Mechanism of action of angiotensin-receptor blocking agents

Angiotensin II is the most active hormone of the reninangiotensin system. In humans, two angiotensin receptors have been identified: AT₁ and AT₂. In adults, most of the effects of angiotensin II are mediated by the AT₁ receptor; the function of the AT₂ receptor is not yet well established. Angiotensin II has both systemic and local paracrine effects. Increased activity of angiotensin II and stimulation of the AT₁ receptor have been linked to the development of several cardiovascular and renal diseases, including hypertension, heart failure, left ventricular hypertrophy, and diabetic nephropathy. Over the past two decades, angiotensin-converting enzymes have been used to manage these diseases. However, the side effects and less-thanmaximum therapeutic effects of angiotensin-converting enzyme inhibitors, particularly in the decrease of mortality associated with congestive heart failure, have led to the development of AT₁-receptor blockers.     

Promoter polymorphism of the beta2 bradykinin receptor gene is associated with essential hypertension.

The present study examined the genetic contribution of the human beta2 bradykinin receptor gene in Japanese subjects with essential hypertension, and identified a -58T/C polymorphism of the core promoter that might be responsible for essential hypertension in Japanese. The study consisted of 100 hypertensive subjects and 100 age- and sex-matched controls. The allelic frequencies were 0.575 for the C allele and 0.425 for the T allele in hypertensive subjects, and 0.465 for the C allele and 0.535 for the T allele in normotensive subjects. The allelic frequencies were in Hardy-Weinberg equilibrium. Significant differences between hypertensive and normotensive subjects were seen in the genotypes distribution (p=0.049) and allelic frequencies (p=0.028), and the beta2 bradykinin receptor gene variant was associated with human essential hypertension in this Japanese population. This new marker may provide a valuable tool for assessing the risk for putative bradykinin-associated common diseases, such as hypertension, and cardiovascular diseases with genetic determinism. These results suggest that the -58 polymorphism of the human beta2 bradykinin receptor gene is an independent risk factor for essential hypertension in the Japanese population.     

Novel actions of angiotensin II via its renal type-2 (AT2) receptor

The vast majority of the biologic effects of angiotensin II have been considered to be mediated by the subtype-1 (AT₁) receptor. The AT₂ receptor is expressed to a low degree in most adult cells and tissues, and its function has not been understood. Recent studies, however, have identified novel actions of angiotensin II mediated by the AT₂ receptor in the kidney. These AT₂ receptor actions have importance in the control of blood pressure and hypertension. The AT₂ receptor mediates a renal vasodilator cascade, including generation of bradykinin, nitric oxide, and cyclic GMP. This action of angiotensin II occurs when the renin-angiotensin system is activated, as in sodium depletion. The AT₂ receptor also appears to mediate prostaglandin (PG) F_α formation, probably by stimulating conversion of PGE2 to PGF_α. The AT₂ receptor plays a counter-regulatory vasodilator role opposing the vasoconstrictor actions of angiotensin II. The AT₁ and AT₂ receptors engage in inter-receptor “cross-talk.” In the absence of the AT₂ receptor, sustained angiotensin II pressor and antinatriuretic hypersensitivity occurs, mediated by a deficiency of bradykinin, nitric oxide, and cyclic GMP. The AT₂ receptor may play an important role in stimulating pressure natriuresis, but definitive studies are required to resolve this issue. The AT₂ receptor mediates several renal actions of angiotensin II, appears to be important in the physiologic regulation of blood pressure, and may be involved in the pathophysiology of hypertension.     

Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese.

Angiotensin II type 1 (AT1) receptor mediates the vasoconstriction and growth-promoting effect of angiotensin II in humans. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166; A1166C) may be associated with essential hypertension (HT). However, several conflicting results have also been reported. Therefore, we conducted an association study between A1166C variants of the AT1 receptor gene and hypertension in the Japanese population. We genotyped this variant in 3,918 subjects (1,492 hypertensive subjects and 2,426 normotensive subjects) recruited from the Suita study. In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of the C allele: 8.1% vs. 7.8%, p=0.74) or women (8.1% vs. 7.7%, p=0.60). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the A1166C polymorphism of AT1 receptor is unlikely to influence blood pressure status in the Japanese population.     

Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT₁ and AT₂ receptors. For that reason, the aim of this work was to study the gene and protein expression of AT₁ and AT₂ receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60?mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT₁ receptors than normotensive rats while the AT₂ expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT₁ and AT₂ receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT₁ and AT₂ receptors. However, the overexpression of AT₂ could be associated with the reduction in the response to Ang II in the early stage of diabetes.     

In hypertension, the kidney breaks your heart

The renin-angiotensin system (RAS) is a master regulator of blood pressure and fluid homeostasis. Because RAS components are expressed in several tissues that may influence blood pressure, studies using conventional gene targeting to globally interrupt the RAS have not determined the contributions of angiotensin II receptor type 1 (AT₁) receptors in specific tissue pools to blood pressure regulation and tissue injury. Recent experiments using kidney cross-transplantation and mice lacking the dominant murine AT₁ receptor isoform, AT 1A, have demonstrated that 1) AT₁ receptors inside and outside the kidney make equivalent contributions to normal blood pressure homeostasis, 2) activation of renal AT 1 receptors is required for the development of angiotensin II-dependent hypertension, and 3) this blood pressure elevation rather than activation of AT₁ receptors in the heart drives angiotensin II-induced cardiac hypertrophy. These findings, together with previous experiments, confirm the kidney’s critical role in the pathogenesis of hypertension and its complications.     

Influence of autoantibodies against AT1 receptor and AGTR1 polymorphisms on candesartan-based antihypertensive regimen: Results from the Study of Optimal Treatment in Hypertensive Patients with Anti-AT1-Receptor Autoantibodies trial

The autoantibodies against angiotensin AT₁ receptors (AT₁-AAs) in patients with essential hypertension exhibited an agonistic action like angiotensin II and maintained high blood pressure (BP). Angiotensin II receptor gene (AGTR1) polymorphisms were associated with BP response to RAS inhibition in the hypertensive population. Furthermore, the BP response to AT₁ receptor blockers varied significantly among individuals with hypertension. We hypothesized that the polymorphisms of the AGTR1 and AT₁-AAs might affect antihypertensive response to AT₁ receptor blockers based in patients with primary hypertension. Patients who received a candesartan-based regimen came from the SOT-AT₁ study (Study of Optimal Treatment in Hypertensive Patients with Anti-AT₁-Receptor Autoantibodies). The established enzyme-labeled immunosorbent assay was used to detect AT₁-AAs in the sera of the patients. Genotype 3 single nucleotide polymorphisms in AGTR1 gene was used by DNA sequencing. The correlations among AT₁-AAs, AGTR1 gene polymorphisms or haplotypes, and the antihypertensive effect candesartan-based were analyzed using SPSS. The percentage of systolic BP reduction that was candesartan-based was greater in AT₁-AA positive groups than in AT₁-AA negative ones (21 ± 8 vs. 18 ± 9; P = .001). Meanwhile, systolic BP reduction that was candesartan-based was more significant in the group of rs5186 AC genotypes than AA homozygotes after adjusting for other confounding factors (37.55 ± 13.7 vs. 32.47 ± 17.27 mm Hg; adjusted P = .028). Furthermore, haplotypes (GCC) and (AAC) had impacts on the antihypertensive effect of candesartan therapy. The AT₁-AAs, AGTR1 gene polymorphisms and haplotypes solely or jointly have influences on candesartan-based antihypertensive response in patients with primary hypertension.     

The renin-angiotensin and adrenergic nervous system in cardiac hypertrophy in fructose-fed rats

BackgroundHyperinsulinemia and insulin resistance are associated with left ventricular hypertrophy (LVH) and cardiovascular complications in hypertensive subjects. The aim of this study was to explore the mechanisms for LVH including activation of the renin-angiotensin system system (RAS) and the sympathetic nervous system and their activation by insulin using a rat model of hyperinsulinemia and insulin resistance.Methods:Male Sprague-Dawley rats were fed a high-fructose or control diet. The fructose-fed rats (FFR) were divided into four subgroups that were administrated either vehicle or the following antihypertensive drugs (n = 6–8) for 4 weeks: 1) olmesartan, an angiotensin II type 1 (AT₁) receptor antagonist; 2) bunazosin, an α₁-receptor blocker; and 3) hydralazine, a direct vasodilator.Results:Fructose feeding induced significant increases in mean systolic blood pressure (BP) levels at 4 weeks (control, 117 v fructose, 131 mm Hg), left ventricular weight, and the sum of the insulin level in response to a glucose tolerance test (2 g/kg). Fructose feeding also increased urinary excretion of epinephrine and norepinephrine, the density of cardiac α₁-adrenergic receptors, and the content of angiotensin II in the left ventricle. All antihypertensive drugs decreased systolic BP, but only the AT₁ receptor antagonist attenuated the development of LVH in FFR. The AT₁ receptor antagonist did not affect glucose-mediated insulin responses, but did suppress urinary catecholamine excretion and cardiac α₁-adrenergic receptor density.ConclusionsLeft ventricular hypertrophy in FFR may be less dependent on systemic elevations of BP and more dependent on the RAS and the sympathetic nervous system. Use of an AT₁ receptor antagonist might be the most beneficial way to prevent progression of LVH through direct effects on tissue RAS and the sympathetic nervous system in FFR. As these changes occur in a rat model with hyperinsulinemia, insulin may have a role in promoting LVH by activating the local RAS and sympathetic nervous system activity.     

Lack of correlation between Mbo I restriction fragment length polymorphism of renin gene and essential hypertension in Japanese.

Predisposition to essential hypertension is associated with gene polymorphisms of the renin angiotensin system (RAS). Gene polymorphisms of the angiotensinogen and angiotensin converting enzyme genes are known to be risk factors for hypertension, while few studies concerning the renin gene polymorphism have been published. In the present investigation, we carried out a case control study using a Japanese population to examine the genetic influence of the renin gene on the predisposition to hypertension. Patients (n=235) recruited from outpatients at Osaka University Hospital and diagnosed with essential hypertension or receiving long-term antihypertensive medication participated in the study. Normotensive control subjects (n=510) without a history of hypertension and without diabetes mellitus were recruited from the same population, and were sex-matched with experimental subjects. A polymorphism in intron 9 of the human renin gene was determined as the Mbo I restriction fragment length polymorphism (Mbo I-RFLP). There was no significant association between Mbo I-RFLP of the renin gene and predisposition to essential hypertension in Japanese (p>0.05, chi2=2.1). These results suggest that the Mbo I (+) allele of the renin gene does not increase the risk for hypertension in Japanese.     

Hyper-responsiveness to angiotensin II is related to cardiac structural adaptation in hypertensive subjects.

BACKGROUND: Angiotensin II has been found to be a growth stimulating factor for myocardial cells. In humans, angiotensin II infusion causes vasoconstriction in systemic and renal vasculature and leads to aldosterone secretion. Our hypothesis was that hyper-responsiveness to angiotensin II is related to left ventricular mass in human essential hypertension. METHODS AND RESULTS: In 30 normotensive individuals and 30 subjects with mild essential hypertension (white men, mean age 26+/-3 years), the responsiveness to angiotensin II was assessed by measuring changes in mean arterial pressure, renal blood flow, glomerular filtration rate and aldosterone secretion in response to i.v. angiotensin II infusion (0.5 and 3.0 ng/kg per min). The provoked changes to angiotensin II infusion were similar in the normotensive and hypertensive group with the exception of an exaggerated increase in mean arterial pressure in hypertensives (14+/-5 versus 10+/-5 mm Hg, P<0.001 at 3.0 ng/kg per min angiotensin II). The increase in mean arterial pressure was correlated with left ventricular mass in hypertensive subjects (angiotensin II 0.5 ng/kg per min: r = 0.49, P<0.005; angiotensin II 3.0 ng/kg per min: r = 0.35, P<0.05); no such correlation was found in the normotensive group. After taking into account baseline mean arterial pressure and body mass index, the increase in mean arterial pressure to angiotensin II 0.5 ng/kg per min was still correlated with left ventricular mass (partial r = 0.50, P<0.01). Similarly, the change of glomerular filtration rate but not of renal blood flow in response to angiotensin II 0.5 ng/kg per min was correlated with left ventricular mass, (r = 0.42, P<0.02) in the hypertensive group but not in the normotensive one. This relationship remained significant even after taking baseline glomerular filtration rate, mean arterial pressure and body mass index into account (partial r = 0.43, P<0.05). CONCLUSION: Hyper-responsiveness to angiotensin II is related to an increased left ventricular mass in hypertensive subjects independent of blood pressure.     

At1 Receptor Density Changes During Development of Hypertension in Hyperinsulinemic Rats

In a previous study we showed that the renin-angiotensin system (RAS) plays a role in the etiology of fructose-induced hypertension. To our knowledge, no previous study has evaluated changes in angiotensin II (Ang II) type I receptor (AT₁) density in fructose-fed rats that are insulin resistant and hypertensive. The purpose of this study was to determine the changes in plasma Ang II and AT₁ density associated with the elevation of blood pressure in fructose-treated rats. Male Sprague-Dawley rats were divided into two groups and were fed either normal rat chow or a 60% fructose-enriched diet for four weeks. Plasma Ang II and serum insulin levels of the fructose-treated rats were significantly elevated (p<0.01) by the end of the second week of fructose treatment. Plasma Ang II levels of the fructose-fed rats returned to basal levels by the end of the fourth week of dietary treatment, whereas the serum insulin levels consistently remained elevated. Blood pressure was significantly elevated in the fructose-fed rats within two weeks of fructose treatment. Elevation of blood pressure was associated with left ventricular hypertrophy. Furthermore, there was a significant increase in AT₁ receptor density in the ventricles and a significant decrease in AT₁ receptor density in the aortas of fructose-fed rats at the end of fourth week. There were no significant changes in receptor density in the hypothalami or adrenal glands of fructose-treated rats. These results suggest that chronic fructose treatment activates the renin-angiotensin system, which is manifested by an increase in plasma Ang II, elevation of blood pressure, cardiac hypertrophy, and changes in AT₁ receptor density.     

Role of angiotensin II type 2 receptor during regression of cardiac hypertrophy in spontaneously hypertensive rats

We previously reported that the AT₁ receptor antagonist valsartan and the angiotensin converting enzyme (ACE) inhibitor enalapril decrease DNA synthesis and stimulate apoptosis in interstitial fibroblasts and epicardial mesothelial cells during regression of ventricular hypertrophy in spontaneously hypertensive rats (SHR). To examine the role of the AT₂ receptor in this model, we studied hearts from SHR treated with valsartan or enalapril either alone or combined with the AT₂ antagonist PD123319 for 1 or 2 weeks. Apoptosis was evaluated by quantification of DNA fragmentation or by TUNEL labeling. At 1 week, valsartan significantly increased ventricular DNA fragmentation, increased apoptosis in epicardial mesothelial cells, and decreased DNA synthesis. At 2 weeks, ventricular DNA content and cardiomyocyte cross-sectional area were significantly reduced. These valsartan-induced changes were attenuated by PD123319 co-administration. However, valsartan-induced increases in apoptosis of left ventricular interstitial non-cardiomyocytes was unaffected by the AT₂ blocker. Enalapril-induced changes were similar to those observed with valsartan but were not affected by co-treatment with PD123319. These results demonstrate that AT₁ and AT₂ receptors act in a coordinated yet cell-specific manner to regulate cell growth and apoptosis in the left ventricle of SHR during AT₁ receptor blockade but not ACE inhibition.     

The Role of Type 1 Angiotensin Receptors on T Lymphocytes in Cardiovascular and Renal Diseases

The renin–angiotensin system plays a critical role in the pathogenesis of several cardiovascular diseases, largely through activation of type I angiotensin (AT₁) receptors by angiotensin II. Treatment with AT₁ receptor blockers (ARBs) is a proven successful intervention for hypertension and progressive heart and kidney disease. However, the divergent actions of AT₁ receptors on individual cell lineages in hypertension may present novel opportunities to optimize the therapeutic benefits of ARBs. For example, T lymphocytes make important contributions to the induction and progression of various cardiovascular diseases, but new experiments indicate that activation of AT₁ receptors on T cells paradoxically limits inflammation and target organ damage in hypertension. Future studies should illustrate how these discrepant functions of AT₁ receptors in target organs versus mononuclear cells can be exploited for the benefit of patients with recalcitrant hypertension and other cardiovascular diseases.     

Lack of association of the angiotensin converting enzyme gene polymorphism with essential hypertension in a chinese population

To examine the association between insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene and essential hypertension in a Chinese population, a case-control study was conducted using 157 hypertensive and 115 normotensive subjects. The I/D polymorphism of the ACE gene was identified by polymerase chain reaction. Plasma ACE activity was determined using spectrophotometry. The difference of allele frequencies between normotensives and hypertensives was statistically significant (X² = 4.467, P = .035), while the gentotype distribution was not different between normotensive and hypertensive subjects (X² = 3.954, P = .138). Plasma ACE activity was highest in the DD genotype, followed by the ID genotype, and the lowest in the II genotype (P = .0001 in normotensives and P = .163 in hypertensives, respectively). Thus, we conclude that the ACE gene polymorphism is not associated with essential hypertension in this Chinese population, but plasma ACE activity is genetically determined in the normotensive Chinese.     

原发性高血压患者血管紧张素转化酶和血管紧张素受体基因多态性的研究

目的　探讨血管紧张素转化酶 ( ACE)及血管紧张素 - 1型受体 ( AT1 R)基因多态性与原发性高血压 ( EHT)的关系。方法　应用聚合酶链反应及 PCR加酶解方法检测 1 50例健康人 ( NT)及 1 52例 EHT患者 ACE I/ D基因多态性的 ACE及 AT1 R A1 1 6 6 C突变。结果　 EHT组ACE I/ D基因多态性等位基因频率 I为 0 .50 ,D为 0 .50 ,D等位基因频率及基因型频率显著高于 NT组 ( P<0 .0 5) ;而两者之间的 AT1 R A1 1 6 6 C的C等位基因频率差异无显著性 ( P>0 .0 5)。结论　 ACE基因可能是 EHT的重要遗传因素 ,AT1 R基因 A1 1 6 6 C多态性与 EHT无关     

Specifics of distribution of polymorphic markers of the renin-angiotensin-system genes, relation to ventricular hypertrophy in patients with essential hypertension of Uzbek nationality

AIM: To study distribution of polymorphisms of angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), aldosterone synthase (CYP11B2) genes, and their association with processes of left ventricular remodeling in men of uzbek nationality with essential hypertension (EH). MATERIAL AND METHODS: Patients with stage 1-2 EH were genotyped for carrying I/D polymorphism of ACE gene, A1166C polymorphism of AT1R gene, and C(-344)T polymorphism of CYP11B2 gene. Echocardiography was used for measurement of left ventricular myocardial mass index. RESULTS AND CONCLUSIONS: Special features of distribution of studied genes among uzbek men were the following: accumulation of ID-genotype of I/D polymorphic marker of ACE gene among patients with EH, predominance of I-allele and II-genotype of ACE gene in healthy persons; accumulation of AA-genotype and A-allele of A1166C polymorphic marker of AT1R gene in patients with EH and healthy persons, while CC genotype was found only in patients with EH; predominance of CT genotype of C(-344)T polymorphic marker of CYP11B2 gene in patients with EH and healthy persons with high prevalence of T-allele in patients with EH. Carriage of TT genotype of C(-344)T polymorphic marker of CYP11B2 was associated with higher values of diastolic blood pressure. Associations were revealed between carriage of TT-genotype and T-allele of CYP11B2 gene, AC+CC-genotypes of AR1R gene and severity of left ventricular hypertrophy.     

Update: Role of the angiotensin type-2 (AT2) receptor in blood pressure regulation

In the past, virtually all of the physiologic actions of angiotensin II (ANG II) were thought to be mediated by the type-1 ANG II receptor. However, there is now a compelling body of evidence suggesting that the type-2 (AT₂) receptor is an important regulator of renal function and blood pressure (BP). The AT₂ receptor stimulates a bradykinin (BK)-nitric oxide (NO)-cyclic GMP vasodilator cascade in blood vessels and in the kidney. Recent studies have shown that absence of the AT₂ receptor lends to pressor and natriuretic hypersensitivity to ANG II. Furthermore, there is now excellent evidence that the AT2 receptor mediates pressure natriuresis. The AT₂ receptor also stimulates the conversion of prostaglandin E2 (PGE₂) to PGF₂. In addition, it is now apparent that the therapeutic reduction in BP with AT₁ receptor blockade (eg, losartan, valsartan, candesartan) is mediated by ANG II stimulation of the AT₂ receptor, leading to increased levels of BK, NO, and cGMP. Current evidence predicts that AT₂ receptor agonists would be beneficial in the treatment of hypertension.     

The DD genotype of the angiotensin converting enzyme gene is negatively associated with right ventricular hypertrophy in male patients with chronic obstructive pulmonary disease.

The renin angiotensin system plays an important role in the development of pulmonary artery remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary hypertension as may occur in patients with COPD. Several polymorphisms of genes encoding for components of the renin angiotensin system such as the M235T polymorphism in the angiotensinogen gene, the 287-base-pair insertion (I)/deletion (D) polymorphism at intron 16 of the ACE gene, and the A1166C polymorphism in the angiotensin II type 1 receptor gene have been associated with an increased risk of cardiovascular diseases. With respect to the pulmonary circulation, only limited data exist on possible associations between polymorphisms of these genes and pulmonary hypertension and/or right ventricular hypertrophy. The objective of the present study was to investigate a possible relationship between polymorphisms of the renin angiotensin system and electrocardiographic evidence of right ventricular hypertrophy in patients with COPD. We therefore determined the angiotensinogen (M235T), angiotensin converting enzyme (I/D), and angiotensin II type 1 receptor (A1166C) genotypes in 87 patients with severe COPD and correlated these data with electrocardiographic parameters of right ventricular hypertrophy. Thirty-one patients (36%) of 87 patients with COPD showed electrocardiographic evidence of right ventricular hypertrophy. In the male, but not in the female, subgroup, the angiotensin-converting enzyme DD genotype was negatively associated with electrocardiographic evidence of right ventricular hypertrophy (male: chi2 = 3.8, p = 0.05; female: chi2 = 0.05, p = 0.82). We found no associations between the investigated polymorphisms in the angiotensinogen and angiotensin II type 1 receptor genes and electrocardiographic evidence of right ventricular hypertrophy.