BACKGROUND: Exposure to methylmercury (MeHg) is predominantly attributed to consumption of marine products. However, the general population is exposed to low MeHg levels, which can induce chronic inflammation. Although some MeHg-related microRNAs (miRNAs) have been reported, their functions remain elusive. The objective of this study was to identify the miRNAs induced by low-level MeHg exposure in a human endothelial cell line (HAECs). This study aimed to determine the specific miRNAs induced by low-level MeHg exposure using a HAECs as a potential novel and sensitive biomarker. The roles of miRNAs in inflammatory processes have been examined. METHODS: Using HAECs, a miRNA microarray assay was performed to identify miRNAs with altered expression upon exposure to a non-cytotoxic MeHg level (0.1 and 1.5 µM). The expression patterns of interleukin-6 and -8, cyclooxygenase 2 (COX-2), RelB, and prostaglandin E₂ (PGE₂) were examined after transfection of the identified miRNAs with mimics/inhibitors. RESULTS: Although the microarray assay identified six MeHg-specific miRNAs, miR-3613-5p, upregulated by 0.1 and 1.5 µM MeHg exposures, demonstrated the best reproducibility in HAECs. Transfection with the miR-3613-5p mimic enhanced the MeHg-induced inflammatory responses, including PGE₂ and COX-2 protein levels, whereas the miR-3613-5p inhibitor suppressed these inflammatory responses. CONCLUSION This study observed that miR-3613-5p is induced by low-dose MeHg exposure, plays a crucial role in the inflammatory process, and could serve as a novel and sensitive biomarker for low-level MeHg exposure.
Methylmercury Compounds/adverse effects* ; Humans ; MicroRNAs/genetics* ; Endothelial Cells/metabolism* ; Inflammation/genetics* ; Cell Line ; Aorta/drug effects* ; Biomarkers/metabolism*

This study aimed to investigate the potential mechanism and the compatibility significance of Tanyu Tongzhi Formula in treating atherosclerosis(AS) in mice based on the transforming growth factor-β(TGF-β)/Smad2/3 signaling pathway. Eight C57BL/6J mice were as assigned to a normal control group and fed a regular diet, while 35 ApoE~(-/-) mice of the same strain were fed a high-fat diet for 8 weeks to establish an AS model. The model mice were randomly divided into a model group, a Tanyu Tongzhi group(18.2 mg·kg~(-1)), a Huatan(phlegm-resolving) group(10.4 mg·kg~(-1)), and a Quyu(blood stasis-resolving) group(7.8 mg·kg~(-1)), with 8 mice in each group. Except for the normal group, all other groups continued to be fed a high-fat diet for 8 weeks to maintain the AS model, and then the mice were treated by gavage for 8 weeks. Plasma levels of total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), interleukin-1β(IL-1β), and interleukin-18(IL-18) were measured using enzyme-linked immunosorbent assay(ELISA). Hematoxylin and eosin(HE) staining, oil red O staining, and Russell-Movat pentachrome staining were performed to observe the pathological changes in the aortic tissue. The proportions of aortic plaque area, lipid-stained area, collagen fibers, and elastic fibers were calculated. Immunofluorescence was used to detect the protein expression levels of matrix metalloproteinase 2(MMP2) and tissue inhibitor of metalloproteinases 2(TIMP2). Western blot was used to detect the protein expression levels of TGF-β1, TGF-β2, Smad2/3, and Smad7 in aortic tissue. Real-time fluorescence quantitative PCR(RT-qPCR) was used to measure the mRNA expression levels of TGF-β receptor(TGF-βR), TGF-β1, Smad2/3, Smad7, intercellular adhesion molecule-1(ICAM-1), and vascular cell adhesion molecule-1(VCAM-1) in aortic tissue. The results showed that compared with the normal control group, the model group had increased plasma TC and LDL-C, significantly decreased HDL-C, and significantly elevated plasma IL-1β and IL-18 levels. The model group also exhibited an increased proportion of aortic plaque area, lipid-stained area, and collagen fiber area, along with significantly upregulated MMP2 and downregulated TIMP2 expression in the aortic arch. Additionally, the expression levels of TGF-βR, TGF-β1, and p-Smad2/3 proteins and mRNA in the aortic tissue were significantly elevated, while Smad7 expression was decreased. Compared with the model group, the Tanyu Tongzhi group showed significantly reduced plasma TC and LDL-C levels, significantly increased HDL-C levels, and significantly decreased plasma IL-1β and IL-18 levels. The Tanyu Tongzhi group also exhibited a significant reduction in aortic plaque size and severity, a significant downregulation of MMP2 expression in the aortic arch, and significantly decreased ICAM-1 and VCAM-1 mRNA expression levels. Moreover, the Tanyu Tongzhi group demonstrated significantly reduced expression levels of TGF-β1 and p-Smad2/3 proteins and mRNA in the aortic tissue, and an increased expression level of Smad7 protein to varying degrees. Compared with the Tanyu Tongzhi group, the Quyu group had significantly higher LDL-C levels and elevated plasma IL-1β and IL-18 levels. The Huatan group showed upregulated MMP2 expression and downregulated TIMP2 expression in the aortic arch. In conclusion, Tanyu Tongzhi Formula, which is composed based on the pathogenesis of phlegm and blood stasis, maintains vascular homeostasis by primarily regulating lipid metabolism and controlling inflammatory factors through the Huatan group, and maintaining vascular wall permeability, inhibiting plaque development, and stabilizing plaques through the Quyu group. The mechanism of action may involve inhibiting TGF-β1 expression in the aorta, reducing Smad2/3 phosphorylation, and simultaneously increasing Smad7 expression.
Animals ; Atherosclerosis/metabolism* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Mice, Inbred C57BL ; Male ; Transforming Growth Factor beta/genetics* ; Humans ; Homeostasis/drug effects* ; Aorta/metabolism* ; Smad2 Protein/genetics* ; Smad3 Protein/genetics*

OBJECTIVE: To determine the effects of hawthorn extract on serum lipid levels, pathological changes in aortic atherosclerosis plaque, inflammatory factors, and apoptosis-related protein and mRNA expression in apolipoprotein E gene knockout (ApoE) mice. METHODS: Thirty-six ApoE mice were fed with a high-fat diet starting at the age of 8 weeks. Mice were randomly divided into 3 groups by a random number table including model group, hawthorn extract group, and simvastatin group, 12 mice in each group. Twelve 8-week-old C57BL/6 mice were fed a basic diet and served as control. The mice in the control and model groups were administered 0.2 mL saline daily, the mice in the hawthorn extract and simvastatin groups were administered with 50 mg/kg hawthorn extract or 5 mg/kg simvastatin daily for 16 weeks. After 16 weeks, plasma lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined by an enzymatic assay. Aortic atherosclerotic lesions were observed by light microscopy, scanning and transmission electron microscopy, respectively. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), adiponectin (APN), and hypersensitive C-reactive protein (hs-CRP) were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expressions of Bax and Bcl-2 in the aorta were assessed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RESULTS: Compared to the control group, the plasma levels of TC, TG and LDL-C were significantly increased and HDL-C were significantly decreased in the model group (P<0.01). Compared to the model group, treatment with hawthorn extract significantly decreased the plasma levels of TC, TG, and LDL-C and increased the plasma level of HDL-C in ApoE mice (P<0.01). The levels of MCP-1, IL-1ß, and hs-CRP in the model group were significantly increased and APN was significantly decreased compared with the control group (P<0.01). Compared to the model group, treatment with hawthorn extract decreased the levels of MCP-1, IL-1ß, and hs-CRP and increased the APN level (P<0.01). Compared to the control group, the protein and mRNA expression of Bax in the model group were significantly increased and the expression of Bcl-2 was significantly decreased (P<0.01). Hawthorn extract also reduced the protein and mRNA expression of Bax and increased the Bcl-2 expression in the aorta (P<0.01). CONCLUSION Hawthorn extract has anti-atherosclerosis and stabilizing unstable plaque effects. The mechanism may be related to the inflflammation and apoptosis signaling pathways.
Animals ; Aorta ; pathology ; ultrastructure ; Apoptosis ; drug effects ; Atherosclerosis ; blood ; complications ; drug therapy ; Crataegus ; chemistry ; Inflammation ; blood ; complications ; drug therapy ; Inflammation Mediators ; metabolism ; Lipids ; blood ; Male ; Mice, Inbred C57BL ; Plant Extracts ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; bcl-2-Associated X Protein ; metabolism

OBJECTIVES: To investigate the effects of Astragaloside IV (AST) on diastolic function of rat thoracic aorta rings which was injured by microvesicles derived from hypoxia/reoxygenation (H/R)-treated human umbilical vein endothelial cells (HUVECs), and the mechanism of AST. METHODS: H/R-induced endothelial microvesicles (H/R-EMVs) were generated from cultured HUVECs under the condition of hypoxia for 12 hour/Reoxygenation for 4 hour, H/R-EMVs were stored in D-Hank's solution. Male Wistar rats were underwent thoracotomy, the thoracic aorta with intact endothelium were carefully removed and cut into 3~4 mm rings. The experiment was divided into six groups. H/R-EMVs group:thoracic aortic rings of rats were incubated in culture medium and treated with H/R-EMVs in a final concentration of 10g/ml; different doses of AST groups:thoracic aortic rings of rats were treated with 10, 20, 40, 60 mg/L AST co-incubated with 10g/ml H/R-EMVs respectively; control group were treated with the same volume of D-Hank's solution. Duration of incubation was 4 h, each group was tested in five replicate aortic rings. Effects of AST on endothelium-dependent relaxation were detected. The production of nitric oxide (NO) and the level of endothelial NO synthase (eNOS), phosphorylated eNOS (p-eNOS, Ser-1177), serine/threonine kinase (Akt), phosphorylated Akt (p-Akt, Ser-473), extracellular regulated protein kinases (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2, Thr202/Tyr204) of rat thoracic aortic rings were detected. RESULTS: Teng/ml H/R-EMVs could impaire the relaxation of rat thoracic aortic rings significantly (<0.01). Compared with H/R-EMVs group, relaxation of rat thoracic aortic rings was increased by 20, 40 and 60 mg/L AST in a concentration-dependent manner (<0.01), the level of NO production was also enhanced (<0.05, <0.01). The level of t-eNOS, t-Akt and ERK1/2 was not changed, but the level of p-eNOS, p-Akt and p-ERK1/2 increased by the treatment with AST (<0.01). CONCLUSIONS AST could effectively ameliorate endotheliumdependent relaxation of rat thoracic aortic rings impaired by H/R-EMVs in a concentration-dependent manner, the mechanism might involve the increase in production of NO, and the protein level of p-eNOS, p-Akt and p-ERK1/2.
Animals ; Aorta, Thoracic ; drug effects ; Cell-Derived Microparticles ; pathology ; Human Umbilical Vein Endothelial Cells ; Humans ; In Vitro Techniques ; MAP Kinase Signaling System ; Male ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Wistar ; Saponins ; pharmacology ; Triterpenes ; pharmacology ; Vasodilation

The study aimed to investigate the intervening role of Didang decoction (DDD) at different times in macrovascular endothelial defense function, focusing on its effects on the AMP-activated protein kinase (AMPK) signaling pathway. The effects of DDD on mitochondrial energy metabolism were also investigated in rat aortic endothelial cells (RAECs). Type 2 diabetes were induced in rats by streptozotocin (STZ) combined with high fat diet. Rats were randomly divided into non-intervention group, metformin group, simvastatin group, and early-, middle-, late-stage DDD groups. Normal rats were used as control. All the rats received 12 weeks of intervention or control treatment. Western blots were used to detect the expression of AMP-activated protein kinase α1 (AMPKα1) and peroxisome proliferator-activated receptor 1α (PGC-1α). Changes in the intracellular AMP and ATP levels were detected with ELISA. Real-time-PCR was used to detect the mRNA level of caspase-3, endothelial nitric oxide synthase (eNOS), and Bcl-2. Compared to the diabetic non-intervention group, a significant increase in the expression of AMPKα1 and PGC-1α were observed in the early-stage, middle-stage DDD groups and simvastatin group (P < 0.05). The levels of Bcl-2, eNOS, and ATP were significantly increased (P < 0.05), while the level of AMP and caspase-3 were decreased (P < 0.05) in the early-stage DDD group and simvastatin group. Early intervention with DDD enhances mitochondrial energy metabolism by regulating the AMPK signaling pathway and therefore may play a role in strengthening the defense function of large vascular endothelial cells and postpone the development of macrovascular diseases in diabetes.
AMP-Activated Protein Kinases ; metabolism ; Adenosine Triphosphate ; metabolism ; Animals ; Aorta ; drug effects ; metabolism ; Cardiovascular Diseases ; metabolism ; prevention & control ; Caspase 3 ; metabolism ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; metabolism ; Diabetes Mellitus, Type 2 ; complications ; drug therapy ; metabolism ; Diptera ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endothelial Cells ; drug effects ; metabolism ; Endothelium, Vascular ; drug effects ; metabolism ; Energy Metabolism ; drug effects ; Leeches ; Mitochondria ; drug effects ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; metabolism ; Phytotherapy ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Prunus persica ; Rats, Sprague-Dawley ; Rheum ; Signal Transduction

OBJECTIVETo observe the expression of Ginkgo biloba Tablet (GbT) on scavenger receptor A (SRA) of the aortic wall and changes of serum inflammatory factors in atherosclerotic rats, and to explore its new mechanism for fighting against atherosclerosis (AS).

METHODSTotally 45 male Wistar rats were randomly divided into the control group, the model group, the GbT group, 15 rats in each group. Levels of blood glucose, blood lipids, blood calcium, serum C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (slCAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in all rats. The expression of SRA in the aortic wall of atherosclerotic rats was observed by immunohistochemical assay. The correlation between the expression of SRA and levels of in-flammatory factors was also observed.

RESULTSCompared with the control group, blood glucose and blood calcium obviously increased (P < 0.05); levels of TG, TC, and LDL-C were significantly elevated (P < 0.01); neointimal areas were significantly thickened, increased intima percentage was significantly enlarged, narrowed lumen index was significantly reduced; levels of CRP, sICAM-1, and sVCAM-1 were significantly elevated in the model group (all P < 0.01). Compared with the model group, blood glucose and blood calcium obviously decreased (P < 0.05); levels of TG, TC, and LDL-C significantly decreased (P < 0.01) in the GbT group. Aortic lumens were obviously narrower in the model group than in the GbT group (P < 0.05). SRA expressed at the aortic wall. The aforesaid 3 indices were significantly improved in the GbT group than in the model group (P < 0.01). Serum levels of CRP, sICAM-1, and sVCAM-1 were significantly decreased in the GbT group than in the model group (P < 0.01). Serum levels of CRP, sICAM-1, and sVCAM-1 were positively correlated with the percentage of SRA positive expression area (r = 0.701, 0.604, 0.581, all P < 0.01).

CONCLUSIONSSerum levels of inflammatory factors in atherosclerotic rats were elevated, and the expression of SRA in the aortic wall was enhanced. The expression of SRA was closely correlated with serum levels of inflammatory factors. GbT could decrease serum levels of inflammatory factors and inhibit the expression of SRA.

Animals ; Aorta ; drug effects ; metabolism ; Atherosclerosis ; drug therapy ; Blood Glucose ; analysis ; C-Reactive Protein ; analysis ; Calcium ; blood ; Drugs, Chinese Herbal ; pharmacology ; Ginkgo biloba ; chemistry ; Intercellular Adhesion Molecule-1 ; blood ; Lipids ; blood ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Scavenger Receptors, Class A ; metabolism ; Tablets ; Vascular Cell Adhesion Molecule-1 ; blood

PURPOSE: Oxidative stress during CO2 pneumoperitoneum is reported to be associated with decreased bioactivity of nitric oxide (NO). However, the changes in endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and arginase during CO2 pneumoperitoneum have not been elucidated. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomized into three groups. After anesthesia induction, the abdominal cavities of the rats of groups intra-abdominal pressure (IAP)-10 and IAP-20 were insufflated with CO2 at pressures of 10 mm Hg and 20 mm Hg, respectively, for 2 hours. The rats of group IAP-0 were not insufflated. After deflation, plasma NO was measured, while protein expression levels and activity of eNOS, iNOS, arginase (Arg) I, and Arg II were analyzed with aorta and lung tissue samples. RESULTS: Plasma nitrite concentration and eNOS expression were significantly suppressed in groups IAP-10 and IAP-20 compared to IAP-0. While expression of iNOS and Arg I were comparable between the three groups, Arg II expression was significantly greater in group IAP-20 than in group IAP-0. Activity of eNOS was significantly lower in groups IAP-10 and IAP-20 than in group IAP-0, while iNOS activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. Arginase activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. CONCLUSION: The activity of eNOS decreases during CO2 pneumoperitoneum, while iNOS activity is significantly increased, a change that contributes to increased oxidative stress and inflammation. Moreover, arginase expression and activity is increased during CO2 pneumoperitoneum, which seems to act inversely to the NO system.
Animals ; Aorta/*physiology ; Arginase/*antagonists & inhibitors ; Enzyme Inhibitors/administration & dosage/pharmacology ; Inflammation/etiology/*prevention & control ; Injections, Subcutaneous ; Lung Injury/etiology/prevention & control ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Oxidative Stress/*drug effects ; Pneumoperitoneum/*complications/drug therapy ; Rats ; Rats, Sprague-Dawley

PURPOSE: In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. MATERIALS AND METHODS: We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed beta-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. RESULTS: There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). CONCLUSION: In MFS patients who underwent ARR, the addition of RAAS blockade to beta-blocker was associated with reduction of aortic dilatation and clinical events.
Adrenergic beta-Antagonists/pharmacology ; Aged ; Aneurysm, Dissecting/complications/mortality/surgery ; *Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors/*therapeutic use ; Aorta/pathology/*surgery ; Aortic Aneurysm/complications/mortality/surgery ; Aortic Valve ; Female ; Humans ; Male ; Marfan Syndrome/mortality/*surgery ; Middle Aged ; Renin-Angiotensin System/*drug effects

OBJECTIVE: This multi-center, randomized, double-blind, phase 3 trial was conducted to compare the safety and efficacy of contrast agents iohexol-380 and iohexol-350 for coronary CT angiography in healthy subjects. MATERIALS AND METHODS: Volunteers were randomized to receive 420 mgI/kg of either iohexol-350 or iohexol-380 using a flow rate of 4 mL/sec. All adverse events were recorded. Two blinded readers independently reviewed the CT images and conflicting results were resolved by a third reader. Luminal attenuations (ascending aorta, left main coronary artery, and left ventricle) in Hounsfield units (HUs) and image quality on a 4-point scale were calculated. RESULTS: A total of 225 subjects were given contrast media (115 with iohexol-380 and 110 with iohexol-350). There was no difference in number of adverse drug reactions between groups: 75 events in 56 (48.7%) of 115 subjects in the iohexol-380 group vs. 74 events in 51 (46.4%) of 110 subjects in the iohexol-350 group (p = 0.690). No severe adverse drug reactions were recorded. Neither group showed an increase in serum creatinine. Significant differences in mean density between the groups was found in the ascending aorta: 375.8 ± 71.4 HU with iohexol-380 vs. 356.3 ± 61.5 HU with iohexol-350 (p = 0.030). No significant differences in image quality scores between both groups were observed for all three anatomic evaluations (all, p > 0.05). CONCLUSION: Iohexol-380 provides improved enhancement of the ascending aorta and similar attenuation of the coronary arteries without any increase in adverse drug reactions, as compared with iohexol-350 using an identical amount of total iodine.
Angiography* ; Aorta ; Contrast Media ; Coronary Vessels ; Creatinine ; Drug-Related Side Effects and Adverse Reactions ; Image Enhancement ; Iodine ; Phenobarbital ; Volunteers

INTRODUCTIONCentral aortic systolic pressure (CASP) has been shown to be a stronger predictor of cardiovascular events than brachial blood pressure (BP). Different classes of drugs have differential effects on CASP and brachial BP. This open prospective cohort study aimed to observe changes in CASP (measured using radial tonometry) among hypertensive Asians after 12 weeks of treatment with valsartan, an angiotensin receptor blocker (ARB).

METHODSPatients with treatment-naïve hypertension or uncontrolled hypertension who were on non-ARB therapy were eligible for inclusion. Patients with uncontrolled BP (i.e. ≥ 140/90 mmHg) received valsartan for 12 weeks. The patients' brachial systolic and diastolic BP (SBP and DBP), and CASP changes were monitored using the BPro® watch.

RESULTSThe mean age of the 44 enrolled patients was 35 years. At baseline, the mean BP and CASP were 150.2/91.4 ± 10.6/9.4 mmHg and 136.3 ± 12.2 mmHg, respectively. Valsartan reduced SBP, DBP and CASP by 14.9 ± 10.7 mmHg, 10.9 ± 8.4 mmHg and 15.3 ± 10.9 mmHg, respectively (all p < 0.001). Every 1.0-mmHg reduction in brachial SBP resulted in a 0.8-mmHg reduction in CASP (p < 0.001). A CASP cut-off of 122.5 mmHg discriminated between controlled and uncontrolled BP (sensitivity 74%, specificity 88%).

CONCLUSIONUsing radial tonometry, we demonstrated good correlation between CASP and brachial SBP reductions after 12 weeks of treatment with valsartan in our study cohort. Correlation analysis between CASP and SBP reductions may be useful for demonstrating whether a drug is able to lower CASP beyond lowering SBP.

Adult ; Angiotensin Receptor Antagonists ; pharmacology ; Aorta ; drug effects ; Blood Pressure ; Blood Pressure Monitoring, Ambulatory ; Diastole ; Female ; Humans ; Hypertension ; drug therapy ; Male ; Manometry ; methods ; Middle Aged ; Prospective Studies ; Receptors, Angiotensin ; metabolism ; Systole ; drug effects ; Valsartan ; therapeutic use ; Young Adult