Molecular biology of the vascular renin-angiotensin system.

Considerable evidence has been accumulated for a renin-angiotensin system in the blood vessel wall with local generation of both angiotensin I and angiotensin II that plays an important role in blood pressure regulation. A major source for vascular renin is renal renin taken up by the arterial wall from the circulation. However, recent studies suggest that, in addition, local synthesis of components of the renin-angiotensin cascade also takes place in the vessel wall. The contribution that these locally derived components make to the functions of the vascular renin-angiotensin system remains to be elucidated. Studies, particularly in vitro, suggest that vascular pathways for angiotensin generation not involving renin or angiotensin-converting enzyme may also exist. As in the case of the locally derived components of the renin-angiotensin cascade, the role of these alternate pathways in the physiology of the vascular wall remain to be defined.     

Linkage disequilibrium analysis of the renin-angiotensin system genes

The genes of the renin-angiotensin system (RAS) are important candidates to confer susceptibility to cardiovascular diseases. A large number of association studies between cardiovascular traits and the polymorphisms in RAS have been conducted, although inconsistent results are often reported. The patterns of linkage disequilibrium in RAS genes have also been reported in different populations. However, our understanding of the genetic architecture underlying the RAS is still limited despite rapid progress in empiric studies regarding the patterns of the human genome as a whole. In this review, the linkage disequilibrium among the polymorphisms within the four RAS genes and current association analyses involving the RAS are discussed, as well as some of the gaps of knowledge and possible solutions.     

肾素-血管紧张素系统与肝纤维化发生

目的：组织纤维化的发生与局部肾素－血管肾张素系统（renin-angiotensin system,RAS)激活有关,本研究,旨在通达观察血管紧张素转化酶抑制剂和血管紧张素1型（AT1）受体阻断剂对实验性肝纤维化的疗效,以期明确RAS在肝纤维化发病中的作用,并对AT1受体在肝内表达的特点及肝星状细胞（HSC）的是否表达该受体作初步探讨,方法：给预SD大鼠CCl4的同时,给预血管紧张素转化酶抑制剂依那普利（10mg.kg^-1,d^-1)和AT1受体阻断剂氯沙坦（10mg.kg^-1.d^-1),共6周,利用图像分析系统对肝纤维化程度进行评价,肝组织AT1受体表达受用免疫组化法检测,结果：依那普利和氯沙坦均可显著抑制大鼠肝纤维化的发生（P＜0．05）,联合应用相同剂量的依那普利和氯沙坦疗效与单独应用比较,差异无显著性（P＞0．05）,但可抑制氯沙坦治疗后血清血管紧张素II水平的升高（P＜0．05）,正常大鼠AT1受体主要表达于血管壁,在肝纤维化,该受体分布与α－平滑肌动蛋白（α-SMA)G表达纤维间隔分布一致,结论：肝纤维化的发生与RAS激活有关,RAS抑制剂具有良发的抗纤维化作用,但联合应用转化酶抑制剂和AT1受体阻断剂,并不断加其抗纤维化疗效,肝纤维化发生过程中,肝星状细胞功能的改变可能与其表达AT1受体有关。     

Effects of calcium channel and renin-angiotensin system blockade on intravascular and neurohormonal mechanisms of hypertensive vascular disease

Several classes of antihypertensive drugs have been shown to improve vascular function through mechanisms other than reducing blood pressure (BP) alone. Certain dihydropyridine calcium channel blockers (CCBs) and inhibitors of the renin-angiotensin system (RAS) increase nitric oxide (NO) bioavailability and decrease oxidative stress, thereby improving endothelial activity and vascular function. Pulse wave analyses have shown that these agents reduce the impact of pressure wave reflections on central systolic BP (SBP), consistent with a decrease in arterial stiffness. The complementary vascular mechanisms of these drug classes suggest that combination therapy may be effective for improving clinical outcomes. In animal model studies, combination calcium channel/RAS blockade has been shown to be more effective in improving endothelial dysfunction than treatment with drugs from either class alone. Furthermore, results from recent clinical trials suggest a greater reduction in central aortic SBP, pulse pressure, and cardiovascular events with calcium channel/RAS blockade vs. beta-blocker/diuretic therapy. These studies support the potential benefit of combination calcium channel and RAS blockade in the prevention and treatment of cardiovascular disease.     

Genotypic interactions of renin-angiotensin system genes in myocardial infarction

BACKGROUND: Three-gene interactions among the genetic polymorphisms of the renin-angiotensin system (RAS) associated with acute myocardial infarction (AMI) have not been examined in a single population. We hypothesized that all types of gene-to-gene associations may occur in AMI, but that some will have a higher risk, depending on the gene frequencies. METHODS: Polymorphisms of the AGT (M235T), ACE (I/D) and AGTR1 (A1166C) genes in AMI patients and controls were analyzed using the polymerase chain reaction. Classic coronary risk factors were analyzed in all individuals. RESULTS: Logistic regression analysis of these factors and the genetic polymorphisms demonstrated that smoking, family history of CAD, arterial hypertension and total cholesterol were the most significant contributors to AMI. The genotypic frequencies for all three genes alone were similar between the infarction and control groups, with no increased risk of developing AMI. Double homozygous combinations for normal alleles (MM of AGT, II of ACE and AA of AGTR1) had a lower risk of AMI (odds ratio<0.38), indicating a protective effect in these individuals. In genotypic combinations that included at least one unfavorable allele, the risk (odds ratio) of developing AMI was 2.92, 2.63 and 2.68 for AGT vs. ACE, AGT vs. ATR1 and ACE vs. AGTR1, respectively. The positive interaction among the three genes and the risk of AMI had an odds ratio of 3.78 with a 95% CI of 0.88-12.85. CONCLUSIONS: The risk of developing AMI is higher whenever there are unfavorable alleles in gene-to-gene associations in the RAS.     

Associations between hypertension and genes in the renin-angiotensin system

The genes of the renin-angiotensin system have been subjected to intense molecular scrutiny in cardiovascular disease studies, but their contribution to risk is still uncertain. In this study, we sampled 192 African American and 153 European American families (602 and 608 individuals, respectively) to evaluate the contribution of variations in genes that encode renin-angiotensin system components of susceptibility to hypertension. We genotyped 25 single-nucleotide polymorphisms in the renin-angiotensin system genes ACE, AGT, AGTR1, and REN. The family-based transmission/disequilibrium test was performed with each single-nucleotide polymorphism and with the multilocus haplotypes. Two individual single-nucleotide polymorphisms were significantly associated with hypertension among African Americans, and this result persisted when both groups were combined. The associations were confirmed in haplotype analysis for REN, AGTR1, and ACE in African Americans. Consistent but less significant evidence was found in European Americans. We also randomly sampled unrelated individuals across families to obtain 84 cases and 108 controls among the African Americans and 41 cases and 113 controls in the European Americans. Single-nucleotide polymorphism and haplotype analyses again showed consistent, albeit weaker, results. Thus, in this biracial population sample, we find evidence that interindividual variation in the renin-angiotensin system genes contributes to hypertension risk.     

Variants of renin-angiotensin system genes and echocardiographic left ventricular mass

Aims Variants of renin–angiotensin system genes are shown tobe associated with cardiovascular pathology. The associationbetween renin–angiotensin system genes and left ventricularmass was investigated in a population-based case-control study. Methods and Results The association between echocardiographic left ventricular massand both insertion/deletion polymorphism of the angiotensin-convertingenzyme gene and the methionine|adthreonine variant at position235 of the angiotensinogen gene was studied in a random cohortof 430 hypertensive and 426 control subjects. No differencesin the adjusted left ventricular mass values between the differentgenotypes were seen among either the hypertensive or the controlsubjects, whether men or women, or in the subgroups of normotensiveor physically active subjects. Gene variation had no statisticallysignificant synergistic effect on left ventricular mass values.In control women, the deletion allele of the angiotensin-convertingenzyme gene was associated with an increased risk of left ventricularhypertrophy. However, this finding was based on a small numberof women with left ventricular hypertrophy and should be interpretedwith caution. Conclusion Variations in renin–angiotensin system genes had no majoreffect on left ventricular mass in this middle-aged population-basedcohort of hypertensives and control subjects.     

The renin-angiotensin system and vascular and dipsogenic regulation in elasmobranchs

The role of a renin-angiotensin-like system (RAS) in the regulation of blood pressure and drinking has been investigated in the elasmobranch, Scyliorhinus canicula. Injection of exogenous angiotensin II produced, as expected, a vasopressor response, though injection of the converting enzyme inhibitor, Captopril, alone produced little change in resting blood pressure. Papaverine, a smooth muscle relaxant, reduced blood pressure which completely recovered within 30 min. A subsequent injection of Captopril produced a rapid vasodepressor response with no recovery over 2 hr. The low basal levels of drinking in dogfish were not altered by Captopril injection but angiotensin II-induced increased drinking and papaverine administration resulted in markedly stimulated water intake, which was inhibited by coadministration with Captopril. Captopril inhibition of the recovery in blood pressure and associated dipsogenic response following the papaverine-induced hypotension is consistent with the activation of a RAS-like system in the dogfish. This and other evidence supporting the presence of a RAS-like system in elasmobranchs are discussed in relation to other vertebrates.     

Systemic hypertension and the renin-angiotensin system in diabetic vascular complications

Antihypertensive treatment in the diabetic patient is a critical issue because hypertension has an impact on all of the vascular complications of diabetes, including nephropathy, retinopathy, atherosclerosis, and left ventricular hypertrophy. These complications are a consequence of altered endothelial-vascular smooth muscle interrelations that ultimately enhance vasoconstriction and after the remodeling processes in the vascular wall. Several observations suggest that the renin-angiotensin system (RAS) may be an important contributor to these processes in diabetes mellitus. In both animal and human studies, angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to slow the progression of glomerulosclerosis, prevent abnormal remodeling processes in the heart following injury, and slow the progression of atherosclerosis. In particular, ACE inhibitors appear to protect the kidney more than would be expected from simply the lowering of blood pressure and decreasing of intraglomerular pressure, possibly because angiotensin II has both hemodynamic and direct effects on the glomerulus. Paradoxically, however, the activity of the circulating RAS is low in diabetic patients. Part of these seemingly inconsistent observations may be due to (1) potential activity of tissue RASs, (2) increased sensitivity to angiotensin II in diabetes, or (3) an effect of ACE inhibition on other systems in addition to the RAS. Investigation of these mechanisms will be important in determining the therapeutic role of inhibition of the RAS in diabetes mellitus.     

Endothelial vascular function in hypertensive patients after renin-angiotensin system blockade

It is unclear whether single and combined pharmacologic inhibition of the renin-angiotensin-aldosterone system have similar effects on endothelial function and blood pressure (BP). The authors evaluated 63 hypertensive patients divided into 4 groups (hydrochlorothiazide 25 mg/d; irbesartan [IRBE] 150 mg/d; quinapril [QUIN] 20 mg/d; or IRBE 150 mg/d + QUIN 20 mg/d) and 25 healthy normotensive subjects (normal) followed for 12 weeks. Endothelium-dependent dysfunction measured as flow-mediated dilation at Weeks 0 and 12 were: normal, 11.5%+/-2.4% vs 13.5%+/-2.0%; hydrochlorothiazide, 7.3%+/-2.0% vs 12.8%+/-3.1%; QUIN, 7.2%+/-2.8% vs 13.2%+/-2.1%; IRBE, 7.1%+/-2.8% vs 13.0%+/-2.9%; and IRBE + QUIN, 7.5%+/-1.9% vs 12.8%+/-3.0%. Nitroglycerin-mediated responses were: normal, 26.0%+/-1.9% vs 24.0%+/-2.5%; hydrochlorothiazide, 17.0%+/-2.2% vs 18.3%+/-2.6%; QUIN, 17.8%+/-3.2% vs 23.4%+/-3.0%; IRBE, 16.8%+/-3.6% vs 24.7%+/-2.0%; and IRBE + QUIN, 17.3%+/-3.0% vs 25.1%+/-2.5%. Antihypertensive therapy restored BP to normal and improved the endothelium-dependent and -independent dysfunction after renin-angiotensin-aldosterone system blockade. In a further finding, the combined effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade was not superior to the action of either of these treatments separately.     

Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.     

Postnatal development of the renin-angiotensin system in thyroidectomized rats

Postnatal changes in plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate (PRS) and plasma angiotensin II concentration (AII) were studied in young thyroidectomized rats from the 4th to the 10th week of life. Although there were no differences in the PRA pattern between thyroidectomized and euthyroid animals, an increase in PRC from the 6th week of life, together with a reduction of the glomerular filtration rate (GFR) and an increase in the fractional excretion of sodium (FENa) from the 8th week of life, was observed in young hypothyroid animals. Moreover, in thyroidectomized animals, PRS and AII declined until the 10th week of age, while in euthyroid animals an increase of PRS and AII was observed between the 8th and 10th weeks of life. These results show that the changes in sodium renal handling following thyroidectomy could have an influence on the RAS components.     

肾素—血管紧张素系统三个基因与糖尿病视网膜病变的相关性

目的研究肾素-血管紧张素系统三个关键基因与糖尿病机网膜病变的相关情况。方法对211例中国汉族人（2型糖尿病150例,其中49例有视网膜病变;对照者61例）,检测血管紧张素Ⅰ转换酶基因（ACE）、血管紧张素原基因（AGT）及血管紧张素Ⅱ受体1基因（AGTRI）DNA标记。结果ACE与病程早期（≤1年）出现的视网膜病变相关．基因型频率比较中P＝0．009～0．054;等位基因比较中P＝0．001～0．015。AGTR1及AGT与病程＞1年者的视网膜病变相关,前者基因型频率比较中P＝0．009～0．053;等位基因P＝0．013;后者基因型比较中,P＝0．021～0．045;等位基因P＝0．008～0．035。Logistic回归分析在校正并发冠心病及高血压状态后支持上述结果。结论肾素-血管紧张素系统基因参与中国人2型糖尿病视网膜病变的发病。