angiotensin-i and Hypertrophy--Left-Ventricular

The renin-angiotensin system, through the effects of angiotensin II, may be involved in the pathogenesis of essential hypertension and associated left ventricular hypertrophy. Treatment with angiotensin-converting enzyme inhibition (ACEI) lowers blood pressure and reduces left ventricular hypertrophy. ACEI, however, may not completely inhibit the production of angiotensin II and its effects, and adverse effects like cough and rise in creatinine have been associated with ACEI and reduced degradation of bradykinin. The first selective antagonist of the angiotensin II-1 (AT1) receptor, losartan, has recently been approved. The LIFE study has been started, in which 8,300 hypertensive patients with left ventricular hypertrophy in Scandinavia and the USA will be randomized to blinded treatment with either atenolol or losartan to compare the effects on cardiovascular morbidity and mortality over a period of five years.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Losartan; Randomized Controlled Trials as Topic; Scandinavian and Nordic Countries; Tetrazoles; United States

The renin-angiotensin system, through the effects of angiotensin II, may be involved in the pathogenesis of essential hypertension and associated left ventricular hypertrophy. Treatment with angiotensin-converting enzyme inhibition (ACEI) lowers blood pressure and reduces left ventricular hypertrophy. ACEI, however, may not completely inhibit the production of angiotensin II and its effects, and adverse effects like cough and rise in creatinine have been associated with ACEI and reduced degradation of bradykinin. The first selective antagonist of the angiotensin II-1 (AT1) receptor, losartan, has recently been approved. The LIFE study has been started, in which 8,300 hypertensive patients with left ventricular hypertrophy in Scandinavia and the USA will be randomized to blinded treatment with either atenolol or losartan to compare the effects on cardiovascular morbidity and mortality over a period of five years.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Humans; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Losartan; Randomized Controlled Trials as Topic; Scandinavian and Nordic Countries; Tetrazoles; United States

Left ventricular hypertrophy (LVH) makes the heart vulnerable to ischemia/reperfusion (IR) injury. Angiotensin (Ang) (1-7) is recognized as a cardioprotective peptide. We investigated the effect of polyphenol resveratrol on myocardial IR injury after hypertrophy and examined cardiac content of Ang (1-7) and transcription of its receptor (MasR). Rats were divided into sham-operated, LVH, IR, LVH + IR, and resveratrol + LVH + IR groups. Myocardial hypertrophy and IR models were created by abdominal aortic banding and left coronary artery occlusion, respectively. To evaluate the electrocardiogram parameters and incidence of arrhythmias, electrocardiogram was recorded by subcutaneous leads (lead II). Blood pressure was measured through the left carotid artery. Infarct size was determined by the triphenyl tetrazolium chloride staining. The Ang (1-7) level was evaluated by immunohistochemistry. The Mas receptor mRNA level was assessed by the real-time real time reverse transcription polymerase chain reaction technique. QT-interval duration, infarct size, and incidence of ischemia-induced arrhythmia were significantly higher in the LVH + IR group. However, in the resveratrol-treated group, these parameters were decreased significantly. The cardiac level of Ang (1-7) was decreased in untreated hypertrophied hearts (LVH and LVH + IR groups). Pretreatment with resveratrol normalized the cardiac level of Ang (1-7). The mRNA level of Mas receptor was increased in all of hypertrophied hearts in the presence or absence of resveratrol. Resveratrol can decrease IR injury in rats with LVH. The anti-ischemic effect of resveratrol may be related to the enhancement of Ang (1-7)/MasR axis.

Topics: Angiotensin I; Animals; Disease Models, Animal; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Peptide Fragments; Proto-Oncogene Mas; Rats, Wistar; Resveratrol; Tachycardia, Ventricular; Ventricular Fibrillation

Exercise promotes physiological cardiac hypertrophy and activates the renin-angiotensin system (RAS), which plays an important role in cardiac physiology, both through the classical axis [angiotensin II type 1 receptor (AT1R) activated by angiotensin II (ANG II)] and the alternative axis [proto-oncogene Mas receptor (MASR) activated by angiotensin-(1-7)]. However, very intense exercise could have deleterious effects on the cardiovascular system. We aimed to analyze the cardiac hypertrophy phenotype and the classical and alternative RAS axes in the myocardium of mice submitted to swimming exercises of varying volume and intensity for the development of cardiac hypertrophy. Male

Topics: Angiotensin I; Angiotensin II; Animals; Cardiomegaly; Hypertrophy, Left Ventricular; Male; Mice, Inbred BALB C; Myocardium; Peptide Fragments; Physical Conditioning, Animal; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Swimming; Ventricular Remodeling

The intratubular renin-angiotensin system (RAS) is thought to play an essential role in hypertensive renal disease, but information regarding sex-related differences in this system is limited. The present study investigated sex differences in the intratubular RAS in two-kidney, one-clip (2K1C) rats. A 2.5-mm clip was placed on the left renal artery of Sprague-Dawley rats, and rats were euthanized 3 or 5 wk after the operation. Systolic blood pressure increased in 2K1C rats in both sexes but was significantly higher in male rats than in female rats, and an antihypertensive effect was not observed in 2K1C ovariectomized (OVX) female rats. Compared with male 2K1C rats, intratubular angiotensin-converting enzyme (ACE) and ANG II were repressed, and intratubular ACE2, angiotensin (1-7), and Mas receptor were increased in both kidneys in female 2K1C rats 5 wk after surgery. Comparison with male and female rats and intratubular mRNA levels of ACE and ANG II type 1 receptor were augmented in OVX female rats, regardless of the clipping surgery 3 wk postoperation. ANG II type 2 receptor was upregulated in female rats with or without OVX; thus, the ANG II type 1-to-type 2 receptor ratio was higher in male rats than in female rats. In conclusion, female rats were protected from hypertensive renal and cardiac injury after renal artery clipping. An increase in the intratubular nonclassic RAS [ACE2/angiotensin (1-7)/Mas receptor] and a decrease in the ANG II type 1-to-type 2 receptor ratio could limit the adverse effects of the classic RAS during renovascular hypertension in female rats, and estrogen is suggested to play a primary role in the regulation of intratubular RAS components.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Constriction; Disease Models, Animal; Estrogens; Female; Hypertension; Hypertrophy, Left Ventricular; Kidney Tubules; Macrophages; Male; Ovariectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renal Artery; Renin-Angiotensin System; Sex Factors; Signal Transduction

HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed.. Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group).. HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT.. This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Diet, High-Fat; Fructose; Gene Expression Regulation; High-Intensity Interval Training; Hypertension; Hypertrophy, Left Ventricular; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptidyl-Dipeptidase A; Random Allocation; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Ventricular Remodeling

Angiotensin-(1-7) [ANG-(1-7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1-7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency (

Topics: Angiotensin I; Animals; Blood Pressure; Diet, High-Fat; Echocardiography; Female; Heart; Heart Function Tests; Hypertension; Hypertrophy, Left Ventricular; Immunohistochemistry; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled

Angiotensin-(1-7) [ANG-(1-7)] plays a counterregulatory role to angiotensin II in the renin-angiotensin system. In trained spontaneous hypertensive rats, Mas expression and protein are upregulated in ventricular tissue. Therefore, we examined the role of ANG-(1-7) on cardiac hemodynamics, cardiac functions, and cardiac remodeling in trained two-kidney one-clip hypertensive (2K1C) rats. For this purpose, rats were divided into sedentary and trained groups. Each group consists of sham and 2K1C rats with and without ANG-(1-7) infusion. Swimming training was performed for 1 h/day, 5 days/wk for 4 wk following 1 wk of swimming training for acclimatization. 2K1C rats showed moderate hypertension and left ventricular hypertrophy without changing left ventricular function. Chronic infusion of ANG-(1-7) attenuated hypertension and cardiac hypertrophy only in trained 2K1C rats but not in sedentary 2K1C rats. Chronic ANG-(1-7) treatment significantly attenuated increases in myocyte diameter and cardiac fibrosis induced by hypertension in only trained 2K1C rats. The Mas receptor, ANG II type 2 receptor protein, and endothelial nitric oxide synthase phosphorylation in ventricles were upregulated in trained 2K1C rats. In conclusion, chronic infusion of ANG-(1-7) attenuates hypertension in trained 2K1C rats.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Heart Ventricles; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney; Male; Nitric Oxide Synthase Type III; Peptide Fragments; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Surgical Instruments; Swimming

Angiotensin converting enzyme-2 (ACE-2) is a monocarboxypeptidase that metabolises angiotensin (ANG)-II into angiotensin 1-7 (ANG 1-7), thereby functioning as a negative regulator of the renin-angiotensin system. We investigated whether treatment with ANG-II type 1 receptor blocker, olmesartan medoxomil is associated with the attenuation of cardiac myosin-induced dilated cardiomyopathy (DCM) through recently established new axis of ACE-2/ANG 1-7 mas receptor. DCM was elicited in Lewis rats by immunisation with cardiac myosin, and 28 days after immunisation, the surviving Lewis rats were divided into two groups and treated with either olmesartan medoxomil (10 mg/kg/day) or vehicle. Myocardial protein and mRNA levels of ACE-2, ANG 1-7 mas receptor were upregulated in the olmesartan-treated group compared with those of vehicle-treated DCM rats. In contrast, Olmesartan treatment effectively suppressed the myocardial protein and mRNA expressions of inflammatory markers in comparison to the vehicle-treated DCM rats. Olmesartan treatment significantly reduced fibrosis, hypertrophy and their marker molecules (OPN, CTGF, ANP and GATA-4, respectively), as well as matrix metalloproteinases compared with those of vehicle-treated DCM rats. Enhanced myocardial protein levels of phospho-p38 MAPK, phospho-JNK and phospho MAPKAPK-2 in the vehicle-treated DCM rats were prevented by olmesartan treatment. In addition, olmesartan treatment significantly lowered the protein expressions (Nitrotyrosine, p47phox and p67phox) and superoxide radical production compared with those of vehicle-treated DCM rats. Our present study might serve as a new therapeutic target of DCM in cardiovascular diseases and cardiac myosin-induced DCM via the modulation of ACE-2/ANG 1-7 mas receptor axis in rats with DCM after myosin-immunisation.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Biomarkers; Cardiac Myosins; Cardiomyopathy, Dilated; Endopeptidases; Fibrosis; Gene Expression Regulation; Heart; Hypertrophy, Left Ventricular; Imidazoles; Mitogen-Activated Protein Kinases; Olmesartan Medoxomil; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Receptors, G-Protein-Coupled; RNA, Messenger; Tetrazoles

The renin-angiotensin system (RAS) is involved in the cardiac and vascular remodeling associated with cardiovascular diseases. Angiotensin (Ang) II/AT(1) axis is known to promote cardiac hypertrophy and collagen deposition. In contrast, Ang-(1-7)/Mas axis opposes Ang II effects in the heart producing anti-trophic and anti-fibrotic effects. Exercise training is known to induce cardiac remodeling with physiological hypertrophy without fibrosis. We hypothesize that cardiac remodeling induced by chronic exercise depends on the action of Ang-(1-7)/Mas axis. Thus, we evaluated the effect of exercise training on collagen deposition and RAS components in the heart of FVB/N mice lacking Mas receptor (Mas-KO). Male wild-type and Mas-KO mice were subjected to a moderate-intense swimming exercise training for 6 weeks. The left ventricle (LV) of the animals was sectioned and submitted to qRT-PCR and histological analysis. Circulating and tissue angiotensin peptides were measured by RIA. Sedentary Mas-KO presented a higher circulating Ang II/Ang-(1-7) ratio and an increased ACE2 expression in the LV. Physical training induced in Mas-KO and WT a similar cardiac hypertrophy accompanied by a pronounced increase in collagen I and III mRNA expression. Trained Mas-KO and trained WT presented increased Ang-(1-7) in the blood. However, only in trained-WT there was an increase in Ang-(1-7) in the LV. In summary, we showed that deletion of Mas in FVB/N mice produced an unbalance in RAS equilibrium increasing Ang II/AT(1) arm and inducing deleterious cardiac effects as deposition of extracellular matrix proteins. These data indicate that Ang-(1-7)/Mas axis is an important counter-regulatory mechanism in physical training mediate cardiac adaptations.

Topics: Angiotensin I; Angiotensin II; Animals; Collagen; Collagen Type I; Collagen Type III; Gene Expression Regulation; Heart; Hypertrophy, Left Ventricular; Male; Mice; Mice, Knockout; Peptide Fragments; Physical Conditioning, Animal; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Ventricular Remodeling

This study was designed to investigate the effect of angiotensin (1-7), a Mas receptor agonist, and A-779, a Mas receptor antagonist, in rats with diabetic cardiomyopathy (DC).. Rats treated with a single injection of streptozotocin (50 mg/kg, intraperitoneal), developed DC after 8 weeks. The extent of DC was assessed by measuring the left ventricular weight/body weight (LVW/BW) ratio, absolute LVW, left ventricular developed pressure (LVDP), maximum change in left ventricular pressure over time (dp/dtmax), minimum change in left ventricular pressure over time (dp/dtmin), left ventricular (LV) protein content, LV collagen content, lipid profile, and serum nitrite/nitrate concentration. Test drug treatment was given from week 4 to week 8.. Angiotensin (1-7) treatment attenuated DC by significantly increasing LVDP, dp/dtmax, dp/dtmin, serum nitrite/nitrate concentration and significantly decreasing the LVW/BW ratio and LV collagen content. For the first time, this study has documented that endogenous angiotensin (1-7) regulates lipid profile in rats, and that treatment with angiotensin (1-7) significantly attenuates diabetes-induced changes in lipid profile. However, LV protein content and absolute LVW remain unaffected after treatment.. Angiotensin (1-7) significantly attenuates DC in rats because of vasodilatory, antiproliferative and anifibrotic properties but also because of a significant decrease in dyslipidemia, the major culprit for cardiac dysfunctions in diabetes.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dyslipidemias; Fibrosis; Heart Ventricles; Hypertrophy, Left Ventricular; Lipids; Nitrates; Nitrites; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Time Factors; Ventricular Function, Left; Ventricular Pressure

Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin-angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Female; Hemodynamics; Hypertrophy, Left Ventricular; MicroRNAs; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Physical Conditioning, Animal; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Dietary Carbohydrates; Disease Models, Animal; Fructose; Hypertension; Hypertrophy, Left Ventricular; Insulin; Insulin Resistance; Male; Peptide Fragments; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

We evaluated the development of arterial hypertension, cardiac function, and collagen deposition, as well as the level of components of the renin-angiotensin system in the heart of transgenic rats that overexpress an angiotensin (Ang)-(1-7)-producing fusion protein, TGR(A1-7)3292 (TG), which induces a lifetime increase in circulating levels of this peptide. After 30 days of the induction of the deoxycorticosterone acetate (DOCA)-salt hypertension model, DOCA-TG rats were hypertensive but presented a lower systolic arterial pressure in comparison with DOCA-Sprague-Dawley (SD) rats. In contrast to DOCA-SD rats that presented left ventricle (LV) hypertrophy and diastolic dysfunction, DOCA-TG rats did not develop cardiac hypertrophy or changes in ventricular function. In addition, DOCA-TG rats showed attenuation in mRNA expression for collagen type I and III compared with the increased levels of DOCA-SD rats. Ang II plasma and LV levels were reduced in SD and TG hypertensive rats in comparison with normotensive animals. DOCA-TG rats presented a reduction in plasma Ang-(1-7) levels; however, there was a great increase in Ang-(1-7) ( approximately 3-fold) accompanied by a decrease in mRNA expression of both angiotensin-converting enzyme and angiotensin-converting enzyme 2 in the LV. The mRNA expression of Mas and Ang II type 1 receptors in the LV was not significantly changed in DOCA-SD or DOCA-TG rats. This study showed that TG rats with increased circulating levels of Ang-(1-7) are protected against cardiac dysfunction and fibrosis and also present an attenuated increase in blood pressure after DOCA-salt hypertension. In addition, DOCA-TG rats showed an important local increase in Ang-(1-7) levels in the LV, which might have contributed to the attenuation of cardiac dysfunction and prefibrotic lesions.

Topics: Analysis of Variance; Angiotensin I; Animals; Collagen Type I; Collagen Type III; Desoxycorticosterone; Heart Function Tests; Hypertension; Hypertrophy, Left Ventricular; Immunohistochemistry; Peptide Fragments; Rats; Rats, Transgenic; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventricular Remodeling

Angiotensin-(1-9) is present in human and rat plasma and its circulating levels increased early after myocardial infarction or in animals treated with angiotensin-converting enzyme inhibitor. However, the cardiovascular effects of this peptide are unknown.. To determine whether angiotensin-(1-9) is a novel anti-cardiac hypertrophy factor in vitro and in vivo and whether this peptide is involved in the pharmacological effects of cardiovascular drugs acting on the renin-angiotensin system.. The administration of angiotensin-(1-9) to myocardial infarcted rats by osmotic minipumps (450 ng/kg per min, n = 6) vs. vehicle (n = 8) for 2 weeks decreased plasma angiotensin II levels, inhibited angiotensin-converting enzyme activity and also prevented cardiac myocyte hypertrophy. However, cardiac myocyte hypertrophy attenuation triggered by angiotensin-(1-9) was not modified with the simultaneous administration of the angiotensin-(1-7) receptor antagonist A779 (100 ng/kg per min, n = 6). In experiments in vitro with cultured cardiac myocytes incubated with norepinephrine (10 micromol/l) or with insulin-like growth factor-1 (10 nmol/l), angiotensin-(1-9) also prevented hypertrophy. In other experimental setting, myocardial infarcted rats (n = 37) were randomized to receive either vehicle (n = 12), enalapril (10 mg/kg per day, n = 12) or angiotensin II receptor blocker candesartan (10 mg/kg per day, n = 13) for 8 weeks. Both drugs prevented left ventricle hypertrophy and increased plasma angiotensin-(1-9) levels by several folds. Angiotensin-(1-9) levels correlated negatively with different left ventricular hypertrophy markers even after adjustment for blood pressure reduction.. Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Cardiomegaly; Cell Enlargement; Cells, Cultured; Enalapril; Humans; Hypertrophy, Left Ventricular; In Vitro Techniques; Insulin-Like Growth Factor I; Male; Myocardial Infarction; Myocytes, Cardiac; Norepinephrine; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles; Ventricular Function, Left

The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation.. Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses.. Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups.. Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Carotid Sinus; Collagen; Denervation; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Renin-Angiotensin System

To determine circulating angiotensin-(1-7) [Ang-(1,7)] levels in rats with different angiotensin converting enzyme (ACE) genotypes and to evaluate the effect of hypertension on levels of this heptapeptide, plasma levels of angiotensin II (Ang II) and Ang-(1-7) were determined by HPLC and radioimmunoassay in (a) normotensive F0 and F2 homozygous Brown Norway (BN; with high ACE) or Lewis (with low ACE) rats and (b) in hypertensive F2 homozygous male rats (Goldblatt model). Genotypes were characterized by PCR and plasma ACE activity measured by fluorimetry. Plasma ACE activity was 2-fold higher (p < 0.05) in homozygous BN compared to homozygous Lewis groups. In the Goldblatt groups, a similar degree of hypertension and left ventricular hypertrophy was observed in rats with both genotypes. Plasma Ang II levels were between 300-400% higher (p < 0.05) in the BN than in the Lewis rats, without increment in the hypertensive animals. Plasma Ang-(1-7) levels were 75-87% lower in the BN rats (p < 0.05) and they were significantly higher (p < 0.05) in the hypertensive rats from both genotypes. Plasma levels of Ang II and Ang-(1-7) levels were inversely correlated in the normotensive rats (r = -0.64; p < 0.001), but not in the hypertensive animals. We conclude that there is an inverse relationship between circulating levels of Ang II and Ang-(1-7) in rats determined by the ACE gene polymorphism. This inverse relation is due to genetically determined higher ACE activity. Besides, plasma levels of Ang-(1-7) increase in renovascular hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Female; Genotype; Hypertension; Hypertrophy, Left Ventricular; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Rats; Rats, Inbred Lew; Rats, Mutant Strains

To test the hypothesis that chronic administration of angiotensin-(1-7) [Ang-(1-7)] attenuates cardiac hypertrophy in rats in vivo.. Coarctation of the suprarenal abdominal aorta was performed in 41 8-week-old male Sprague Dawley rats. Twenty-four hours after the operation, osmotic minipumps were surgically implanted subcutaneously in the rats, which were randomly divided into 3 groups, including a sham-operation group (n=15) receiving infusion with normal saline, a suprarenal aortic coarctation group (n=12), and a suprarenal aortic coarctation group (n=14) with Ang-(1-7) treatment at the dose of 25 mug x kg(-1) x h(-1). Four weeks later, the systolic and diastolic blood pressures were measured and the left ventricular mass index (LVMI, mg/g) was calculated from the ratio of left ventricular weight to body weight. The concentrations of Ang II in the plasma and myocardium were measured by radioimmunoassay, and myocardial interstitial collagen volume fraction (ICVF) was determined by quantitative morphometry of the sections with Picrosirius red staining using an automated image analyzer.. Suprarenal abdominal aortic coarctation induced a significant increase in carotid artery systolic and diastolic blood pressure, heart weight, LVMI, ICVF, and the concentration of Ang II in the myocardium (P<0.01). Chronic administration of Ang-(1-7) attenuated the increase in the heart weight, LVMI, ICVF and left ventricular diastolic end pressure (LVEDP) caused by suprarenal abdominal aortic coarctation (P<0.05). Ang-(1-7) also increased the formerly decreased maximum left ventricular pressure reduction rate (-dP/dt(max)) (P<0.05), but had no effect on blood pressure and the concentration of Ang II in the myocardium. No difference was noted in plasma concentration of Ang II between the 3 groups.. Ang-(1-7) attenuates cardiac hypertrophy and fibrosis and preserved the impaired left ventricular function induced by left ventricular pressure-overload in rats. These effects are not associated with the changes in the concentrations of Ang II in the left ventricular myocardium and plasma.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Aortic Coarctation; Blood Pressure; Fibrosis; Hypertrophy, Left Ventricular; Male; Myocardium; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist.. MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 micrograms/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks.. Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects.. Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Dose-Response Relationship, Drug; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Isoquinolines; Losartan; Male; Myocardial Infarction; Organ Size; Quinapril; Rats; Rats, Wistar; Tetrahydroisoquinolines

Cardiac volume overload by an aortocaval shunt increases left ventricular end-diastolic pressure (LVEDP) and plasma and cardiac renin activity and results in LV hypertrophy. To a similar extent, the angiotensin-converting enzyme (ACE) inhibitors enalapril and quinapril prevent the increase in LVEDP. However, only quinapril attenuates the development of LV hypertrophy. We hypothesize that a low affinity of enalapril for cardiac ACE results in continuing generation of cardiac angiotensin II and thus hypertrophic growth of cardiomyocytes.. In the present study, we assessed plasma and cardiac angiotensins I and II 1 and 7 days after aortocaval shunt and the effects of enalapril and quinapril started 3 days before surgery on plasma and cardiac angiotensin I and II at the same time points. Aortocaval shunt increased plasma angiotensin II at 1 day by 180%, but only a small increase (by 40%) persisted at 7 days. Aortocaval shunt increased LV angiotensin II by 100% and 65% at 1 and 7 days, respectively. Both blockers similarly prevented the increase in plasma angiotensin II by aortocaval shunt at both time points. In contrast, only quinapril prevented the rise in LV angiotensin II induced by shunt at 1 and 7 days.. Aortocaval shunt increases LVEDP and plasma and cardiac angiotensin II and results in LV hypertrophy. Only prevention of the increase in LVEDP and in plasma and cardiac angiotensin II attenuates the development of LV hypertrophy, consistent with the concept that angiotensin II is involved in the development of cardiac hypertrophy by aortocaval shunt by both hemodynamic and cardiac trophic effects. This study is the first to show that differences in affinity for cardiac ACE may determine the effect of ACE inhibitors on cardiac angiotensin II and therefore cardiac hypertrophy.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Hypertrophy, Left Ventricular; Isoquinolines; Male; Myocardium; Quinapril; Rats; Rats, Wistar; Tetrahydroisoquinolines; Ventricular Pressure

The objective of the present study was to determine the relationship between plasma renin levels, and the development of hypertension and cardiac hypertrophy in TGR (mREN2)27 hypertensive rats. Systolic blood pressure and left ventricular mass index (LVMI) were measured in transgenic heterozygote and normotensive Sprague Dawley control rats at 25, 35, 45, 55, 65, and 75 days of age together with determinations of plasma active renin and prorenin, and renal and adrenal tissue renin, which were assayed at pH 6.5, 7.4, and 8.5. The systolic blood pressure and the LVMI of the transgenic rats were significantly increased compared to control rats by 55 and 65 days of age, respectively. Plasma active renin of the transgenic rats, measured at physiological pH, was significantly higher from 55 days of age, increasing in parallel with blood pressure and remaining significantly higher than controls at all age groups tested. Assays of both plasma and adrenal renin at various pHs showed a profile of angiotensin I generation that matched mouse renin more closely than that of rat renin. The ratio of angiotensin I (Ang I) generation at pH 8.5 and pH 6.5 was 0.5 for normal rat plasma but was between 3 and 5 for mouse plasma. Plasma prorenin and adrenal tissue renin from transgenic rats exhibited a pH profile consistent with the major portion being mouse renin. However, the low level of kidney renin observed in the transgenic rats exhibited a pH ratio (8.5/6.5) identical to that of normal rat renin (0.5), suggesting that residual renin within the kidney was predominantly of rat origin. These data indicate that plasma renin levels closely parallel the development of high blood pressure and LVMI and show that interpretation of the renin status of this strain is critically dependent on the assay conditions used. Under the conditions used in this study it was found that the TGR(mRen2)27 rat is a high mouse plasma renin model of hypertension.

Topics: Adrenal Glands; Aging; Angiotensin I; Animals; Animals, Genetically Modified; Blood Pressure; Body Weight; Echocardiography; Hydrogen-Ion Concentration; Hypertension; Hypertrophy, Left Ventricular; Kidney; Mice; Organ Size; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Renin

Previously, we reported that an orally active angiotensin II (Ang II) receptor antagonist Losartan induces regression of left ventricular hypertrophy with reduction in the tissue Ang II contents in spontaneously hypertensive rats (SHR). To further address the role of the cardiac renin-angiotensin system in the pathophysiology of hypertensive left ventricular hypertrophy, we examined the effects of TCV-116, a newly developed, highly specific nonpeptide Ang II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin I (Ang I) and Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with TCV-116 (1 mg/kg per day) lowered blood pressure markedly. TCV-116 reduced significantly the left ventricular weight by about 11% compared with control animals. The left ventricular Ang I and Ang II contents were lowered by TCV-116 (12.9 +/- 1.4 vs. 30.4 +/- 2.5 pg/tissue, control, p < 0.01, for Ang I; 15.1 +/- 0.6 vs. 18.7 +/- 0.4 pg/tissue, control, p < 0.01, for Ang II), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and TCV-116-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.681, p < 0.01). These results not only further support the view that cardiac Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension, but imply also that TCV-116 induces regression of hypertensive left ventricular hypertrophy through suppression of the tissue renin-angiotensin system.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensins; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Heart Atria; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Male; Organ Size; Rats; Rats, Inbred SHR; Renin; Tetrazoles

The intracardiac conversion rate of angiotensin (Ang) I to Ang II and the expression of angiotensin converting enzyme (ACE) mRNA are amplified in rat hearts with left ventricular hypertrophy (LVH). To examine whether the accelerated intracardiac Ang II generation in LVH is related to an induction of cardiac ACE, we studied localization and function of cardiac ACE in hypertrophied rat hearts using specific ACE inhibitors.. Cardiac ACE was localized and quantified in hearts from male Wistar rats with LVH due to chronic experimental aortic stenosis and from control rats. With the ACE inhibitor 125I-351A, a derivative of lisinopril, as a radioligand on coronal sections of LVH and control hearts, in vitro autoradiography demonstrated ACE binding in aorta, coronary arteries, atria, and ventricles of both groups. Quantitative analyses revealed that ACE density (counts per minute per cross-sectional area of tissue) was twofold higher within the myocardium of hypertrophied left ventricles compared with controls (p < 0.005). Quantitative morphometry demonstrated a modest increase in the fractional volume of myocytes as well as capillary volume without an increase in the fractional volume of endothelial cells in left ventricular tissue from aortic stenosis rats. These data suggest that an increase in endothelial cell volume per se cannot alone account for the observed doubling of ACE density and support an upregulation of ACE production in hypertrophied tissue. The role of cardiac ACE in intracardiac conversion of Ang I to Ang II and its specific inhibition was studied in isolated, isovolumic beating, buffer-perfused LVH and control hearts. Biochemical conversion rates as well as functional changes in response to 3 x 10(-7) M Ang I were examined in the absence or presence of the ACE inhibitor enalaprilat (4 x 10(-6) M). After a brief stabilization period, groups of LVH and control hearts were subjected to the following infusion protocols: 15 minutes of vehicle followed by 30 minutes of Ang I plus vehicle, 15 minutes of enalaprilat followed by 30 minutes of Ang I plus enalaprilat (enal/Ang I), or 45 minutes of vehicle only to allow comparison with a time control. Intracardiac Ang I-to-Ang II conversion rate was fourfold higher in LVH than in control hearts (p < 0.05). Infusion of enalaprilat reduced the intracardiac Ang I-to-Ang II conversion rate in LVH hearts by 70% (p < 0.05 versus Ang I). At similar levels of constant coronary flow per gram, Ang I increased coronary perfusion pressure by 23 +/- 5 mm Hg (p < 0.01 versus vehicle) in LVH hearts and by 36 +/- 10 mm Hg (p < 0.005 versus vehicle) in control hearts. When enalaprilat was infused with Ang I, the increase in perfusion pressure was limited to 5 +/- 5 mm Hg (NS versus vehicle) in LVH hearts and 12 +/- 3 mm Hg (p < 0.05 versus vehicle) in control hearts and was significantly lower than in hearts infused with Ang I only (p < 0.. These observations indicate that ACE protein is increased within the myocardium of LVH hearts, extending recent findings of increased cardiac ACE activity and mRNA levels in this model of pressure-overload LVH in the rat. Blockade of the enzyme by an ACE inhibitor decreases intracardiac Ang I-to-Ang II conversion rate and prevents the functional changes of Ang I-to-Ang II activation

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Dipeptides; Enalaprilat; Hypertrophy, Left Ventricular; Iodine Radioisotopes; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Up-Regulation; Ventricular Function, Left