes of Ang receptors, namely AT1, AT2, AT3 and AT4, of which AT3 and AT4 are still under research, and ATRA can be divided into: (1) selective AT1 receptor antagonists (ATRA); (2) selective AT2 receptor antagonists (ATRA); and (3) dual AT1/AT2 (balanced) receptor antagonists according to their receptor subtypes. ATRA is currently marketed only as AT1RA. The marketed AT1RAs can be divided into 3 major categories: (i) dibenzotetraimidazole AT1RAs, such as cloxacin, irbesartan, candesartan, etc.; (ii) non-dibenzotetraimidazole AT1RAs, such as eprosartan, telmisartan, etc.; and (iii) non-heterocyclic AT1RAs, such as valsartan, etc. [10].
Losartan This drug can block various pharmacological effects (including those inducing vasoconstriction and aldosterone release) produced by endogenous and exogenous Ang. It selectively acts on the AT1 receptor and does not affect the function of other hormone receptors or important ion channels in the cardiovascular system, does not inhibit the angiotensin converting enzyme (kinase) that degrades bradykinin, and does not affect the metabolic process of Ang and bradykinin. The drug is well absorbed after oral administration, and the active metabolites of carboxylic acid type and other inactive metabolites are formed after first-pass metabolism, and the bioavailability is about 33%. The blood concentration of the drug and its active metabolites reach the peak at 1h and 3-4h after taking the drug; the half-life is 2h and 6-9h respectively; the plasma protein binding rate is more than 99%; the plasma clearance is 600ml/min and 50ml/min respectively; the renal clearance is 74ml/min and 26ml/min respectively; they are excreted from urine and feces.
Valsartan is highly selective in blocking AT1 receptors, blocking both classical and non-classical pathways, and completely blocking the action of Ang, which is 2000 times more selective for AT1 than AT2 and has no effect on other receptors, thus indirectly increasing the physiological effect of AT2. The drug does not need to be biotransformed to achieve its pharmacological activity and has a rapid onset of action. It is rapidly absorbed from the gastrointestinal tract after oral administration, and its efficacy is not affected when taken with food. The dose of 80 mg/d is commonly used and can be gradually increased to 160 mg/d or even 320 mg/d. The bioavailability of the drug in humans is about 25%, the time to reach peak plasma concentration is 2 h, the steady-state volume of distribution is 17 L, the plasma protein binding rate is 85%-99%, and the clearance half-life is (6±1) h [16]. The drug effectively lowers blood pressure smoothly for 24 h with a trough-to-peak ratio of 69% and does not alter the rhythm of blood pressure changes. Metabolism in the liver is minimal, and no dose adjustment is required in patients with mild to moderate hepatic impairment. It is excreted in its original form, of which 70% is excreted by bile and 30% by the kidney. It can also improve renal hemodynamics and reduce urinary protein excretion.
(ii) Comparison of AT1RA and ACEI
(1) AT1RA can block various functions mediated by AT1 receptor subtypes, and its beneficial effects seem to be stronger than those of ACEI regardless of the pathway of origin; (2) AT1RA selectively blocks AT1 receptor subtypes and does not cause the accumulation of bradykinin and substance P. Therefore, the adverse effects of dry cough caused by ACEI can be significantly reduced; therefore, it is suitable for cases in which ACEI cannot be tolerated, without cough, slowed heart rate, edema, or cough. Therefore, it is suitable for cases where ACEI is not tolerated, without side effects such as cough, slowed heart rate, edema, first dose reactive hypotension, and blood pressure rebound after stopping the drug. However, it is obvious that AT1RA cannot act through bradykinin, and its antihypertensive effect is somewhat affected. (3) AT1RA blocks the physiological function mediated by AT1 receptor subtype, and the proportion of AT2 receptor subtype in plasma and tissues will be relatively increased, then the physiological function mediated by AT2 receptor subtype may be enhanced, and its benign effect of lowering blood pressure and inhibiting cell proliferation will be exerted. In contrast, after ACEI application, AngII levels are decreased, not only for AT1 receptor stimulation, but also for AT2 receptor stimulation. ④Because ATlRA has no significant effect on intra-glomerular hemodynamics, ATlRA does not have similar effects of ACEI in reducing high intra-glomerular pressure and improving hyperfiltration. ATlRA does not cause a decrease in transient GFR and can keep GFR relatively high, thus delaying dialysis time. ⑤ The dose required for AT1 receptor antagonists in some experiments is high, and the renoprotective effect appears later. In addition, the levels of Ang in blood and tissues did not decrease after the application of AT1RA, but the fraction bound to the AT1 receptor was significantly reduced, while the concentration of Ang that could not bind to the receptor may have increased, and the possible effects on the organism have yet to be elucidated.
(iii) Combination of ACEI and ATlRA
ACEI and ATl receptor antagonists both block the RAS system, but their blocking links are different and their mechanisms of action are also different. Clinical studies have shown that the combined use of ACEl and ATl receptor antagonists can significantly reduce proteinuria, and their proteinuria-lowering effects are not dependent on the hypotensive and/or GFR-lowering effects. The combination of these two agents does not lead to a significant decrease in blood pressure and GFR while enhancing the proteinuria-lowering effect.
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