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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed that chronic angiotensin-converting enzyme (ACE) inhibition prevented the increase in aortic collagen in spontaneously hypertensive rats (SHRs) independently of blood pressure reduction. The aim of the present study was to determine whether the effects of ACE inhibition on aortic fibrosis were due to inhibition of angiotensin II formation, preservation of bradykinin, or a combination of both. Four week-old SHRs were treated for 4 months with the ACE inhibitor quinapril, quinapril with the bradykinin B2 receptor antagonist Hoe 140, or the angiotensin II AT1 receptor antagonist CI996. Control SHR and Wistar-Kyoto (WKY) rats received a placebo for the same period of time. At the end of the treatment, as compared to conscious SHR and WKY controls, quinapril completely prevented the development of hypertension, whereas quinapril-Hoe 140 and the AT1 receptor antagonist produced only a partial reduction of blood pressure. In relation with blood pressure changes, aortic hypertrophy was significantly prevented by quinapril but not by quinapril-Hoe 140 or CI996. In contrast, aortic collagen accumulation was completely prevented by all three treatments. The study provides evidence that in young live SHRs, the prevention of aortic collagen accumulation is independent of blood pressure changes and bradykinin preservation and involves exclusively angiotensin II inhibition through AT1 receptors.
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PMID:Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats. 940 11

The aim of this study was to determine the effects of angiotensin II (Ang II) on the vascular wall, that are independent of its effects on systemic blood pressure. Ang II has been shown to have different effects on vascular growth in vitro and in vivo. The generally weak effects of Ang II in cell culture may be due to the absence of blood-borne factors and interactions between different cell types, dedifferentiation of cells and receptor loss. On the other hand, studies with administration of Ang II in vivo are complicated by effects on blood pressure and it is not clear whether the effects of Ang II are direct or secondary. In order to overcome some of these limitations, we delivered Ang II locally to the left carotid artery of normotensive rats with a perivascular drug delivery system, in doses that did not affect systemic blood pressure. Ang II was applied perivascularly to the artery in doses of 0.05, 0.5, 5 and 50 ng/h for 14 days. A vehicle-treated group and the right carotid artery served as controls. Other groups received noradrenaline as a control for the vasoconstrictive actions of Ang II. Ang II, but not noradrenaline, induced a dose-dependent thickening of the adventitia with increased cellularity which was characterized by DNA synthesis, neovascularization, and collagen deposition. Administration of specific ligands for the AT1 and AT2 receptors in the presence or absence of Ang II indicates that the increased cellularity and collagen deposition are mediated via the AT1 receptor, are inhibited via stimulation of the AT2 receptor, and that the angiogenesis may be mediated via the AT2 receptor. In conclusion, Ang II, independent of its effect on systemic blood pressure, induces a specific and receptor-dependent adventitial growth response when delivered perivascularly to the carotid artery.
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PMID:Local application of angiotensin II to the rat carotid artery induces adventitial thickening. 942 96

Tissue repair appears in the infarcted heart at both infarcted and noninfarcted myocardium. Experimental evidence gathered to date indicates that myoFb are the predominant cell responsible for collagen formation at sites of repair in the rat heart and related structures. These phenotypically transformed fibroblast-like cells are not normal residents of ventricular tissue. They appear on day 4 at sites of injury and remain abundant for weeks therefore. MyoFb express type I collagen mRNA and ACE and AT1 receptors. ACE inhibitors or AT1 receptor antagonists attenuate collagen accumulation in both infarcted and noninfarcted myocardium. These findings suggest locally generated AngII may have an autocrine function in regulating myoFb collagen turnover.
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PMID:Local angiotensin II and myocardial fibrosis. 943 11

Cardiac expression of angiotensin II (Ang II) AT1 and AT2 receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using 125I-(Sar1,Ile8)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT2 receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT2 binding sites (Kd = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT2 binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT1 binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial 125I-(Sar1,Ile8)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT2 receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of 125I-351A. Specific myocardial AT2 receptor mRNA transcripts (approximately 3 kb) were identified and exhibited alternative splicing of untranslated 5' exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT2 sites in the diseased heart suggest that cells bearing the AT2 receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.
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PMID:Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. 943 95

Cardiac fibroblasts, an abundant cell of the left ventricle (LV), proliferate and synthesize collagen in the heart after acute injury and during pressure overload hypertrophy. From many studies, angiotensin II (ANG II) receptors have been implicated in promoting collagen formation by the rat cardiac fibroblast. The present study examined species variability in ANG II receptor expression. Cultured rat fibroblasts expressed 43,000 +/- 15,000 ANG II (AT1-specific) receptors per cell (dissociation constant = 0.92 +/- 0.34 nM), whereas rabbit and neonate human cardiac fibroblast cultures expressed few receptors. Angiotensin increased intracellular Ca2+ concentration in rats but not in rabbit or human cardiac fibroblasts and stimulated arachidonic acid release in rat but not rabbit fibroblasts. In situ, 6 days after coronary artery ligation, angiotensin receptor expression was increased 34.8 +/- 13.4-fold in the infarcted area relative to the noninfarcted tissue in the rat LV, whereas rabbit hearts demonstrated only a 3.2 +/- 1.6-fold increase in ANG II binding within the infarcted tissue. These species differences in receptor expression raise questions as to the role of angiotensin as a mediator of collagen formation across species and as a direct target of angiotensin-converting enzyme inhibitors to regulate cardiac fibroblast function.
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PMID:Species variability in angiotensin receptor expression by cultured cardiac fibroblasts and the infarcted heart. 953 Jan 91

This review describes how angiotensin AT1 receptor antagonists (eg, candesartan cilexetil, losartan) effectively protect against end-organ damage including stroke, cardiac hypertrophy, renal dysfunction, glomerulosclerosis, and/or vascular hypertrophy in the models of stroke-prone spontaneously hypertensive rats (SHRSP), SHR, DOCA/salt hypertensive rats, Dahl hypertensive rats and/or 5/6 nephrectomised rats. Particularly in SHRSP and DOCA/salt hypertensive rats, candesartan cilexetil markedly reduced the incidence of stroke and renal injury even at doses which had no effect on blood pressure (BP), suggesting that the tissue protective effects of angiotensin AT1 antagonists are not attributable simply to the normalisation of BP. In the heart, kidney and vascular tissues of SHRSP and the kidney of DOCA/salt hypertensive rats, the mRNA levels for transforming growth factor (TGF)-beta1 and extracellular matrix components (fibronectin, collagen type I, III and IV and laminin) were increased, and the increases of the gene expression were inhibited by treatment with candesartan cilexetil. In addition, there are some reports indicating that angiotensin AT1 receptor antagonists inhibit directly hypertrophy or proliferation of cultured cardiac myocytes and nonmyocytes (fibroblast), cultured mesangial cells and cultured vascular smooth muscle cells, which were stimulated by angiotensin II. These in vitro and in vivo findings suggest that local tissue AT1 receptor stimulation, being accompanied by the increased gene expression of TGF-beta1 and extracellular matrix components may partially contribute to the pathogenesis of cardiovascular end-organ damage.
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PMID:Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage. 965 51

Antiatherogenic effects of imidapril and involvement of renin angiotensin system were examined in experimental atherosclerosis induced by feeding a high-cholesterol diet to Cynomolgus monkeys. Eighteen male monkeys were divided into three groups and placed under (1) normal diet (normal group), (2) high-cholesterol diet (control group), (3) high-cholesterol diet with imidapril (20 mg/kg body wt/day, orally) treatment (imidapril group). At the end of the experiment, the normal group showed no apparent atherosclerosis in their aorta evaluated by oil red-O staining, while the control group exhibited marked atherosclerotic involvement of the intimal surface of the aorta (58.4 +/- 9.3%, P < 0.01). Imidapril reduced systolic blood pressure and atherosclerotic involvement (24.1 +/- 5.5%, P < 0.05). Total cholesterol content of the descending thoracic aorta was also significantly reduced in the imidapril group. In the atherosclerotic vessels, angiotensin converting enzyme (ACE) activity evaluated by quantitative in vitro autoradiography was significantly increased in the intimal lesion. Further evaluation revealed angiotensin II (Ang II) type I (AT1) receptor density was significantly increased in the medial lesion and type II (AT2) receptor density in the adventitia. When the progression of atherosclerosis was impeded by imidapril treatment, the ACE activity level as well as the AT1 and AT2 receptor density remained at normal. Expression of mRNA for fibronectin, TGF-beta1, types I and III collagen was studied by Northern blot analysis. No significant differences in types I and III collagen mRNA levels were found between the control and imidapril group. On the other hand, mRNA expression for fibronectin and TGF-beta1 were much lower in the imidapril group than in the control group. These results suggest that increased production of Ang II and activated receptors may be involved in atherosclerotic process in this model and also antiatherogenic effect of imidapril may be derived from reduction of local Ang II production as well as its hypotensive action.
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PMID:Induction of angiotensin converting enzyme and angiotensin II receptors in the atherosclerotic aorta of high-cholesterol fed Cynomolgus monkeys. 967 83

T1alpha is a recently identified gene expressed in the adult rat lung by alveolar type I (AT1) epithelial cells but not by alveolar type II (AT2) epithelial cells. We evaluated the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on T1alpha expression using either soluble factors or changes in cell shape to influence phenotype. For studies on the effects of soluble factors on T1alpha expression, rat AT2 cells were grown on polycarbonate filters in serum-free medium (MDSF) or in MDSF supplemented with either bovine serum (BS, 10%), rat serum (RS, 5%), or keratinocyte growth factor (KGF, 10 ng/ml) from either day 0 or day 4 through day 8 in culture. For studies on the effects of cell shape on T1alpha expression, AT2 cells were plated on thick collagen gels in MDSF supplemented with BS. Gels were detached on either day 1 (DG1) or day 4 (DG4) or were left attached until day 8. RNA and protein were harvested at intervals between days 1 and 8 in culture, and T1alpha expression was quantified by Northern and Western blotting, respectively. Expression of T1alpha progressively increases in AEC grown in MDSF +/- BS between day 1 and day 8 in culture, consistent with transition toward an AT1 cell phenotype. Exposure to RS or KGF from day 0 prevents the increase in T1alpha expression on day 8, whereas addition of either factor from day 4 through day 8 reverses the increase. AEC cultured on attached gels express high levels of T1alpha on days 4 and 8. T1alpha expression is markedly inhibited in both DG1 and DG4 cultures, consistent with both inhibition and reversal of the transition toward the AT1 cell phenotype. These results demonstrate that both soluble factors and alterations in cell shape modulate T1alpha expression in parallel with AEC phenotype and provide further support for the concept that transdifferentiation between AT2 and AT1 cell phenotypes is at least partially reversible.
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PMID:Modulation of t1alpha expression with alveolar epithelial cell phenotype in vitro. 968 47

In various cardiovascular disorders, circulating or myocardial angiotensin II (Ang II) levels are increased, leading to excess collagen synthesis of cardiac fibroblasts. To characterize signal transduction mechanisms of Ang II, we examined changes in intracellular Ca2+ concentration ([Ca2+]i) of fura-2-loaded cultured adult rat cardiac fibroblasts by fluorescence photometry. [Ca2+]i was increased by Ang II via AT1 receptors in a dose-dependent manner (EC50 = 2.4 x 10(-8) mol/l) involving two distinct phases, an initial Ca2+ peak and a sustained elevated plateau phase. The initial Ca2+ peak occurred transiently and independently of the duration of Ang II application. While the magnitude of the transient Ca2+ peak did not differ in a nominally Ca(2+)-free (3 mmol/l EGTA) solution, the Ang II-mediated sustained plateau phase of [Ca2+]i was dependent on extracellular Ca2+. Thus, the initial transient Ca2+ peak appears to arise from intracellular Ca2+ stores, whereas the plateau phase involves an external Ca2+ influx. Since collagen synthesis of cardiac fibroblasts is maximally stimulated by Ang II or by fetal bovine serum (FBS), the effects of Ang II and FBS on [Ca2+]i were compared. The magnitude of the transient Ca2+ peak induced by 10(-7) mol/l Ang II was comparable to that of 10% FBS indicating that the rise in [Ca2+]i might be involved in the signal transduction pathway of Ang II-mediated collagen synthesis of cardiac fibroblasts.
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PMID:Angiotensin II and intracellular calcium of adult cardiac fibroblasts. 968 97

All studies analyzing the localization of angiotensin II (Ang II) receptors in the human kidney have been performed at the protein level using 125I-Ang II as a probe. In this study, cellular localizations of Ang II type l (AT1-R) and type 2 (AT2-R) receptor mRNAs in the adult human renal cortex were examined for the first time using in situ hybridization, and their expression patterns determined by RNase protection assay were compared with those in other human tissues. In the human renal cortex obtained from tumor-free portions in renal cell carcinoma, AT1-R mRNA levels were about 8- to 10-fold higher than AT2-R mRNA levels. Human liver and aorta predominantly expressed AT1-R mRNA, while human right atrium contained both AT1-R and AT2-R mRNAs. Ligand-binding assays revealed that the total Ang II receptor number in the human renal cortex was 16.0 +/- 3.3 fmol/mg protein, similar to that in liver (17.7 +/- 5. 8) but significantly higher than in right atrium (11.6 +/- 3.2) and aorta (5.6 +/- 2.7). Relative distribution ratios of AT1-R and AT2-R numbers in the renal cortex and right atrium were 82/17 and 56/42%, respectively. In situ hybridization study indicated that strongest AT1-R mRNA signals were located in interlobular arteries and tubulointerstitial fibrous regions surrounding interlobular arteries and glomeruli, followed in decreasing order by glomeruli and cortical tubules. Expression of AT2-R mRNA was highly localized in interlobular arteries. Cells present in tubulointerstitial regions were positive for vimentin and collagen type 1, indicating that the majority of the cells present in the regions are fibroblasts. Presence of strong AT1-R mRNA signals in the tubulointerstitial fibrous regions surrounding arteries and glomeruli and the expression of AT2-R mRNA in the interlobular artery were the first evidence, suggesting a pharmacological framework for the differential effects of Ang II receptor subtype mediated renal function in the adult human kidney.
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PMID:Tissue-specific expression of human angiotensin II AT1 and AT2 receptors and cellular localization of subtype mRNAs in adult human renal cortex using in situ hybridization. 973 Jun 99


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