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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT1 receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT1 density, and gene expression in aldosterone-salt-treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red-stained collagen. AT1 receptor density was determined by (125I-Sar1-Ile8)-Ang II competition binding, and AT1 mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT1 receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT1 density and that of right ventricular AT1 mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT1 receptors. They also suggest that the cardiac AT1 receptor is a target for aldosterone.
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PMID:Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. 1020 34

The potential antithrombotic action of losartan, an AT1 receptor antagonist, administered to two-kidney, one-clip rats (2K1C) in an experimental model of venous thrombosis was evaluated. The involvement of nitric oxide (NO) in this effect was also studied. Venous stasis was induced by ligation of the vena cava. Losartan after single dose (10 mg/kg, p.o.) significantly reduced the venous thrombus growth. The antithrombotic action of losartan in 2K1C rats was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg s.c.) and restored by L-arginine (1000 mg/kg s.c.). Platelet adhesion to fibrillar collagen significantly decreased after administration of losartan. No changes in primary hemostasis and platelet aggregation were observed. Moreover, coagulation parameters such as activated partial thromboplastin time, prothrombin time and euglobulin clot lysis time were found unchanged after losartan administration either in systemic circulation or at the place of thrombus formation. Our results indicate that antithrombotic activity of losartan in 2K1C rats is NO--dependent; observed inhibition of platelet adhesion could also play a role in this phenomenon.
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PMID:Antithrombotic activity of losartan in two kidney, one clip hypertensive rats. A study on the mechanism of action. 1021 Jan 58

The renin-angiotensin-aldosterone system has emerged as a potential candidate for the accumulation of collagen in cardiac fibroblasts. The traditional renin-angiotensin-aldosterone system can be considered a system in which circulating angiotensin II or aldosterone is delivered to target tissue or cells. However, an independent local renin-angiotensin system has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of angiotensin II can be mediated. These actions of angiotensin II are primarily mediated through angiotensin II receptors of the subtype I (AT1). When evaluating the effects of angiotensin II in situ, changes in circulating levels and local production both have to be taken into account. Functional angiotensin II receptors have been documented in cardiac fibroblasts although the presence of aldosterone receptors in cardiac fibroblasts is obscure, and the expression of mRNA for mineralocorticoid receptors in cardiac fibroblasts has been described. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha 1 (I) collagen, pro-alpha 1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The ability of angiotensin II to induce collagen synthesis and expression of collagen in cardiac fibroblasts may be mediated by an increase in transforming growth factor-beta 1 in an autocrine/paracrine fashion. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. The discordant findings that have been reported concerning the in vitro effect of aldosterone on collagen synthesis in cardiac fibroblasts can at least partly be attributed to differences in methodology such as the use of the total population or a sub-population of cardiac fibroblasts. In vivo, chronic infusion of angiotensin II or aldosterone increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats. The cardioprotective mechanism of action of ACE inhibitors can be attributed to local blockade of the formation of angiotensin II, to the degradation of bradykinin or to the release of nitric oxide and/or eicosanoids. Angiotensin-converting enzyme inhibitors also reduced collagen deposition in rat myocardium following myocardial infarction suggesting that collagen deposition may in part result from mechanisms other than through AT1 receptors. However, further research is necessary to unravel the various mechanisms involved in the action of angiotensin-converting enzyme inhibitors or of AT1 receptor antagonists on collagen deposition in the myocardium.
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PMID:Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. 1038 25

Angiotensin II (ANG II) induces cellular hypertrophy of cultured proximal tubular cells from various species. This hypertrophic response is associated with an increase in synthesis of basement membrane-associated collagen type IV. Previous investigations by our group have shown that ANG II stimulates mRNA and protein expression of the "classic" alpha1 and alpha2(IV) chains in cultured murine proximal tubular cells (murine cortical tubules [MCT cells]). Since it is clearer today that kidney basement membranes also contain heterotrimers of novel type IV collagens, the aim of the present study was to evaluate whether ANG II may influence the expression of alpha3 and alpha5(IV) collagen chains in MCT cells. A single dose of 10-8-10-6 M ANG II stimulated mRNA expression of alpha3(IV), but not of alpha5(IV), in MCT cells cultured in serum-free media. This response was mediated through AT1-receptors because losartan, but not an AT2-receptor antagonist, abolished the ANG II-induced expression of alpha3(IV) transcripts. Transient transfection of MCT cells with transforming growth factor-beta1 (TGF-beta1) antisense phosphorothioate-modified oligonucleotides partly abolished the ANG II-induced alpha3(IV) mRNA expression. Furthermore, Western blots of cellular lysates incubated with polyclonal antibodies generated against the recombinant collagen chains revealed that ANG II stimulated alpha3(IV) but not alpha5(IV) protein expression. This stimulation was partly prevented by co-incubation with a neutralizing anti-TGF-beta1-3 antibody. In summary, our data indicate that ANG II stimulates expression of the alpha3(IV) collagen chain in cultured MCT cells, due in part to TGF-beta1 activation.
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PMID:Angiotensin II induces alpha3(IV) collagen expression in cultured murine proximal tubular cells. 1041 44

Synthesis of aldosterone (Aldo) and corticosterone (B) has been recently reported in rat heart. However, regulation of this synthesis in pathophysiological states remains unknown. Thus, this study aimed to analyze effects of a one-month myocardial infarction (MI) on cardiac steroidogenic system. Levels of terminal enzymes of B (11 beta-hydroxylase: 11 beta H) and aldo (Aldo-synthase: AS) synthesis were assayed by quantitative RT-PCR. Cardiac Aldo and B levels were assessed by celite colum chromatography and radioimmunoassay. MI raised AS mRNA levels by 2.0-fold (p < 0.05) but downregulated that of 11 beta H by 2.4 fold (p < 0.05) in the noninfarcted part of the left ventricle (LV). Cardiac steroids production followed a similar pattern of regulation. Aldo level was increased in MI (319 +/- 85 vs 87 +/- 11 pg/mg of protein in control, p < 0.05) whereas that of B fell (2,412 +/- 318 vs 4,624 +/- 857 pg/mg of protein in control, p < 0.05). MI also induced an 1.9-fold increase in cardiac Ang II level. Such cardiac regulations were prevented by Ang II-AT1 receptor antagonist losartan (8 mg/kg/day) treatment. The Aldo receptor antagonist spironolactone (20 mg/kg/day) had no effect. Plasma Aldo and B, and adrenal 11 beta H and AS mRNA levels were unchanged whatever the treatment. The MI-induced collagen deposition in noninfarcted area of the LV was reduced by both spironolactone and losartan treatments by 1.6- and 2.5-fold, respectively. These data indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac Ang II via AT1 receptor and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.
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PMID:[Role of cardiac aldosterone in post-infarction ventricular remodeling in rats]. 1048 52

Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert. Earlier morphologic studies suggested healing at the infarct site was complete within 6-8 weeks following MI and resultant scar tissue, albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they express alpha-smooth muscle actin (alpha-SMA) and these microfilaments confer contractile behavior in response to various peptides and amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth factor (TGF)-beta1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous tissue in noninfarcted myocardium.
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PMID:Infarct scar: a dynamic tissue. 1077 28

An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11beta-hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV reduces total mortality by 30%.
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PMID:Induction of cardiac fibrosis by aldosterone. 1088 42

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
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PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.
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PMID:Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure. 1102 48

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
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PMID:Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. 1135 55


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