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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myocardial fibrosis can be defined as an abnormal increase in collagen concentration of either ventricle. This accumulation of collagen, represented predominantly by fibrillar type I collagen, can occur a) on a reactive basis in the interstitial space and adventitia of intramyocardial coronary arteries and does not require myocyte necrosis, or b) as a replacement for necrotic myocytes, where it is considered a scar. Both forms can be found in the same ventricle. Various factors have been found to contribute to the reactive and reparative fibrosis that appears in both ventricles in acquired hypertension. In the case of microscopic scarring, myocyte necrosis is related to catecholamine or angiotensin II- mediated toxicity, reduced potassium stores that accompany chronic mineralocorticoid excess, and coronary vascular remodeling. Reactive fibrosis is associated with elevations in plasma aldosterone concentrations that are inappropriate relative to dietary sodium intake. These findings set the stage for additional in vivo and in vitro studies that may shed more light on our understanding of the factors that regulate the accumulation of fibrous tissue in the myocardium--a major determinant of pathologic structural remodeling which enhances its susceptibility to reentrant arrhythmias and ventricular dysfunction.
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PMID:Factors associated with reactive and reparative fibrosis of the myocardium. 149 73

An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. 213 51

Myocardial fibrosis resulting from arterial hypertension alters myocardial structure and function. Myocardial fibrosis is characterized by a pathological accumulation of types I and III collagens. We used an aldosterone antagonist (spironolactone) and an angiotensin II antagonist (losartan) to elucidate the respective role of these hormones and hypertension in the development of myocardial fibrosis in the Goldblatt model of two-kidney, one clip hypertension in the rat. Fibrosis was assessed by computer-assisted morphometry in the interstitial space, around coronary arteries, in microscar areas, and on left ventricular sections stained with Sirius red and by biochemical techniques. Morphometry was performed with both standard light and polarization microscopy; this latter method was used to quantify yellow-red and green collagen fibers. Concurrently, type I and type III collagen mRNAs were evaluated by a semiquantitative polymerase chain reaction method. The collagen content of the untreated two-kidney, one clip hypertensive rats increased mainly around the coronary arteries; the number and surface area of microscars also increased in chronic hypertension. Losartan treatment decreased systolic pressure and yellow-red collagen fiber content in all areas, whereas spironolactone treatment decreased green collagen fiber content without decreasing systolic pressure. mRNA levels for types I and III collagens showed profiles similar to those of yellow-red and green collagen fiber contents, respectively, suggesting that yellow-red collagen fibers are mainly type I collagen fibers and green collagen fibers are mainly type III collagen fibers. These results suggest that angiotensin II, possibly together with hypertension, and aldosterone, independently of hypertension, have a major influence on myocardial fibrosis, inducing type I and type III collagen deposits, respectively, mainly around coronary arteries.
Hypertension 1995 Jul
PMID:Left ventricular fibrosis in renovascular hypertensive rats. Effect of losartan and spironolactone. 760 12

In the two-kidney one-clip hypertensive Goldblatt model of nephrosclerosis, the aim of this study was to detect, during the first twenty-eight days of high blood pressure, interstitial and periarterial (interlobular arterial and arteriolar) kidney changes. Morphometric analysis for type I collagen, in situ hybridization for type I and IV collagen mRNAs and immunohistochemistry for inflammatory cells were used to quantify and localize the following lesions: 1) A very early increase of collagen I proteins and mRNAs soon as the first 3 days and an important influx of inflammatory cells (macrophages and T-helper lymphocytes) were observed concomitantly. Then, these phenomenons decrease until the end of the experiment. 2) The interstitium reacts in the same way but with a lower intensity and with a time shifting. The main interstitial changes were seen after the second week of hypertension. 3) A same periarterial collagen I increase was measured during the first 3 days of hypertension in both clipped kidney and unclipped kidney. This hypertension-independent manifestation in the clipped kidney does not increase in later times of hypertension as it does in the unclipped kidney. A possible explanation is given by the angiotensin II concentration higher in the clipped kidney than in the unclipped kidney, and by direct angiotensin II effects as growth factor. 4) Periarterial fibrosis and macrophages or T-helper lymphocytes infiltration were co-localized. The intensity of both phenomenons is well correlated. These facts suggest that inflammatory cell infiltration and interstitial fibrosis are strongly and early linked.
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PMID:[Early matrix and cellular modifications in a hypertension model induced in rats (Goldblatt model). Quantitative and morphometric study]. 876 30

Increased pressure, as may occur with hypertension, may alter cellular function by inducing repetitive mechanical strain. However, increased pressure itself may directly alter cellular function independent of stretching of cells. We undertook the present study to determine whether increased applied pressure could alter uptake of IgG complexes by macrophages. Increased pressure was applied to confluent macrophages grown on plastic culture plates using a pressure chamber apparatus kept inside the incubator at 37 degrees C and pressure regulated using a rotator pump and adjustable outlet valve. Macrophages that were subjected to increased pressure were found to have a significantly greater uptake of IgG complexes in a dose-dependent manner. The effect of increased pressure could be abrogated by carrying out experiments in calcium-free medium while this exerted no effect on uptake by macrophages under control conditions. Increased uptake of IgG complexes by macrophages subjected to increased applied pressure could also be attenuated by incubation with the calcium channel blockers amlodipine and cinnarizine. To determine whether the effect of increased pressure was related to the plastic substrate on which the cells are grown, cells were also seeded onto type I collagen gels and uptake of IgG complexes was measured. Uptake by macrophages on the type I collagen substrate was significantly enhanced with increased applied pressure compared to control (p < 0.01). These studies demonstrate that exposure of macrophages to increased pressure enhances their uptake of IgG complexes via a mechanism that appears to involve an increase in intracellular calcium. This effect might play a role in some of the consequences of systemic arterial and glomerular capillary hypertension.
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PMID:Increased applied pressure enhances the uptake of IgG complexes by macrophages. 885 94

Experimental pharmacology and studies on hypertension frequently use genetically hypertensive animal models like the SHR or the Lyon hypertensive rat LH. In order to further characterize these two models we measured the expression levels of three major extracellular matrix components in the aortic wall, tropoelastin (TE) and type I and type III collagen, during postnatal development. The type I collagen expression decreases progressively during the first twelve weeks of postnatal development without significant differences between SHR and LH, or their normotensive controls, WKY or LN respectively. No differences were detected either for the expression levels of TE and type III collagen between the hypertensive strains and their respective controls. However, direct comparison of the two hypertensive strains SHR and LH, revealed a specific, strong increase of TE and type III expression for the LH at 5 and 12 weeks (p < 0.001 and 0.005 respectively). The evolution of the ratios of expression levels between the two collagens (type III/type I) on one side and of TE and collagen type I (TE/type I) on the other side were similar for the hypertensive strains and their respective controls, but diverged significantly for LH and SHR animals (up to p < 0.001 depending on the age group). Both indicators, III/I and TE/I, are considerably higher in LH compared to SHR from 5 weeks of postnatal development onwards. Our results indicate that the genes for TE and type I and III collagen are regulated during postnatal development of LH and SHR. It is however not possible at this point to establish a link between mRNA levels and hypertension in these animals. Nevertheless, the ratios III/I and TE/I seem to be good phenotypic markers for the characterisation of LH and SHR strains.
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PMID:[Two strains of genetically hypertensive rats, LH and SRH, have distinct profiles of postnatal expression of tropoelastin and type III collagen in the aortic wall]. 894 66

In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.
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PMID:Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease. 899 38

Transforming growth factor-beta (TGF-beta) is usually secreted as a large latent complex associated with latent TGF-beta binding protein-1 (LTBP-1), which is known to bind to extracellular matrix (ECM) components. Although the LTBP-ECM interaction has been suggested to play a role in the activation and biological action of TGF-beta, the precise mechanism is still unclear. In glomerular hypertension mesangial cells are believed to perceive the increased cyclic strain and we have recently reported that cyclic mechanical stretch in vitro enhances the expression of ECM components via an autocrine/paracrine secretion of TGF-beta in cultured rat mesangial cells. Therefore, in this study we examined the role of LTBP-1 in the stretch-induced, TGF-beta-mediated ECM expression. Mesangial cells expressed mRNA for short and long forms of LTBP-1 (LTBP-1S and LTBP-1L, respectively). Mesangial cells were subjected to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles/min for 24 to 36 hours in the presence of polyclonal antibody raised against human LTBP-1 or synthetic oligopeptides corresponding to the N-terminal portions of human LTBP-1, which may work as competitive inhibitors against the LTBP-ECM association. Both anti-LTBP-1 antibody (Ab39) and synthetic oligopeptides inhibited the stretch-induced mRNA expression of type I collagen and fibronectin in a dose-dependent manner, but the inhibition by Ab39 or the oligopeptides was recovered by adding recombinant TGF-beta. Ab39 or the oligopeptides did not change the effect of exogenously added TGF-beta, such as growth-inhibition in mink lung epithelial cells. These results suggest that mesangial cells secrete TGF-beta as a large latent complex, and the LTBP-ECM interaction may be a pivotal step in TGF-beta action and ECM accumulation, providing a new therapeutic strategy against progression of glomerulosclerosis and other fibrotic diseases.
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PMID:Anti-latent TGF-beta binding protein-1 antibody or synthetic oligopeptides inhibit extracellular matrix expression induced by stretch in cultured rat mesangial cells. 960 92

Hypertension is often associated with the development of nephroangio- and glomerulo-sclerosis. This pathophysiological process is due to increased extracellular matrix protein, particularly type I collagen, accumulation. This study investigated whether nitric oxide (NO) synthesis is involved in the mechanism(s) regulating activation of the collagen I gene in afferent arterioles and glomeruli. Experiments were performed on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter [procolalpha2(I)]. Measurements of luciferase activity provide highly sensitive estimates of collagen I gene activation. NO synthesis was inhibited by NG-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg per day) for a period of up to 14 wk. Systolic blood pressure was increased after 6 wk of treatment (117+/-2 versus 129+/-2 mmHg, P < 0.01) and reached a plateau after 10 wk (around 160 mmHg). Luciferase activity was increased in freshly isolated afferent arterioles and glomeruli as early as week 4 of L-NAME treatment (150 and 200% of baseline, P < 0.01, respectively). The activation of procolalpha2(I) became more pronounced with time, and at 14 wk increased four- and tenfold compared with controls in afferent arterioles and glomeruli, respectively (P < 0.001). In contrast, luciferase activity remained unchanged in aorta and heart up to 8 wk and was increased thereafter. Increased histochemical staining for extracellular matrix deposition, and particularly of collagen I, was detected in afferent arterioles and glomeruli after 10 wk of L-NAME treatment. This fibrogenic process was accompanied by an increased urinary excretion rate of endothelin. In separate experiments, the stimulatory effect of L-NAME on collagen I gene activation was abolished when animals were treated with bosentan, an endothelin receptor antagonist. Similarly, bosentan reduced the increased extracellular matrix deposition in afferent arterioles and glomeruli during NO inhibition. Interestingly, bosentan had no effect on the L-NAME- induced increase of systolic pressure. These data indicate that NO inhibition induces an early activation of the collagen I gene in afferent arterioles and glomeruli. This activation in the kidney precedes the increase in blood pressure and the procolalpha2(I) activation in heart and aorta, suggesting a specific renal effect of NO blockade on collagen I gene expression that is independent of increased blood pressure and, at least partly, mediated through stimulation of the endothelin receptor. Use of procolalpha2(I) transgenic mice provides a novel and efficient model to study the pathophysiological mechanism(s) regulating renal fibrosis.
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PMID:Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice. Role of endothelin. 963 12

We evaluated the effects of long-term treatment with amlodipine, a calcium antagonist, on nitric oxide synthase (NOS) activity and NOS messenger RNA (mRNA) expression in the left ventricle (LV) and its relation to coronary reserve, and microvascular remodeling in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Seventeen male Sprague-Dawley rats were given L-NAME (60 mg/kg/day) in drinking water for 6 weeks to induce hypertension, and then treated with amlodipine (L-NAME + A, 5 mg/kg/day, n = 9), or a vehicle (L-NAME + V, n = 8) for 4 weeks. Age-matched rats (C, n = 8) served as the control group. An increased blood pressure in L-NAME + V was significantly decreased in L-NAME + A. Nitrite production and endothelial cell (e) NOS mRNA in the LV were significantly decreased in L-NAME + V compared with C, and were significantly increased in L-NAME + A compared with C and L-NAME + V. L-NAME + V had a significantly decreased coronary reserve and capillary density, and a significantly increased type I collagen mRNA expression, wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These parameters in the microvasculature were significantly improved by amlodipine. We concluded that NOS activity and eNOS mRNA were significantly increased by amlodipine in the LV of L-NAME-induced hypertensive rats, and that these increase NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary reserve and microvascular remodeling.
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PMID:Effects of amlodipine on nitric oxide synthase mRNA expression and coronary microcirculation in prolonged nitric oxide blockade-induced hypertensive rats. 1044 67


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