Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronically administered N(omega)nitro-L-arginine methyl ester (L-NAME) produces vascular structural changes and fibrosis of the left ventricle (LV). However, very few studies have evaluated whether the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on these myocardial remodelings are associated with local gene expression of nitric oxide synthase (NOS) and ACE mRNA in the LV. Effects of long term treatment with imidapril, an ACE inhibitor, on gene expression of endothelial-cell NOS (eNOS) and ACE mRNA in the LV and its relation to myocardial remodeling in L-NAME-induced hypertensive rats were evaluated. Fifteen 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 imidapril (L-NAME-I, n = 8, 1 mg/kg/day, subdepressor dose), or a vehicle (L-NAME-V, n = 7) for 4 weeks. Age-matched rats (C, n = 7) served as a control group. Blood pressure in L-NAME-V and L-NAME-I was similar and significantly higher than that in C. The level of eNOS mRNA in the LV was significantly decreased in L-NAME-V compared with C, and was significantly increased in L-NAME-I compared with C and L-NAME-V. The ACE mRNA and type I collagen mRNA expression levels were significantly increased in L-NAME-V compared with C, and significantly suppressed in L-NAME-I compared with L-NAME-V. L-NAME-V demonstrated a significant increase in wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These changes in the microvasculature were improved significantly by imidapril. Myocardial remodeling in L-NAME-induced hypertensive rats was significantly ameliorated by a subdepressor dose of imidapril, which may be due to an increase in local eNOS mRNA expression and a decrease in angiotensin II in the LV.
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PMID:Effect of imidapril on myocardial remodeling in L-NAME-induced hypertensive rats is associated with gene expression of NOS and ACE mRNA. 1070 21

The finding that glomerular mesangial cells produce human type I collagen suggests that the serum levels of carboxy-terminal propeptide of human type I procollagen (P1CP) may reflect the severity of diabetic nephropathy. We therefore investigated the relationship between serum P1CP levels and the extent of diabetic complications in 100 patients (46 males and 54 females) with Type 2 diabetes and in 64 healthy subjects. Serum P1CP was determined by radioimmunoassay. In diabetes, we defined P1CP levels less than 142 ng/ml as a normal P1CP group (group A), whereas we defined them as equal to or greater than 142 ng/ml as a high P1CP group (group B). The diabetic patients had significantly elevated serum P1CP levels compared with the controls. The prevalence of hypertension, proliferative diabetic retinopathy or macroalbuminuria was significantly higher in group B than in group A. Serum P1CP levels showed a significant positive correlation with urinary albumin excretion, but not with fasting blood glucose, glycosylated hemoglobin A(1c) or serum osteocalcin. Macroalbuminuric patients showed significantly higher P1CP levels than the normoalbuminuric patients. In patients in the absence of diabetic nephropathy, no significant differences of P1CP levels were found among the severity of diabetic retinopathy. The present results suggest that serum P1CP levels reflect the progression of diabetic nephropathy in patients with Type 2 diabetes.
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PMID:Serum levels of carboxy-terminal propeptide of human type I procollagen are an indicator for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus. 1070 96

Vascular hypertrophy, which is characterized by proliferation of vascular smooth muscle cells (VSMC) and accumulation of extracellular matrix (ECM), is a major pathological change in blood vessels after chronic exposure to hypertension. Blood pressure is transmitted to the arterial walls and counterbalanced by mechanical stress, leading to stretching of circumferentially oriented VSMC, which may play some role in the pathogenesis of vascular hypertrophy. The present study was designed, therefore, to investigate the effect of mechanical stretch on the expression of ECM components and transforming growth factor-beta (TGF-beta), a potent stimulator for ECM production, and to examine the signal transduction mechanisms of the induction of TGF-beta in cultured rat VSMC. VSMC were subjected to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles per minute for up to 24 h. Mechanical stretch stimulated TGF-beta1 mRNA expression in a time- and elongation-dependent manner. Indeed, the secretion of TGF-beta proteins into the culture media was increased after stretch. Stretch also stimulated mRNA expression of the ECM components, type I and type IV collagen, and fibronectin, which was largely inhibited by addition of neutralizing antibody against TGF-beta. The tyrosine kinase inhibitors genistein and herbimycin A blocked the induction of TGF-beta1 and type I collagen by stretch, while protein kinase C inhibitors, the calcium channel blockers nitrendipine and gadolinium, or Ca removal from the media had no effect. These results suggest that stretch-induced, tyrosine kinase-mediated autocrine/paracrine production of TGF-8 may play a critical role in the progression of vascular remodeling associated with high blood pressure.
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PMID:Tyrosine-kinase dependent TGF-beta and extracellular matrix expression by mechanical stretch in vascular smooth muscle cells. 1077 Feb 55

Studies have demonstrated that local angiotensin II (Ang II) generation is enhanced in repairing kidney and that ACE inhibition or AT(1) receptor blockade attenuates renal fibrosis. The localization of ACE and Ang II receptors and their relationship to collagen synthesis in the injured kidney, however, remain uncertain. Using a rat model of renal injury with subsequent fibrosis created with chronic elevations in circulating aldosterone (ALDO), we examined the distribution and binding density of ACE and Ang II receptors in repairing kidneys, as well as their anatomic relationship to transforming growth factor-beta1 (TGF-beta1) mRNA, type I collagen mRNA, collagen accumulation, and myofibroblasts. Two groups of animals (n=7 in each group) were studied: (1) normal rats served as controls, and (2) uninephrectomized rats received ALDO (0.75 microg/h SC) and 1% NaCl in drinking water for 6 weeks. Compared with control rats, in ALDO-treated rats we found (1) significantly (P<0.01) increased blood pressure, reduced plasma renin activity, and increased plasma creatinine levels, (2) diffuse fibrosis in both renal cortex and medulla, (3) abundant myofibroblasts at these sites of fibrosis, (4) significantly increased (P<0.01) binding density of ACE and Ang II receptors (60% AT(1), 40% AT(2)) at the sites of fibrosis, and (5) markedly increased (P<0.01) expression of TGF-beta1 and type I collagen mRNAs at these same sites. Thus, in this rat model of renal repair, the enhanced expression of ACE, Ang II receptors, and TGF-beta1 is associated with renal fibrosis. Ang II generated at the sites of repair appears to have autocrine/paracrine functions in the regulation of renal fibrous tissue formation alone or through its stimulation of TGF-beta1 synthesis.
Hypertension 2000 May
PMID:Local angiotensin II and transforming growth factor-beta1 in renal fibrosis of rats. 1081 68

Oxidized low-density lipoprotein (OxLDL) has been implicated in atherosclerosis and glomerulosclerosis. LOX-1 is a recently identified OxLDL receptor that is abundantly expressed in vascular endothelial cells. The aim of the present study was to investigate LOX-1 expression in the kidneys of hypertensive rats. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were fed a 0.3% or 8% NaCl diet. Some DS 8% rats were treated with manidipine or hydralazine. LOX-1 gene expression was markedly elevated in the kidneys and glomeruli of hypertensive DS 8% rats compared with those of normotensive DR and DS 0.3% rats. Prolonged salt loading further increased the renal LOX-1 expression in DS rats. The LOX-1 upregulation in DS 8% rats was accompanied by renal overexpression of transforming growth factor-beta 1 and type I collagen, impaired renal function, and histologic glomerulosclerotic changes, all of which were ameliorated by antihypertensive treatment. LOX-1 was indeed expressed in the glomeruli in vivo and in cultured glomerular cells in vitro. However, LOX-1 expression was elevated in the aorta but not the kidneys of spontaneously hypertensive rats, which exhibited hypertension but minor glomerulosclerotic changes. In conclusion, the LOX-1 upregulation in the kidney of DS 8% rats was parallel to glomerulosclerotic changes and renal dysfunction, suggesting a possible pathogenetic role for renal LOX-1 in the progression to hypertensive glomerulosclerosis.
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PMID:Expression of LOX-1, an oxidized low-density lipoprotein receptor, in experimental hypertensive glomerulosclerosis. 1100 13

We examined the role of inflammation in the development of renal interstitial fibrosis in Zucker obese rats, which rapidly present kidney lesions in the absence of hypertension and hyperglycemia. Type I and III collagens were quantified using a polarized light and computer-assisted image analyzer. The expression of mRNA encoding matrix components, adhesion molecules, chemokines, and growth factors was followed by RT-PCR. The presence of synthesized proteins as well as lymphocytes and macrophages was determined by immunohistochemistry. Interstitial fibrosis developed in two phases. The first phase occurred as early as 3 mo and resulted from a neosynthesis of type III collagen and fibronectin and a reduction of extracellular matrix catabolism, in parallel with an overexpression of transforming growth factor-beta(1) and in the absence of any lymphocyte or macrophage infiltration. After 6 mo, interstitial fibrosis worsened with a large accumulation of type I collagen, concomitantly with a large macrophage infiltration. Thus inflammation cannot explain the onset of interstitial fibrosis that developed in young, insulinoresistant, normoglycemic, obese Zucker rats but aggravated this process afterward.
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PMID:Inflammation is probably not a prerequisite for renal interstitial fibrosis in normoglycemic obese rats. 1124 60

Angiotensin II and nitric oxide (NO) may play a role in hypertensive cardiovascular remodeling. We evaluated the effects of long-term treatment with quinapril, an angiotensin converting enzyme (ACE) inhibitor, on expression of endothelial NO synthase (eNOS), ACE, and angiotensin II type 1 (AT1) receptor in the left ventricle and evaluated these relations to myocardial remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Deoxycorticosterone acetate-salt rats were induced with weekly injections of DOCA (30 mg/kg) and 1% saline in drinking water after right nephrectomy. Quinapril (DOCA-QUI, 10 mg/kg/day, subdepressor dose) or AT1 receptor antagonist TCV-116 (DOCA-TCV, 5 mg/kg/day, subdepressor dose) or vehicle (DOCA-V) were given after induction of DOCA-salt hypertension for 5 weeks, and age-matched sham-operated rats (ShC) served as a control group. The eNOS expression in the left ventricle were significantly decreased in DOCA-V compared with ShC, and were significantly increased in DOCA-QUI and DOCA-TCV compared with ShC and DOCA-V. The gene expression of ACE, AT1 receptor, and type I collagen mRNA were significantly increased in DOCA-V compared with ShC, and significantly suppressed in DOCA-QUI compared with DOCA-V. The DOCA-V rats demonstrated a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by quinapril. Myocardial remodeling in DOCA-salt hypertensive rats was significantly ameliorated by a subdepressor dose of quinapril, which may be due to an increase in eNOS mRNA and protein expression and a decrease in ACE and AT1 receptor mRNA expression in the left ventricle.
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PMID:Effects of quinapril on expression of eNOS, ACE, and AT1 receptor in deoxycorticosterone acetate-salt hypertensive rats. 1133 77

It appears that the beneficial action of calcium channel blockers (CCBs) in hypertension may be related to short-term and long-term effects. This paper summarises pharmacological studies aiming to characterise those effects. The primary consequence of the short-term effects is the decrease of blood pressure related to a selective interaction of CCBs with calcium channels in hypertensive vessels. The long-term effects may additionally control the disease through prevention of end organ damage, accompanying the interaction of CCBs with the pathways, leading to the re-expression of embryonic genes and to the overactivation of type I collagen gene, which are amplified by a high-salt diet. ET-1 and tumour growth factor beta-1 could be among the main factors activating those pathways. The processes leading to overexpression of those factors and to tissue remodelling may be controlled by lacidipine, independent of the reduction of blood pressure.
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PMID:New insights into the therapeutic mechanism of action of calcium channel blockers in salt-dependent hypertension: their interaction with endothelin gene expression. 1134 59

Several studies have suggested that high blood pressure is associated with the risk of bone loss. Since various antihypertensive drugs are in wide use for the treatment of hypertension, it is important to investigate the influences of these drugs on bone metabolism. Osteoblasts play a pivotal role in the regulation of bone formation. During differentiation, they sequentially express type I collagen, alkaline phosphatase (ALP), other bone matrix proteins, and finally undergo mineral deposition. In this study, we examined the effects of various antihypertensive drugs on the function of osteoblast using clonal MC3T3-E1 cells. Drugs examined include dihydropyridine-type calcium channel blockers (benidipine, amlodipine, and nifedipine), angiotensin-converting enzyme (ACE) inhibitors (captopril, lisinopril, and enalapril), and angiotensin II receptor type1 (AT1) antagonists (TCV-116 and KW-3433). None of the ACE inhibitors or AT1 antagonists affected ALP activity or cellular DNA content significantly. In contrast, benidipine, amlodipine, and nifedipine increased ALP activity when used in amounts 1 pM, 100 nM, and 100 nM, respectively. Benidipine blocked calcium influx through the L-type voltage dependent calcium channel of MC3T3-E1 more potently than amlodipine or nifedipine. These calcium channel blockers did not change collagen accumulation. Benidipine significantly increased in vitro mineralization at a concentration of 1 nM and higher, while amlodipine did so at 1 microM and nifedipine did not. Comparison of the effective concentration of each calcium channel blocker in our study with the reported maximum serum concentration of each drug suggests that benidipine, but not amlodipine or nifedipine, promotes mineral deposition in human.
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PMID:Effects of various antihypertensive drugs on the function of osteoblast. 1141 49

We have shown that exposure of pregnant ewes to dexamethasone (11.5 mg/d for 2 days) at 27 days of gestation (term, 150 days) led to increased blood pressure and cardiac output in adult offspring. In this study, we hypothesized that dexamethasone-induced hypertension is associated with left ventricular hypertrophy and a reduced cardiac functional reserve (CO(max-0)). Six control animals (group C) and five dexamethasone-exposed animals (group D) were volume-loaded with Hemaccel until the wedge pressure was 13 mm Hg (baseline). The wedge pressure was held constant during an infusion of dobutamine at incremental doses (0.4 to 12 microgram/kg/min) while blood pressure and cardiac output were measured. The same protocol was repeated in each animal 5 days later under mild general anesthesia (1.5% isoflurane), when transthoracic echocardiography (M-mode) was obtained. Group D showed a reduced CO(max-0) in response to dobutamine during both conscious (89+/-22 versus 150+/-25 mL/kg/min in control; P<0.01) and anesthetized states (91+/-38 versus 156+/-56 mL/kg/min in control; P<0.05). Reduced CO(max-0) in group D was associated with higher left ventricular mass index compared with group C (2.6+/-0.67 versus 1.8+/-0.51 g/kg; P<0.05). In addition, group D showed a reduced cardiac contractility reserve (FS(max-0)) in response to dobutamine (21+/-22% versus 54+/-34% in group C; P<0.05). An impaired cardiac functional reserve in group D was associated with increased left ventricular type I collagen content. In conclusion, brief prenatal exposure to dexamethasone led to the development of hypertension, left ventricular hypertrophy, and reduced cardiac functional reserve in adult life.
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PMID:Impaired cardiac functional reserve and left ventricular hypertrophy in adult sheep after prenatal dexamethasone exposure. 1157 28


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