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Administration of the pyrrolizidine alkaloid monocrotaline (MCT) to rats results in hypertensive pulmonary vascular disease characterized by a structurally based increase in pulmonary vascular resistance and right ventricular hypertrophy. Alterations in lung angiotensin converting enzyme activity in MCT-treated rats have suggested a role for angiotensin II (AII) in the pathogenesis of this model of hypertensive pulmonary vascular disease. To determine if increases in AII contribute to the development of pulmonary hypertension in MCT-treated rats, we examined the effect of chronic administration of the nonpeptide AII receptor antagonist Losartan on indices of pulmonary hypertension, Losartan (DuP 753; 10 mg/kg s.c.) administration for 21 days did not prevent the development of hypertensive pulmonary vascular disease in MCT-treated rats. However, 18 hr after the last dose of Losartan, AII (0.1 micrograms/kg i.v.)-induced pressor responses were inhibited by 63% in Losartan-treated rats. Losartan administration in MCT-treated rats did not prevent increases in pulmonary artery pressure or development of right ventricular hypertrophy. Additionally, increases in medial arterial thickness in pulmonary artery vessels (less than 50 microns and 50-100 microns external diameter) from MCT-treated rats were still evident in Losartan-treated rats. However, Losartan administration decreased medial pulmonary artery thickness of 50 to 100 microns external diameter vessels in control rats. These results demonstrate that AII. acting at the AT1 receptor subtype, does not contribute to pulmonary hypertension in this animal model.
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PMID:Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist. 152 21

Angiotensin II (AII) has been reported to have direct hypertrophic actions in mammalian and avian myocardium. In this study we determined whether AII had receptor-mediated effects on stimulating cardiac hypertrophy independent of mechanical stimuli (increased cardiac afterload) in adult rats. Angiotensin II was infused into Sprague-Dawley rats for 7 and 14 days. Following this infusion, left ventricular mass indexed to body weight (LV/BW) increased 18.6 and 17.3%, respectively, compared with control (saline infused) rats. Administration of the nonpeptide AII receptor antagonist Dup 753 prevented the increase in left ventricular hypertrophy. Blockade of converting enzyme with enalapril maleate and treatment with a vasodilator had no effect on the AII-induced hypertrophy. In this animal model, the cardiac hypertrophy appeared to be independent of cardiac afterload, because normalization of blood pressure with hydralazine did not prevent the AII-induced hypertrophy. These in vivo studies indicate that AII-induced cardiac hypertrophy is mediated through AT1 angiotensin receptors.
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PMID:Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Mediation by the AT1 receptor. 153 68

To investigate the contribution of a cardiac renin-angiotensin system to cardiac hypertrophy due to volume overload, the effects of losartan, a non-peptide angiotensin (Ang) II type 1 (AT1) receptor antagonist on left ventricular hypertrophy (LVH) was studied. LVH was produced in male Wistar rats by volume overload secondary to aortic insufficiency (AI). Losartan (10 mg/kg/d) was orally administered for 2 weeks after surgery to both AI and sham-operated (control) rats. Two weeks after surgery, aortic pulse pressure and left ventricular (LV) weight were markedly increased in the AI rats as compared with the control group, whereas cardiac angiotensin converting enzyme (ACE) activity remained unchanged. The effects of the chronic administration of losartan an AT1 receptors were verified by the blockade of Ang II pressor response. Losartan treatment produced a significant reduction in LVH in AI rats without affecting the systolic blood pressure. In separate groups of rats, to elucidate the mechanisms of the attenuation of LVH by treatment with losartan, we determined plasma and LV immunoreactive Ang II content and plasma renin activity (PRA). LV Ang II content increased in AI rats, while plasma Ang II content, PRA and II concentration were increased by the treatment. There was a significant positive correlation between LV weight and LV Ang II content. These results suggest that cardiac Ang II, rather than circulating Ang II, plays an important role in the LVH due to volume overload via the AT1 receptor.
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PMID:Effects of losartan, an angiotensin II antagonist, on the development of cardiac hypertrophy due to volume overload. 749 86

We previously found that augmentation of polycythemia by exogenous human recombinant erythropoietin (EPO) failed to worsen the severity of hypoxic pulmonary hypertension in rats. We asked whether this unexpected finding was related to reductions in cardiac output, left ventricular end-diastolic pressure, pulmonary vascular resistance, or some combination of these factors. Four groups of Sprague-Dawley rats were studied over a 3-wk period: hypoxic (0.5 ATM) and normoxic animals each injected with EPO (500 U/kg sc thrice weekly) or saline (control animals). As observed previously, we found that pulmonary arterial (PA) pressures and right ventricular hypertrophy were not increased in EPO-treated rats despite significant increases in hematocrit and blood viscosity. Cardiac outputs, blood volumes, and left ventricular end-diastolic pressures were similar in EPO-treated and control rats. Acute PA pressure responses to acute normoxia in hypoxic rats and to acute hypoxia in normoxic rats were similar, suggesting no differences in vasoreactivity. However, lungs isolated from EPO-treated hypoxic rats had lower pulmonary vascular resistance than saline-treated hypoxic rats when perfused with blood from normocythemic donor rats. PA medial thickness and the percentage of muscularized small PAs were significantly lower in EPO-treated hypoxic rats. These results indicate that augmented polycythemia fails to worsen hypoxic pulmonary hypertension in rats because of a decrease in the severity of structural remodeling.
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PMID:Pulmonary vascular adaptations to augmented polycythemia during chronic hypoxia. 755 24

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental evidence for effects of ramipril on cardiac and vascular hypertrophy beyond blood pressure reduction. 764 9

Cardiac myocytes (AT-1 cells) derived from heart tumors of mice transgenic for an atrial natriuretic factor promoter, SV40 large T-antigen DNA transgene, demonstrate properties consistent with normal cardiac myocytes but retain the capacity to proliferate in culture. We studied the renin-angiotensin system (RAS) and related growth regulation of these cells because AT-1 cells (or transgenically similar cells) may be useful to repair injured myocardium. This study reveals two separate and distinct findings: 1) AT-1 cells proliferate or hypertrophy in response to angiotensin II (ANG II), depending on their competence to proceed through the cell cycle; and 2) AT-1 cells possess components of a RAS, and angiotensinogen antisense experiments suggest that the RAS is functional in these cells. Specifically, AT-1 cells proliferate in response to ANG II in low-serum medium but hypertrophy in response to ANG II when first treated with mitomycin C (at a concentration that inhibits DNA replication but is not cytotoxic). The ANG II-mediated proliferative and hypertrophic responses are inhibited by DuP 753. In addition, there is a significant increase in the protein-to-DNA ratio of cells, which are proliferation-inhibited in the absence of ANG II treatment (20%, P < 0.05). DuP 753 also inhibits this hypertrophy, suggesting that these cells possess a functional RAS. AT-1 cells contain mRNAs for angiotensin-converting enzyme, renin, angiotensinogen, and the AT1 receptor as determined by sequence analysis of polymerase chain reaction amplification products. Antisense oligonucleotides complementary to the angiotensinogen mRNA specifically inhibit angiotensinogen mRNA accumulation and proliferation of AT-1 cells. In summary, these cells contain a growth-regulating RAS, suggesting that such a system may play a significant role in left ventricular hypertrophy.
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PMID:Identification and antisense inhibition of a renin-angiotensin system in transgenic cardiomyocytes. 773 48

Angiotensin II (Ang II) raises blood pressure (BP) by a number of actions, the most important ones being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal actions. Other Ang II actions include induction of growth, cell migration, and mitosis of vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis. These actions are mediated by type 1 Ang II receptors (AT1), and may be blocked by losartan, a specific blocker of AT1 receptors. In particular, studies employing losartan have shown that Ang II is an important contributor to BP regulation and plays a significant role in hypertension and in the pathophysiology of vascular damage during the course of hypertension. Ang II is also involved in the process of atherosclerosis and in remodelling and repair processes of the myocardium following myocardial infarction. Finally, increased Ang II is an important part of neurohumoral activation in heart failure. Exciting new discoveries concerned with polymorphisms of genes coding for angiotensin converting enzyme (ACE) and angiotensinogen suggest that Ang II may be genetically associated with increased risk for myocardial infarction, hypertension and left ventricular hypertrophy.
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PMID:Role of angiotensin II in blood pressure regulation and in the pathophysiology of cardiovascular disorders. 858 76

Feeding carbohydrate-enriched diets to normal rats has been shown to induce insulin resistance and hyperinsulinemia associated with an elevation of blood pressure. Previously we reported that the renin-angiotensin system (RAS) is likely to be involved in the elevation of blood pressure. The purpose of this study was to determine the changes in plasma angiotensin II (AII) and AII receptor 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 insulin of fructose-treated rats was significantly elevated (p < 0.05) by the end of first week of fructose treatment and remained elevated throughout the study. Plasma AII levels of fructose-fed rats was 3.5 fold greater than the controls at the end of second week and returned to basal levels at the end of the fourth week of dietary treatment. 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. Angiotensin II type I receptor (AT1) density was determined in the left ventricle, aorta, adrenal gland and hypothalamus. There was a significant increase in AT1 receptor density in the ventricle at the end of third and fourth weeks of treatment, whereas there was a significant decrease in the receptor density in the aorta at the end of the fourth week of treatment. Receptor density in the adrenal gland and hypothalamus of fructose-fed rats was similar to their respective controls. The results of this study suggest that the RAS plays a role in the elevation of blood pressure of fructose-fed rats and also contributes to the ventricular hypertrophy observed in these rats.
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PMID:Changes in angiotensin AT1 receptor density during hypertension in fructose-fed rats. 872 85

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.
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PMID:Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. 876 77

The purpose of the present investigation was to compare the effects of angiotensin II (ANG II) other growth factors implicated to play a role in ventricular hypertrophy on cardiac fibroblast changes associated with cardiac remodeling. These changes included induction of early growth response (Egr-1) gene and increases in message levels of extracellular matrix proteins. ANG II treatment (10(-10)-10(-6) M) of rat cardiac fibroblasts induced 1) Egr-1 and 2) a fourfold (P < 0.02) increase in fibronectin and a twofold (P = 0.05) increase in laminin mRNA levels but no increases in that of collagens I, III, or IV at 24-48 h, and 3) a decrease in AT1-receptor mRNA levels to 26% (P < 0.001) of basal at 4-6 h. These effects were all inhibited by the AT1-receptor blocker, losartan, but not AT2-receptor blockers. Immunostaining of cultured cells with antibody against rat fibronectin demonstrated positive staining of cells in serum-free medium; staining was more intense in cells treated with ANG II (10(-6) M, 48 h). Fluorescent-activated cell sorting using an antibody against rat AT1 receptor demonstrated a receptor signal in cells maintained in serum-free medium; however, the receptor signal was not detectable in ANG II-treated cells. Serum and epidermal growth factor (EGF) also induced Egr-1, but norepinephrine (NE) and endothelin (ET) had no effect. Serum increased fibronectin mRNA levels by twofold (P < 0.05). EGF, NE, and ET had no effect on matrix gene expression. Serum, EGF, and NE also transiently downregulated AT1-receptor mRNA levels at 4-6 h of treatment. These results demonstrate that 1) ANG II both induces protooncogene expression and enhances fibronectin mRNA levels in cultured cardiac fibroblasts, whereas EGF only induces Egr-1, and NE and ET have no effects on either function; 2) ANG II effects are primarily mediated by the AT1 receptor; and 3) growth factors can regulate AT1-receptor mRNA levels. Thus ANG II, relative to NE, ET, and EGF, appears to play a prominent and direct role in fibroblast changes associated with cardiac hypertrophy.
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PMID:Comparison of ANG II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts. 876 62


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