Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 +/- 8 vs. 150 +/- 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F(2alpha)-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-beta (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg.kg(-1).day(-1)) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-beta1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 +/- 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-beta1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.
...
PMID:Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-beta, and fibronectin with concomitant increase in nitric oxide bioavailability. 1846 18

Placebo-controlled clinical trials have shown that atorvastatin is beneficial in patients with myocardial ischemia, established coronary artery disease, hypertension and 3 other cardiovascular risk factors (e.g. left-ventricular hypertrophy, type 2 diabetes, smoking), and in diabetes, but not in patients with calcific aortic stenosis. Recently, intensive low density lipoprotein (LDL)-cholesterol lowering with atorvastatin 80 mg/day has been shown to have a greater clinical benefit than atorvastatin 10 mg/day in patients with coronary heart disease and one other high-risk factor (previous myocardial infarction, coronary revascularization or angina), and to be superior to moderate lipid lowering with pravastatin (40 mg/day) in patients with an acute coronary syndrome. However, a smaller study comparing lovastatin 5 mg/day with atorvastatin 80 mg/day was unable to detect any difference in outcomes in patients with stable coronary disease, despite the greater LDL-cholesterol lowering with the atorvastatin, possibly because it was not powered to do so. In a retrospective cohort study, atorvastatin 10 mg/day, pravastatin 20 mg/day, simvastatin 20 mg/day, lovastatin 20 mg/day and fluvastatin 20 mg/day had similar efficacy as secondary prevention after acute myocardial infarction. At present, the evidence from clinical trials is favouring the intensity of the effect on LDL-cholesterol and/or C-reactive protein (CRP) with atorvastatin 80 mg, rather than the use of atorvastatin per se, when greater benefits are observed with the 80 mg dose of atorvastatin compared to other statins. Thus, at present, it is not clear whether atorvastatin is superior to other statins in some indications (coronary heart disease, acute coronary syndromes) or whether it is the intensive lipid lowering that is responsible for the superiority. Atorvastatin has little or no ability to increase high density lipoprotein (HDL)-cholesterol, and this may be a disadvantage in patients with metabolic syndrome or diabetes, where low HDL-cholesterol is a key feature. Thus, other statins should probably be preferred to atorvastatin in patients with diabetes/metabolic syndrome. Alternatively, atorvastatin can be used in combination with a fibrate to increase HDL-cholesterol in patients with diabetes/metabolic syndrome.
...
PMID:Is atorvastatin superior to other statins? Analysis of the clinical trials with atorvastatin having cardiovascular endpoints. 1847 65

Atherosclerosis, especially when manifested as coronary artery disease (CAD), continues to be the number one cause of mortality and morbidity in developed nations and will soon become so in developing countries. Survivors of an acute heart attack have an increased risk of illness and death that is 1.5-15 times greater than in the general population. Sudden death occurs in myocardial infarction (MI) survivors at a rate 4-6 times greater than in the general population. After an initial recognized MI, 25% of male and 38% of female survivors die within 1 year. Within 6 years after a recognized MI, 18% of men and 35% of women will have a second MI, 7% of men and 6% of women will suffer sudden death, and 22% of men and 46% of women will be disabled with heart failure. Aggressive secondary prevention, therefore, is the key to containing and reversing the "malignant" natural history of CAD, since patients with CAD or CAD risk equivalents are already in the "high risk" category according to the Adult Treatment Panel III (ATP III) of the National Cholesterol Education rogram (NCEP). Treatment of dyslipidemia, especially the reduction of low-density lipoprotein (LDL) cholesterol levels to below 100 mg/dl, was recommended by the 2001 NCEP-ATP Guidelines. In 2004, based on the increasing evidence from several major clinical trials between 2001 and 2004, the NCEP-ATP reaffirmed its LDL goal of < 100 mg/dl in patients with CAD or coronary disease risk equivalents (including multiple risk factors), with an optional LDL goal of < 70 mg/dl in very-high-risk patients (including patients with established coronary heart disease plus other highrisk conditions) Findings from major studies, such as the Treating to New Targets (TNT) study, the Scandinavian Simvastatin Survival Study (4S), the Collaborative Atorvastatin Diabetes Study (CARDS), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial and, more recently, the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LAA), lend support to the idea that greater LDL cholesterol lowering than that achieved with standard doses of statins may be warranted in patients with CAD and metabolic syndrome, CAD and diabetes, CAD and congestive heart failure, and CAD and renal insufficiency. On the other hand, additional lipid reduction may also be warranted in patients with risk factors such as diabetes, hypertension or a history of stroke, but without manifest CAD and despite relatively normal cholesterol levels. These newer indications for statins, atorvastatin in particular, as part of more aggressive secondary and primary prevention, are reviewed in this paper.
...
PMID:Expanding roles for atorvastatin. 1859 99

To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 +/- 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 +/- 0.12 mmol/L (24 +/- 5 mg/dl), triglycerides 2.01 +/- 0.98 mmol/L (180 +/- 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 +/- 0.95 mmol/L (94 +/- 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were -6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large alpha-1 apolipoprotein A-I-containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, approximately 0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients.
...
PMID:Comparison of treatment of severe high-density lipoprotein cholesterol deficiency in men with daily atorvastatin (20 mg) versus fenofibrate (200 mg) versus extended-release niacin (2 g). 1899 52

Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO(2) inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (P<0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (P<0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and beta(2)-microglobulin in male and C-reactive protein in female offspring (P<0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (P<0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-alpha were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed.
Hypertension 2009 Apr
PMID:Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner. 1922 Dec 11

Type 2 diabetes mellitus is the leading cause of macrovascular diseases and related death. Additionally, diabetes mellitus is frequently complicated by other cardiovascular risk factors, such as hypercholesterolemia, hypertension, obesity, hypercoagulability, and inflammation. We wanted to evaluate and compare the effects of treating with a one-year course of atorvastatin or simvastatin on inflammatory markers such as high sensitive C-reactive protein (hsCRP), fibrinogen, and ferritin in uncontrolled type 2 diabetic patients. Also, we planned to investigate the correlation between inflammatory markers and metabolic parameters. Fifty type 2 diabetic patients (30 women, 20 men; mean age: 49.9 +/- 8.5 years) were enrolled into the study. Twenty healthy subjects, matched on body mass index and age, were also included in the study as a control group. Diabetic patients were divided into two groups and received simvastatin or atorvastatin (Group S and A, respectively). After 1 year of statin treatment (Group A), there were significant decreases in total cholesterol (217.3 +/- 46.5-173.8 +/- 37.2 mg/dl; P < 0.0001), LDL-cholesterol (146.7 +/- 50.3-102.3 +/- 31.1 mg/dl, P < 0.0001), hsCRP (0.88 +/- 0.62-0.35 +/- 0.18 mg/dl, P < 0.0001), fibrinogen (258.2 +/- 16.9-215.5 +/- 10.6 mg/l; P < 0.0001), and ferritin (118.2 +/- 73.9-81.2 +/- 72.5 ng/ml, P < 0.0001) levels compared to basal values. In the S group, there were significant decreases in total cholesterol (224.4 +/- 61.2-175.0 +/- 47.8 mg/dl; P < 0.0001), LDL-cholesterol (140.9 +/- 56.7-110.9 +/- 42.2 mg/dl, P < 0.0001), hsCRP (0.98 +/- 1.3-0.46 +/- 0.25 mg/dl, P < 0.0001), fibrinogen (265.7 +/- 26.8-222.1 +/- 20.6 mg/l; P < 0.0001), and ferritin (136.7 +/- 101.1-85.6 +/- 32.1 ng/ml, P < 0.0001) levels compared to basal values. At the end of the study, hsCRP, fibrinogen, and ferritin levels were correlated with LDL (r = 0.42; P = 0.005, with hsCRP), (r = 0.40; P = 0.008, with fibrinogen), (r = 0.46; P = 0.002, with ferritin) and HDL (r = -0.50; P < 0.0001, with hsCRP), (r = -0.32; p = 0.042, with fibrinogen), (r = -0.48; P < 0.0001, with ferritin) cholesterol levels. Atorvastatin and simvastatin treatments were found to be effective for the control of hypercholesterolemia and resulted in a significant decrease in acute phase reactants in uncontrolled type 2 diabetic patients.
...
PMID:Effects of one year simvastatin and atorvastatin treatments on acute phase reactants in uncontrolled type 2 diabetic patients. 1925 30

We investigated the effect of atorvastatin on cyclooxygenase (COX) contribution to endothelial dysfunction in spontaneously hypertensive rat (SHR) mesenteric resistance arteries. Atorvastatin (10 mg/kg per day, oral gavage) or its vehicle was administered for 2 weeks to male SHR or Wistar-Kyoto rats. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In Wistar-Kyoto rats, relaxation to acetylcholine was inhibited by N(G)-nitro-L-arginine methyl ester and unaffected by SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), or ascorbic acid. In SHRs, the response to acetylcholine was attenuated, less sensitive to N(G)-nitro-L-arginine methyl ester, unaffected by SC-560, and enhanced by DuP-697 or SQ-29548 (thromboxane-prostanoid receptor antagonist) to a similar extent. Endothelium-dependent relaxation was normalized by ascorbic acid or apocynin (NADPH oxidase inhibitor), which also restored the inhibition by N(G)-nitro-L-arginine methyl ester. In atorvastatin-treated SHRs, relaxation to acetylcholine was normalized, fully sensitive to N(G)-nitro-L-arginine methyl ester, and not affected by SC-560, DuP-697, SQ 29548, or antioxidants. Dihydroethidium assay showed an increased intravascular superoxide generation in SHRs, which was abrogated by atorvastatin. RT-PCR revealed a COX-2 induction in SHR arteries, which was downregulated by atorvastatin. The release of prostacyclin and 8-isoprostane was higher from SHR than Wistar-Kyoto mesenteric vessels. COX-2 inhibition and apocynin decreased 8-isoprostane without affecting prostacyclin levels. Atorvastatin increased phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels in SHR mesenteric vessels and decreased 8-isoprostane release. In conclusion, COX-2-derived 8-isoprostane contributes to endothelial dysfunction in SHR mesenteric arteries. Atorvastatin restores NO availability by increasing phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels and by abrogating vascular NADPH oxidase-driven superoxide production, which also results in a downregulation of COX-2-dependent 8-isoprostane generation.
Hypertension 2009 Jun
PMID:Atorvastatin prevents endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats: role of cyclooxygenase 2-derived contracting prostanoids. 1938 Jun 10

Angiotensin II (Ang II) modulates vasomotor tone, cell growth, and extracellular matrix deposition. This study analyzed the effect of atorvastatin in the possible alterations induced by Ang II on structure and mechanics of mesenteric resistance arteries and the signaling mechanisms involved. Wistar rats were infused with Ang II (100 ng/kg per day, SC minipumps, 2 weeks) with or without atorvastatin (5 mg/kg per day). Ang II increased blood pressure and plasmatic malondialdehyde levels. Compared with controls, mesenteric resistance arteries from Ang II-treated rats showed the following: (1) decreased lumen diameter; (2) increased wall/lumen; (3) decreased number of adventitial, smooth muscle, and endothelial cells; (4) increased stiffness; (5) increased collagen deposition; and (6) diminished fenestrae area and number in the internal elastic lamina. Atorvastatin did not alter blood pressure but reversed all of the structural and mechanical alterations of mesenteric arteries, including collagen and elastin alterations. In mesenteric resistance arteries, Ang II increased vascular O(2)(.-) production and diminished endothelial NO synthase and CuZn/superoxide dismutase but did not modify extracellular-superoxide dismutase expression. Atorvastatin improved plasmatic and vascular oxidative stress, normalized endothelial NO synthase and CuZn/superoxide dismutase expression, and increased extracellular-superoxide dismutase expression, showing antioxidant properties. Atorvastatin also diminished extracellular signal-regulated kinase 1/2 activation caused by Ang II in these vessels, indicating an interaction with Ang II-induced intracellular responses. In vascular smooth muscle cells, collagen type I release mediated by Ang II was reduced by different antioxidants and statins. Moreover, atorvastatin downregulated the Ang II-induced NADPH oxidase subunit, Nox1, expression. Our results suggest that statins might exert beneficial effects on hypertension-induced vascular remodeling by improving vascular structure, extracellular matrix alterations, and vascular stiffness. These effects might be mediated by their antioxidant properties.
Hypertension 2009 Jul
PMID:Atorvastatin prevents angiotensin II-induced vascular remodeling and oxidative stress. 1945 11

The present study was designed to determine whether atorvastatin reduced hypertension-induced cardiac remodeling and whether these effects involved Protein Kinase D (PKD) and Myocyte Enhancer Factor 2D (MEF2D), factors known to be implicated in cardiac hypertrophy and fibrosis. 16-Week-old spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rats were included. Blood pressure and serum lipid concentration were measured. H-E staining, myocardial transverse diameter, and echocardiography were examined to evaluate cardiac hypertrophy. Hydroxyproline content assay and Masson's trichrome staining were used to estimate cardiac fibrosis. Atorvastatin (10, 25 and 50mg/kg/day) was administered for 8 weeks. Increased blood pressure and cardiac remodeling were prominent in SHRs compared with WKY rats. SHRs also had elevated PKD and MEF2D activation. The systolic blood pressure, myocardial transverse diameter and hydroxyproline content were positively correlated with the activation level of PKD and MEF2D in SHRs. Atorvastatin significantly attenuated the activation of PKD and MEF2D. It may be concluded that atorvastatin reverses hypertension-induced cardiac remodeling partially through down-regulation of PKD/MEF2D activation. Our results predict novel therapeutic targets for atorvastatin in treating hypertensive patients.
...
PMID:Atorvastatin reverses cardiac remodeling possibly through regulation of protein kinase D/myocyte enhancer factor 2D activation in spontaneously hypertensive rats. 1968 55

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) reduce cardiovascular events in hypertensive subjects, but their effect on carotid BP, pressure augmentation, and wave reflection is unknown. We compared the effect of atorvastatin with placebo in a substudy of the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA). Hypertensive patients (n=142; age=43 to 79 years; 127 male) with total cholesterol < or = 6.5 mmol/L were randomized to atorvastatin 10 mg or placebo. Carotid BP and flow velocity were measured by tonometry and Doppler ultrasound. Augmentation index (carotid AI(x)) was calculated, and waveforms were separated into backward and forward components by wave intensity analysis. Brachial BP was similar in atorvastatin and placebo groups. Carotid AI(x) and augmentation pressure were significantly less in patients randomized to atorvastatin (mean [SD]: 21.7 [12.1] versus 25.9 [10.3] %; P=0.027 and 10.2 [6.5] versus 13.1 [6.6] mm Hg; P=0.016, respectively), and atorvastatin treatment was associated with significantly less wave reflection from the body. Carotid systolic BP was slightly lower in the atorvastatin group, but there was a statistically significant interaction between lipid-lowering and antihypertensive regimen with lower carotid systolic BP in patients randomized to amlodipine-based therapy and atorvastatin. Carotid wave velocity, timings of waves, and wave intensities did not differ significantly between atorvastatin and placebo groups. Atorvastatin treatment is associated with less augmentation of the carotid BP waveform and less wave reflection from the body. This could contribute to the reduction in risk of cardiovascular events by statins.
Hypertension 2009 Nov
PMID:Atorvastatin treatment is associated with less augmentation of the carotid pressure waveform in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT). 1972 Sep 53


<< Previous 1 2 3 4 5 6 7 Next >>

---