Role of Angiotensin II in Mechanical Stress-Induced Cardiac Hypertrophy

Many lines of evidence have suggested that the renin–angiotensin system plays an important role in the development of cardiac hypertrophy. Pressure overload-induced cardiac hypertrophy is prevented by angiotensin-converting enzyme inhibitors in vivo, and mechanical stretch induces secretion and production of angiotensin II (Ang II) from cardiac myocytes in vitro. Ang II induces cardiomyocyte hypertrophy through the Ang II type 1 (AT1) receptor. All these results suggest that the AT1 receptor-mediated signaling is critical for the development of mechanical stress-induced cardiac hypertrophy. However, we have recently obtained results from AT1 knockout mice suggesting that mechanical stress can induce cardiac hypertrophy without AT1 receptor-mediated Ang II signaling.     

血管紧张素II对心肌细胞蛋白质合成速率和肌球蛋白重链基因表达的作用

目的：研究血管紧张素ＩＩ（ＡｎｇＩＩ）对心肌细胞蛋白质合成速率和肌球蛋白重链（ｍｙｏｓｉｎｈｅａｖｙｃｈａｉｎ，ＭＨＣ）基因表达的影响。方法：采用放射性同位素氚（３Ｈ）－亮氨酸参入量方法观察培养心肌细胞蛋白质合成速率。应用斑点杂交方法分析ＡｎｇＩ对心肌细胞α－ＭＨＣ和β－ＭＨＣ基因表达的作用。结果：在培养的心肌细胞中加入ＡｎｇＩ可明显增加心肌细胞３Ｈ－亮氨酸的参入量，并可诱导心肌细胞α－ＭＨＣ和β－ＭＨＣ基因表达迅速增加，在一定范围内，两者均呈量效关系。ＡｎｇＩ阻断剂沙拉新（ｓａｒ－ａｌａｓｉｎ）可阻断ＡｎｇＩＩ的上述作用。结论：ＡｎｇＩＩ可增加心肌细胞蛋白质合成速率，促进心肌细胞α－ＭＨＣ和β－ＭＨＣ基因表达。     

Actions of Angiotensin II on Isolated Cardiac Myocytes

Studies on isolated cardiac myocytes have demonstrated that the type 1 (AT1) angiotensin II receptor stimulates multiple cellular processes, including growth, gene expression, and contractility. The AT1 receptor of cardiac myocytes has been shown to activate G-protein-mediated signal transduction pathways, such as those linked to phospholipase C and D activation, and many of the actions of angiotensin II on cardiac myocytes are the consequence of protein kinase C (PKC) stimulation and/or increased intracellular calcium. However, angiotensin II-induced protein synthesis may occur via a PKC-independent process involving phosphatidylinositol 3-kinase activation. The AT1 receptor of cardiac myocytes also couples to novel signaling pathways, such as JAK–STAT, that are likely involved in cell growth, gene expression, or a cellular inflammatory response. In addition, angiotensin II may stimulate cell growth and gene expression of cardiac myocytes through an intracrine action involving a nuclear receptor. Paradoxically, angiotensin II has recently been shown to oppose hypertrophy, or even induce apoptosis, of cardiac myocytes through either the AT1 or type 2 (AT2) angiotensin II receptor. AT1 receptor-mediated apoptosis occurs in some ventricular myocytes in culture and appears to result from the stimulation of calcium-dependent endonucleases. Events linking AT2 receptors to inhibition of cell growth are less well defined but may involve activation of phosphatases. Finally, evidence indicates that angiotensin II may also indirectly stimulate the growth of cadiac myocytes through an AT1 receptor-mediated release of a trophic factor from cardiac fibroblasts.     

Mechanisms Involved in Angiotensin II Induced Increases in Cardiac Output in Pithed Rats

This study was conducted to determine the mechanisms by which angiotensin II (Ang-II) acutely increases cardiac output. Pithed Sprague-Dawley rats were prepared for continuous measurement of cardiac output by electromagnetic flowmetry. Ang-II (31 – 1000 ng/kg, i.v.) produced dose-related increases in cardiac output, heart rate and stroke volume. Although the heart rate increases were abolished by beta-adrenoceptor blockade, the cardiac output responses were unchanged due to an offsetting increase in stroke volume. The constancy of the cardiac output response following beta-adrenoceptor blockade suggested that Ang-II increased cardiac output by constricting venous smooth muscle and thereby increasing venous return. This conclusion is supported by the observation that Ang- I I produced marked increases in 1 eft ventri cul ar end diastolic pressure that paralleled the increases in cardiac output. In fact, based on volume loading with Tyrode's solution, the changes in left ventricular end diastolic pressure produced by Ang-I1 should have resulted in even greater increases in cardiac output. However, it appears that the significant rise in peripheral resistance to Ang-cardiac output. In addition, the Ang-II-induced elevations in II tended to counter the effects of increased venous return on cardiac output. In addition, the Ang-II-induced elevations in cardiac output were not altered by alpha-adrenoceptor blockade. Therefore, catecholamines do not play a role in mediating the Ang-II effects. The results of this study support the conclusion that Ang-II is capable of increasing cardiac output by constriction of venous smooth muscle.     

Effects of Angiotensin II on Expression of the Gap Junction Channel Protein Connexin 43 in Neonatal Rat Ventricular Myocytes

Objectives To study the effects of angiotensin II, as a mediator of cardiac hypertrophy, on expression of connexin 43 (Cx43) in cultured neonatal rat ventricular myocytes and correlation of expression of Cx43 and cardiomyocyte hypertrophy. Methods Cardiomyocytes were isolated from newborn SD rats. Angiotensin II was added into the media to induce myocyte hypertrophy. Cultures were exposed to 10～6 mol/L angiotensin II for 72 h, Cx43 expression was characterized by RT-PCR and Immunofluorescence methods. Results Immunofluorescence analysis revealed decreased Cx43 immunoreactivity in cells treated for 72 h with angiotensin II. RT-PCR analysis demonstrated there was an obvious decrease of Cx43 mRNA level in cells exposed to angiotensin II for 72 h. The changes of expression of connexin 43 were related to its entrance into S phase of the cell cycle. Cultured neonatal rat cardiomyocytes were exposed for 72 h to increase concentrations of angiotensin II (1.0×10-9～1.0×10-6mol/L), resulting in significantly decreased Cx43 expression. Conclusions Angiotensin II leads to a concentration-dependent decrease in Cx43 protein in cultured neonatal rat ventricular myocytes by decreasing Cx43 mRNA synthesis. Signal transduction pathways activated by angiotensin II under pathophysiologic conditions of cardiac hypertrophy could initiate remodeling of gap junctions.     

Valsartan,an Angiotensin II Receptor Blocker,Attenuates Cardiac Dysfunction and Oxidative Stress in Isoproterenol-Induced Cardiotoxicity

Valsartan has significant blood pressure lowering effect via modulating renin-angiotensin system although its mechanism of action in isoproterenol (ISO)-induced myocardial injury is largely unknown. We therefore evaluated the effect of valsartan in ISO-induced oxidative stress and cardiotoxicity during β-adrenergic receptor stimulation in rats. ISO (85 mg/kg, s.c.) was administered on thirteenth and fourteenth day for induction of cardiotoxicity. ISO-treated rats showed significant decrease (P < 0.01) in mean arterial pressure (70.2 ± 9.11 vs. 104.86 ± 8.93), maximal positive (1601.3 ± 338.87 vs. 2789.16 ± 301.76), and negative (1495.76 ± 151.78 vs. 2039.6 ± 279.1) rate of developed left ventricular pressure and increase in left ventricular end-diastolic pressure (5.81 ± 0.51 vs. 2.37 ± 0.43) as compared to the sham group. Similarly, significant reduction in CK-MB (91.42 ± 5.88 vs. 142.63 ± 6.9), LDH (50.52 ± 5.18 vs. 73.28 ± 4.29) levels, and anti-oxidant enzymes activities were observed. Valsartan (15, 30, and 60 mg/kg/day, p.o.) pretreatment for 14 days favorably modulated these altered parameters. However, valsartan (60 mg/kg) only showed significant improvement (P < 0.01) in cardiac dysfunction, myocardial injury markers, and anti-oxidant status of myocardium in ISO-induced cardiotoxicity. Histopathology and ultrastructural studies further validated the protective effect of valsartan (60 mg/kg). Altogether, these results suggest that cardioprotective effect of valsartan is mediated through augmenting endogenous anti-oxidant defense system, preserving hemodynamic function and structural integrity of myocardium.     

Clinical and Experimental Aspects of Olmesartan Medoxomil,a New Angiotensin II Receptor Antagonist

Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de‐esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P‐450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10–80 mg dose‐dependently reduced diastolic blood pressure (DBP). Troughto‐peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once‐daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24‐h DBP and SBP were similar to those of cuff DBP measurement. In mild‐to‐moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24‐h blood pressure. In lowering DBP olmesartan medoxomil, at 10–20 mg/day, was as effective as atenolol at 50–100 mg/day. In mild‐to‐moderate hypertensive patients, olmesartan medoxomil, at 5–20 mg once daily, was more effective than captopril at 12.5–50 mg twice daily. At 20–40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5–10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases.     

血管紧张素 II 受体阻滞剂治疗肥厚型心肌病的Meta 分析

目的 使用Meta分析的方法，评价血管紧张素Ⅱ受体拮抗剂（ARBs）类药物对肥厚型心肌病（HCM）的疗效。方法 检索Web of Science， PubMed， EMBASE，Cochrane Central Register of Controlled Trials，中国知网（CNKI），中国生物医学文献光盘数据库（CBMdisk）的文献。纳入与安慰剂或常规治疗相比较的临床随机对照试验，分析ARB类药物治疗HCM的效果。结果 包括228例患者的6个随机对照试验纳入Meta分析，研究显示ARB类药物对于左室射血分数、二尖瓣舒张早期最大血流速度（E）与舒张晚期最大血流速度（A）及左室质量的影响未见统计学差异。结论 ARB类药物对于HCM患者的心脏功能可能没有影响。     

Effects of Exercise Therapy Alone and in Combination with a Calcium Channel Blocker or an Angiotensin Receptor Blocker in Hypertensive Patients

We compared the effects of exercise alone and in combination with a calcium channel blocker (amlodipine) or an angiotensin receptor blocker (valsartan) in hypertensive patients. Our results indicated that exercise therapy exerted similar effects on systolic blood pressure whether administered alone or in combination with amlodipine or valsartan; however, diastolic blood pressure decreased significantly when exercise therapy was combined with amlodipine. However, when combined with valsartan, exercise therapy additionally improved the lipid profile of hypertensive patients. Thus, this study enabled the identification of the drugs suitable for combination with exercise therapy in the treatment of hypertensive patients.     

Three-Month Effects of Candesartan Cilexetil, an Angiotensin II Type 1 (AT1) Receptor Antagonist, on Left Ventricular Mass and Hemodynamics in Patients with Essential Hypertension

Using cine magnetic resonance imaging (MRI) and echocardiography, we investigated the effects of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist, on left ventricular (LV) mass and hemodynamics in patients with essential hypertension. Ten patients (four men and six women) with essential hypertension received candesartan cilexetil 2–8 mg/day orally for 8–12 weeks. After drug administration, systolic blood pressure (BP) decreased from 178.9 ± 17.2 mmHg (mean ± SD) to 150.2 ± 14.3 mmHg (P < 0.0001) and diastolic BP from 101.4 ± 6.5 mmHg to 87.8 ± 11.9 mmHg (P = 0.0021). Both MRI and echocardiography revealed a significant decrease in LV mass index (LVMI) after candesartan cilexetil. MRI indicated that LVMI decreased from 111.3 ± 31.3 g/m2 to 102.6 ± 32.1 g/m2 (P = 0.0484) and echocardiography that LVMI decreased from 123.9 ± 31.1 g/m2 to 115.8 ± 31.4 g/m2 (P = 0.0316). Total systemic vascular resistance decreased significantly during treatment with candesartan cilexetil in both MRI and echocardiography assessment, from 1847.2 ± 636.3 dynes·s·cm–5 to 1540.4 ± 432.0 dynes·s·cm–5 (P = 0.0034) on MRI and from 1820.4 ± 318.8 dynes·s·cm–5 to 1659.0 ± 317.7 dynes·s·cm–5 (P = 0.0060) on echocardiography. These findings suggest that candesartan cilexetil 2–8 mg/day orally for 8–12 weeks is beneficial in the regression of cardiac hypertrophy in patients with essential hypertension.     

Effects of Angiotensin II Receptor Blockers on Relationships Between 24-Hour Blood Pressure,Autonomic Function,and Health-Related QOL

We report the relationship between 24-hour (24-h) blood pressure, autonomic function, and health-related quality of life (HRQOL) in normotensives and hypertensives. The aim of this study was to determine whether there is a relationship between 24-h blood pressure, autonomic function, and HRQOL during treatment with an angiotensin receptor blocker (ARB) in patients with hypertension. Thirteen patients with hypertension were randomly treated with losartan (25–50 mg, n = 5), candesartan (4–8 mg, n = 4), valsartan (80 mg, n = 1), telmisartan (40 mg, n = 2), and olmesartan (10 mg, n = 1), daily. 24-h ambulatory blood pressure (BP) was measured before treatment and 3 months after treatment. Sympathetic nervous activity (the ratio of low frequency to high frequency component (LF/HF)) and parasympathetic nervous activity (high frequency component (HF)) were calculated by analyzing heart rate variability. HRQOL was assessed using a medical outcome study short-form 36-item health survey (SF-36) questionnaire. All of the participants completed the study. Angiotensin receptor blocker treatment reduced 24-h mean BP (MBP) from 107 ± 9 to 100 ± 9 mmHg. 24-h MBP positively correlated with 24-h LF/HF in all subjects who received ARB (R = 0.568, p < 0.04). There were no differences in heart rate, serum albumin level, BUN level, creatinine level, potassium level, or HRQOL score. These findings indicated that ARB reduced BP; however, treatment with ARB did not affect the scores of HRQOL and the relationship between 24-h blood pressure and autonomic function.     

Role of Angiotensin II in Hypertension-Induced Cardiac Hypertrophy and Failure

Besides playing a role in blood-pressure regulation and salt and fluid homeostasis, the octapeptide angiotensin II mediates cell growth and differentiation. Its effects are dependent on angiotensin receptors, of which both AT1 and AT2 receptors are extensively described. In cardiac hypertrophy and heart failure, angiotensin receptors are differentially regulated. It is established that AT1 receptors induce cell growth, while AT2 receptors have been associated with growth inhibition, differentiation, and apoptosis. The availability of receptors controlling cell function within a broad spectrum for a single hormone and the regulation of these receptors during cardiac hypertrophy and failure emphasize a complex role for angiotensin II in cardiac pathogenesis. Due to their functional properties, AT1 and AT2 receptors might counteract each other in cell growth processes. Therefore, the current clinical use of specific AT1 receptor antagonists raises questions as to the role of the AT2 receptor in disease processes such as cardiac hypertrophy and failure. Under AT1 receptor antagonist treatment, AT2 receptors are overexposed to angiotensin II. This article describes a possible role of angiotensin II through its angiotensin receptors AT1 and AT2 in cardiac hypertrophy and heart failure.     

Efficacy of Irbesartan, a Receptor Selective Antagonist of Angiotensin II, in Reducing Portal Hypertension

The use of angiotensin II antagonists in the treatment of portal hypertension remains controversial. Our aims were to assess the effect of Irbesartan on portal pressure and to evaluate its safety in cirrhotic patients with portal hypertension. Twenty-five cirrhotic patients were treated in a pilot study with Irbesartan 300 mg orally once daily for 60 days. Hemodynamic evaluations and biochemical tests were performed before therapy and after two months of treatment. Three patients (12%) discontinued treatment for symptomatic arterial hypotension (mean arterial pressure –26.% ± 3.1 versus basal). In the 18 responders, the hepatic venous pressure gradient diminished by a mean of 18.1% ± 10.5 from baseline (p = 0.02); the gradient decreased by 20% or more in only 5 patients (23%). The mean arterial pressure decreased significantly during therapy (92 ± 7 vs 109 ± 25 mm Hg, P < 0.001). In conclusions, Irbesartan induced a marginal reduction in portal pressure and its safety was limited by the pronounced effects on arterial pressure.     

心可舒片联合ARB类降压药治疗高血压性心脏病致心律失常疗效观察

目的 探讨心可舒片联合血管紧张素Ⅱ受体拮抗剂(ARB)类降压药治疗高血压心脏病致心律失常的疗效.方法 回顾总结门诊就诊的高血压心脏病患者167例,随机分为两组.治疗组83例,给予心可舒片及ARB类降压药;对照组84例,给予空白胶囊及ARB类降压药.观察患者治疗3个月和1年后血压、心律失常情况.结果 治疗3个月后,两组患者血压控制良好,并且两组之间无统计学意义,而心房纤颤、房性早搏、室性早搏等心律失常经治疗3个月后,治疗组有效率明显优于对照组,差异有统计学意义(P<0.05).结论 心可舒片联合ARB类降压药,不仅可以有效控制患者血压水平,而且能够有效改善高血压心脏病所导致的房性早搏、室性早搏、心房纤颤等心律失常.     

Effects of an Angiotensin II Type 1 Receptor Blocker on Aortic Valve Sclerosis in a Preclinical Model

Background

Aortic valve sclerosis (AVS) is a chronic progressive disease involving lipid infiltration, inflammation, and tissue calcification. Despite its high prevalence, there are currently no clinically approved pharmaceuticals for the management of AVS. The objective of the current study was to elucidate the effects of an angiotensin II type 1 receptor blocker, alone or in combination with statin therapy, on the progression of AVS.

Methods

Male New Zealand white rabbits were fed an atherogenic diet for a period of 12 months to induce AVS. Once disease was established, rabbits were randomly assigned to receive no treatment, olmesartan medoxomil, atorvastatin calcium, or a combination of both drugs for a period of 6 months. Disease progression was monitored in vivo using clinically relevant magnetic resonance imaging, and aortic valve cusps were examined ex vivo using histologic and immunohistochemical methods.

Results

Cusp thickness significantly increased (0.58 ± 0.03 vs 0.39 ± 0.03 mm for cholesterol and control animals, respectively; P < 0.0001) and all classic hallmarks of disease progression—including lipid infiltration, inflammation, and tissue calcification—were observed after 12 months. Unfortunately, neither olmesartan medoxomil nor atorvastatin calcium were able to reverse or delay disease progression during the 6-month treatment period. However, several histologic changes were observed in the valvular microenvironment.

Conclusions

The current study suggests that angiotensin receptor blockers, alone or in combination with statin therapy, may not be suitable for management of clinical AVS.     

Relevance of Angiotensin II for Cardiac Hypertrophy and Failure Induced by Cardiac Volume Overload

Angiotensin II can contribute to the development and maintenance of cardiac hypertrophy indirectly via its hemodynamic effects and directly via its cardiac trophic effects. Cardiac volume overload by aortocaval shunt increases plasma angiotensin II as well as angiotensin II generated by cardiac tissue. Plasma angiotensin II contributes to the cardiac volume overload via its hemodynamic effects, since blockers of the renin–angiotensin system attenuate the rise in left ventricular end-diastolic pressure (LVEDP). Increased cardiac angiotensin II, generated by and dependent on cardiac ACE, however, appears to drive the hypertrophic response. For a similar prevention of the rise in circulating angiotensin II and in LVEDP, only an angiotensin-converting enzyme (ACE) inhibitor with high affinity for cardiac ACE (quinapril) also prevents the rise in cardiac angiotensin II and—similar to an AT1 receptor blocker—the development of cardiac hypertrophy. An ACE inhibitor with low affinity for cardiac ACE (enalapril) does not prevent the rise in cardiac angiotensin II by aortocaval shunt and the development of cardiac hypertrophy. In the maintenance phase of cardiac volume overload, cardiac angiotensin II returns to normal and hypertrophic growth and cardiac remodeling cease. In this phase, enalapril causes regression of cardiac hypertrophy in relation to its hemodynamic effects and in a manner similar to an AT1 receptor blocker.In other models of cardiac volume overload (e.g., aortic insufficiency or minoxidil treatment), data on plasma and cardiac angiotensin II are missing, and the role of cardiac angiotensin II in the development and maintenance of cardiac hypertrophy is still to be assessed. Similarly, the role of cardiac angiotensin II in the transition from maintenance phase into heart failure and the progression of heart failure has not yet been studied.     

Effect of Angiotensin II on Calcium Release Phenomena in Normal and Hypertrophied Single Cardiac Myocytes

The effects of angiotensin II (Ang II) (10^-9 M to 10^-7 M) on calcium releases were established in ventricular myocytes from normal and renal hypertensive adult rats. From each peak systolic indo-1 ratio (405 nm/480 nm), amplitude variation, duration (rise time and fall time), and frequency of spontaneous calcium releases were investigated on freshly isolated cardiomyocytes at rest or under electrical stimulation. The following changes were observed: (1) in spontaneous contracting myocytes, an increase in frequency of calcium transients at 10^-7 M in normal cells (+157%, P < 0.05) and at whatever angiotensin II concentration in hypertrophied cells (10^-9 M: +79%, P < 0.05; 10^-8 M +82%, P < 0.01; 10^-7 M: +285%, P < 0.01) with a greater sensitivity of hypertrophied cells to Ang II (P < 0.05 at 10^-9 M, P <0.01 at 10^-8 M). (2) In stimulated myocytes, a prolongation of the duration of calcium atransients at 10^-7 M in normal cells (+68%, P < 0.01) and at 10^-9 M, 10^-8 M, 10^-7 M in hypertrophied cells: (+36%, P < 0.05; +39%, P < 0.01; +77%, P < 0.01) with a greater sensitivity of hypertrophied myocytes (P < 0.05 at 10^-9 M and 10^-8 M). An increase in duration may be explained by the occurrence of calcium releases during the fall time of calcium transients. Thus, both in normal and hypertrophied myocytes, Ang II induced the occurrence of calcium releases with increased sensitivity of hypertrophied cells to Ang II. Such calcium releases are known to be a possible cause of arrhythmias termed "triggered activity".