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1.  Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B 
The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension. However, the mechanisms causing this upregulation are unknown. Oxidative stress is an important regulator of protein expression via activation of transcription factors such as nuclear factor kappa B (NFκB). The present study was carried out to test the hypothesis that oxidative stress contributes to vascular AT1R upregulation via NFκB in human aortic smooth muscle cells (HASMC) and spontaneously hypertensive rats (SHR). HASMC exposed to oxidative stress exhibited a robust increase in AT1R mRNA in HASMC. Furthermore, oxidative stress failed to upregulate AT1Rs in the presence of either an antioxidant catalase or siRNA against p65 subunit of NFκB. To test the role of oxidative stress and NFκB in hypertension, prehypertensive SHR were treated with NFκB inhibitor pyrrolidine dithiocarbamate from 5 weeks to 11–12 weeks of age. At 11–12 weeks of age, SHR exhibited increased NFκB expression, AT1R upregulation and exaggerated Ang II-induced vasoconstriction as compared to age-matched Wistar Kyoto (WKY) rats. PDTC treatment of SHR lowered NFκB expression, normalized AT1R expression and Ang II-induced vasoconstriction. More importantly, PDTC treatment significantly attenuated hypertension development in SHR. In conclusion, vascular oxidative can upregulate AT1R, via mechanisms involving NFκB, and contribute to the development of hypertension.
PMCID: PMC4445646  PMID: 25198883
AT1 receptors; NFκB; oxidative stress; PDTC; vasoconstriction
2.  Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats 
We examined effects of normal (NS) and high salt (HS) on blood pressure (BP) and cortico-medullary distribution of dopamine D1 receptor (D1R), angiotensin AT1 receptor (AT1R), NADPH oxidase-gp91phox, and sodium transporters (NHE-3, Na, K ATPase) in adult and aged rats. Aged rats fed with NS diet had higher BP, which further increased with HS. HS increased D1R mRNA and protein levels in cortex and medulla of adult rats. NS or HS fed-aged rats had higher AT1R and gp91phox mRNA levels in cortex and medulla. Aged rats fed with NS diet had higher gp91phox protein levels in cortex. HS diet increased AT1R and gp91phox protein levels in medulla of aged rats. Aged rats fed with NS or HS diet had higher NHE-3 protein levels in medulla. HS increased Na, K ATPase protein levels in medulla of aged rats. HS increased urinary kidney injury molecule-1 (KIM-1) but not protein or albumin levels in aged rats. These results suggest that cortical gp91phox and medullary NHE-3 contribute to age-related hypertension. Whereas D1R (cortical and medullary) together with medullary AT1R, gp91phox and Na, K-ATPase contribute to salt sensitivity in aged rats. And, KIM-1 may be a better marker for kidney damage.
PMCID: PMC4415353  PMID: 25562528
Angiotensin II; aging; dopamine; GPCR; kidney oxidative stress
3.  Associations between arterial stiffness and platelet activation in normotensive overweight and obese young adults 
Obese individuals have elevated platelet activation and arterial stiffness, but the strength and temporality of the relationship between these factors remain unclear. We aimed to determine the effect of increased arterial stiffness on circulating platelet activity in overweight/obese young adults. This analysis included 92 participants (mean age 40 years, 60 women) in the Slow Adverse Vascular Effects of excess weight (SAVE) trial, a clinical trial examining the effects of a lifestyle intervention with or without sodium restriction on vascular health in normotensive overweight/obese young adults. Carotid-femoral (cf), brachial-ankle (ba), and femoral-ankle (fa) pulse wave velocity (PWV) served as measures of arterial stiffness and were measured at baseline and 6, 12, and 24 months follow-up. Platelet activity was measured as plasma beta-thromboglobulin (β-TG) at 24 months. Higher plasma β-TG was correlated with greater exposure to elevated cfPWV (p=0.02) and baPWV (p=0.04) during the preceding two years. After adjustment for serum leptin, greater exposure to elevated baPWV remained significant (p=0.03) and exposure to elevated cfPWV marginally significant (p=0.054) in predicting greater plasma β-TG. Greater arterial stiffness, particularly central arterial stiffness, predicts greater platelet activation in overweight/obese individuals. This relationship might partly explain the association between increased arterial stiffness and incident atherothrombotic events.
PMCID: PMC3742736  PMID: 23654212
platelet activation; arterial stiffness; pulse wave velocity; obesity; weight loss
4.  Clinical and Pharmacotherapeutic Relevance of the Double-Chain Domain of the Angiotensin II Type 1 Receptor Blocker Olmesartan 
We previously reported that the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan has two important interactions to evoke inverse agonism (IA). We refer to these interactions as the “double-chain domain (DCD).” Since the clinical pharmacotherapeutic relevance of olmesartan is still unclear, we examined these effects in rats and humans. We analyzed the effects at an advanced stage of renal insufficiency in Dahl salt-sensitive hypertensive rats (Study 1). Rats were fed a high-salt diet from age 9 weeks and arbitrarily assigned to three treatment regimens at age 16 to 21 weeks: olmesartan (2 mg/kg/day) with DCD, a compound related to olmesartan without DCD (6 mg/kg/day, R-239470) or placebo. We also compared the depressor effects of olmesartan to those of other ARBs in patients with essential hypertension (Study 2). Thirty essential hypertensive outpatients who had been receiving ARBs other than olmesartan were recruited for this study. Our protocol was approved by the hospital ethics committee and informed consent was obtained from all patients 12 weeks prior to switching from ARBs other than olmesartan to olmesartan. In Study 1, olmesartan induced a more prominent suppression of the ratio of urinary protein excretion to creatinine at age 21 weeks without lowering blood pressure among the three groups. In Study 2, the depressor effect of olmesartan was significantly stronger than those of other ARBs, which do not contain the DCD. These additive effects by olmesartan may be due to DCD.
PMCID: PMC3891519  PMID: 20374187
double-chain domain; angiotensin II type 1 receptor blocker; olmesartan; renal dysfunction; Dahl salt-sensitive rat
5.  Reactive Oxygen Species and Dopamine Receptor Function in Essential Hypertension 
Essential hypertension is a major risk factor for stroke, myocardial infarction, and heart and kidney failure. Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones and humoral factors. However, the mechanisms leading to impaired dopamine receptor function in hypertension states are not clear. Compelling experimental evidence indicates a role of reactive oxygen species (ROS) in hypertension, and there are increasing pieces of evidence showing that in conditions associated with oxidative stress, which is present in hypertensive states, dopamine receptor effects, such as natriuresis, diuresis, and vasodilation, are impaired. The goal of this review is to present experimental evidence that has led to the conclusion that decreased dopamine receptor function increases ROS activity and vice versa. Decreased dopamine receptor function and increased ROS production, working in concert or independent of each other, contribute to the pathogenesis of essential hypertension.
PMCID: PMC3722595  PMID: 19330604
reactive oxygen species; essential hypertension; dopamine receptor
6.  Serum aldosterone is associated with inflammation and aortic stiffness in normotensive overweight and obese young adults 
Circulating aldosterone is increased in obesity and is associated with arterial stiffening in hypertensives and older adults. We aimed to determine whether serum aldosterone is associated with pulse wave velocity (PWV), a measure of arterial stiffness, in normotensive overweight and obese adults aged 20–45 years (n=344). We measured heart-femoral, femoral-ankle and brachial-ankle PWV. The sample was 77% female with mean BMI 32.9 kg/m2 (SD 3.9), median serum aldosterone 106.5 pg/mL (IQR 79.9, 155.5), and mean 24-hour urinary sodium excretion 185.9 mEq/day (SD 69.6). Higher serum aldosterone was not significantly correlated with any PWV measure in bivariate analysis. However, in multiple linear regression, adjusting for age, sex, race, height, heart rate, mean arterial pressure, and waist circumference, higher log aldosterone was associated with greater log heart-femoral PWV (β(se)=0.042(0.021), p=0.049). After adjusting for C-reactive protein, this association was no longer significant (β(se)=0.035(0.021), p=0.10). Circulating aldosterone may play an important role in vascular inflammation and aortic stiffening in normotensive overweight and obese adults.
PMCID: PMC3262912  PMID: 22007645
aldosterone; arterial stiffness; inflammation; obesity; RAAS
7.  Epigenetics and microRNAs in Preeclampsia 
Strong evidence suggests a potential link among epigenetics, microRNAs (miRNAs), and pregnancy complications. Much research still needs to be carried out to determine whether epigenetic factors are predictive in the pathogenesis of preeclampsia (PE), a life-threatening disease during pregnancy. Recently, the importance of maternal epigenetic features, including DNA methylation, histone modifications, epigenetically regulated miRNA, and the effect of imprinted or non-imprinted genes on trophoblast growth, invasion, as well as fetal development and hypertension in pregnancy, has been demonstrated in a series of articles. This article discusses the current evidence of this complicated network of miRNA and epigenetic factors as potential mechanisms that may underlie the theories of disease for PE. Translating these basic epigenetic findings to clinical practice could potentially serve as prognostic biomarkers for diagnosis in its early stages and could help in the development of prophylactic strategies.
PMCID: PMC3399917  PMID: 22468840
epigenetics; preeclampsia; pregnancy; microRNA; DNA methylation; imprinted genes
8.  Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension 
We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
PMCID: PMC3231850  PMID: 21950654
mineralocorticoid receptor antagonist; hypertension; end organ protection; eplerenone; Dahl salt-sensitive rats
9.  Direct Vasoactive Effects of the Chromogranin A (CHGA) Peptide Catestatin in Humans In Vivo 
Catestatin is a bioactive peptide of chromogranin A (CHGA) that is co-released with catecholamines from secretory vesicles. Catestatin may function as a vasodilator and is diminished in hypertension. To evaluate this potential vasodilator in vivo without systemic counterregulation, we infused catestatin to target concentrations of ~ 50, ~ 500, ~5000 nM into dorsal hand veins of 18 normotensive men and women, after pharmacologic venoconstriction with phenylephrine. Pancreastatin, another CHGA peptide, was infused as a negative control. After preconstriction to ~ 69%, increasing concentrations of catestatin resulted in dose-dependent vasodilation (P = 0.019), in female subjects (to ~ 44%) predominantly. The EC50 (~ 30 nM) for vasodilation induced by catestatin was the same order of magnitude to circulating endogenous catestatin (4.4 nM). No vasodilation occurred during the control infusion with pancreastatin. Plasma CHGA, catestatin, and CHGA-to-catestatin processing were then determined in 622 healthy subjects without hypertension. Female subjects had higher plasma catestatin levels than males (P = 0.001), yet lower CHGA precursor concentrations (P = 0.006), reflecting increased processing of CHGA-to-catestatin (P < 0.001). Our results demonstrate that catestatin dilates human blood vessels in vivo, especially in females. Catestatin may contribute to sex differences in endogenous vascular tone, thereby influencing the complex predisposition to hypertension.
PMCID: PMC3109075  PMID: 20662728
catestatin; chromogranin A; vasodilation; veins
10.  Matrix Metalloproteinases: Discrete Elevations in Essential Hypertension and Hypertensive End-Stage Renal Disease 
The contribution of inflammation to hypertension and target organ damage is under investigation. The matrix metalloproteinase (MMP) enzymes are inflammatory mediators that may contribute to hypertension and its target organ consequences. Here we probe MMPs as inflammatory mediators in hypertension, by studying all three MMP classes in uncomplicated hypertension as well hypertension with profound renal damage, such as hypertensive end-stage renal disease (ESRD). We assayed plasma levels of five MMPs: one collagenase (MMP-1), two gelatinases (MMP-2, MMP-9), and two stromelysins (MMP-3, MMP-10). In hypertension, MMP-9 was elevated versus normotensive controls. Systolic blood pressure (SBP) in all three subject groups positively correlated with MMP-9. In hypertensive-ESRD, MMP-2 and MMP-10 were elevated compared to both hypertensive and normotensive subjects. Several correlations occurred across MMPs, suggesting coordinate biosynthetic control. Our results suggest discrete patterns of MMP overexpression in hypertension, with MMP-9 elevated early, and MMP-2 and MMP-10 linked to target organ damage.
PMCID: PMC2875383  PMID: 19886850
essential hypertension; end-stage renal disease (ESRD); matrix metalloproteinase (MMP); inflammation
The development of hypertension is accompanied by changes in the rheological properties of blood, particularly by increased red blood cell (RBC) aggregation leading to further pathological complications. However, it is not clear whether these changes in aggregation are caused only by increased concentrations of plasma adhesion proteins or if alterations in RBC membranes are also involved. The aim of the present study was to determine if RBC aggregability is altered during hypertension and if these changes correlate with alterations in RBC membrane protein concentrations. Aggregability changes were evaluated by comparing fibrinogen (Fb)-induced aggregation of RBCs from spontaneously hypertensive rats (SHR) with RBCs from age matched normotensive Wistar Kyoto (WKY) rats. ANOVA showed a significant increase in dose-dependent Fb-induced aggregation of RBCs in the SHR group. Analysis of Coomassie-stained gels of RBC membrane proteins using SDS-PAGE showed a significant increase in the amount of a protein at 110 kD in the SHR group. These results show that increased RBC aggregability is accompanied by alterations in RBC membrane protein composition during hypertension development.
PMCID: PMC2823260  PMID: 12109779
Erythrocytes; Fibrinogen; Hypertension; Membrane proteins
12.  Chronobiologically Explored Effects of Telmisartan# 
Effects of Micardis (Telmisarian), alone or with low-dose aspirin, on blood pressure and other cardiovascular endpoints are examined in 20 patients with MESOR-hypertension in a crossover, double-blind, randomized study consisting of three Stages, each lasting 7 days: I-placebo, II-Micardis, and III-Micardis with low-dose aspirin. Treatment was administered each day at a different circadian stage, upon awakening, and 3, 6, 9, 12, 15 and 18 hr after awakening. During each stage, the following variables were measured at 3-hr intervals during waking: systolic and diastolic blood pressure, heart rate, ejection fraction, intrarenal resistive index, acceleration time, and serum creatinine. Each data series was analyzed by single cosinor. Results were summarized by population-mean least squares spectra. At matched treatment times, the MESOR and circadian amplitude of each variable were compared among the three treatments by paired t-tests. A prominent circadian rhythm characterizes all variables. Micardis was associated not only with a lowering of blood pressure, but also with a reduction of the circadian blood pressure amplitude. The ejection fraction was increased, and the resistive index and acceleration time were decreased, the effect being more pronounced when low-dose aspirin was added to Micardis. Any circadian-stage dependent effect of Micardis, with or without low-dose aspirin, will require monitoring over spans longer than a single day for a given treatment administration time.
PMCID: PMC2600588  PMID: 15835374
blood pressure; chronodiagnosis; chronotherapy; circadian hyper-amplitude-tension (CHAT); ejection fraction; heart rate; low-dose aspirin; Micardis (Telmisartan)
13.  Improved Early-Phase Insulin Response after Candesartan Treatment in Hypertensive Patients with Impaired Glucose Tolerance 
As the effect of renin-angiotensin system (RAS) blockade on β-cells in clinical situations remains unclear, new evidence has been presented that angiotensin-converting enzyme (ACE) inhibitors and angiotensin ‖ receptor blockers (ARBs) may delay or prevent the development of insulin resistance and diabetes through novel mechanisms. This study aimed to determine the effects of ARBs on insulin excretion by β-cells. Hypertensive patients with impaired glucose tolerance were randomly divided into two groups: group A (n = 6), which received 8 mg/day of oral candesartan for three months, and controls (n = 6). Before and after administration, a 75 g oral glucose tolerance test was conducted to compare various parameters. No significant differences in age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, or fasting immunoreactive insulin (IRI) were identified between the groups before administration. After three months, there were no significant changes in BMI, SBP, and DBP for the controls and in BMI and DBP for group A. However, SBP was significantly decreased from 144 ± 2.6 mmHg to 125 ± 4.6 mmHg in group A. Insulinogenic index tended to be slightly decreased for controls, but was significantly increased from 0.32 ± 0.0 to 0.47 ± 0.1 for group A. No significant changes in HOMA-R were identified in either group. To the best of our knowledge, no previous studies have documented a RAS inhibitor improving early-phase insulin response; thus, the present study may be the first of its kind.
PMCID: PMC2495588  PMID: 18633754
candesartan; IGT; insulinogenic index; insulin secretion
14.  Effect of High Fat Loading in Dahl Salt-Sensitive Rats 
Salt sensitivity of blood pressure (BP) is speculated to be a characteristic in obesity-induced hypertension. To elucidate the influence of obesity on salt-sensitive hypertension, we examined the effect of fat loading on BP, renal damage, and their progression induced by salt excess in Dahl salt-sensitive (S) rats. High fat (HF: 45% fat diet: 8 weeks) diet increased BP with greater weight gain and visceral fat accumulation than low fat (10% fat) diet. In HF-fed rats, plasma glucose, plasma insulin, and urinary catecholamine increased, and urinary protein tended to be elevated. Moreover, excessive salt (8% salt diet: 8 weeks)-induced hypertension and proteinuria was accelerated in HF-fed rats. Therefore, fat loading increased BP in Dahl S rats possibly through insulin-resistance and sympathetic excitation. Moreover, fat loading accelerated salt-induced BP elevation and renal damage, suggesting excessive intake of both fat and salt, such as a civilized diet, exert the synergic harmful effects.
PMCID: PMC2730819  PMID: 19811354
obesity; salt sensitivity of blood pressure; urinary protein; insulin resistance; sympathetic nervous system
15.  Three-Year Safety and Effectiveness of Fixed-Dose Losartan/Hydrochlorothiazide Combination Therapy in Japanese Patients with Hypertension Under Clinical Setting (PALM-1 Extension Study) 
Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.
PMCID: PMC3507276  PMID: 22533546
losartan; hydrochlorothiazide; Japanese; uric acid; hypertension
16.  Follow-Ups of Metabolic, Inflammatory and Oxidative Stress Markers, and Brachial–Ankle Pulse Wave Velocity in Middle-Aged Subjects without Metabolic Syndrome 
This study investigates the association among metabolic risk factors, inflammatory and oxidative stress markers, and brachial–ankle pulse wave velocity (ba-PWV). We conducted a 3-year longitudinal, observational study of 288 middle-aged adults not meeting the criteria for metabolic syndrome (MetS) at the initial screening. We measured metabolic risk factors, inflammatory and oxidative stress markers, and ba-PWV. Within the 3-year study period, 15.6% (45 out of 288) of participants developed MetS. At the 3-year follow-up, patients were categorized as those with MetS (n = 45) and those without MetS (n = 243). Patients with MetS had significantly unfavorable initial measurements of baseline body mass index (BMI), waist circumference (WC), blood pressure (BP), triglyceride (TG), high-density lipoprotein (HDL)-cholesterol, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and ba-PWV. After 3 years, participants without MetS showed significant increases in WC, diastolic BP (DBP), total- and low-density lipoprotein (LDL)-cholesterol, malondialdehyde (MDA), oxidized-LDL (ox-LDL), and ba-PWV and a significant decrease in HDL-cholesterol and free fatty acids (FFA). Subjects who developed MetS showed significant increases in BMI, WC, BP, TG, glucose, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), MDA, ox-LDL, and ba-PWV and a significant decrease in HDL-cholesterol. Changes in BMI, WC, BP, TG, HDL-cholesterol, glucose, HOMA-IR index, FFA, C-reactive protein (P = .022), IL-6 (P = .004), leukocyte count (P < .001), MDA (P = .002), ox-LDL (P = .015), and ba-PWV (P = .001) differed significantly between the two groups after adjustment for baseline values. Changes in ba-PWV were positively correlated with the changes in systolic and DBP, total-cholesterol, glucose, leukocyte count, and MDA. The age-related increase in arterial stiffness is greater in the presence of MetS with higher levels of inflammatory and oxidative stress markers.
PMCID: PMC3740820  PMID: 23148723
MetS; inflammatory; oxidative stress markers; brachial–ankle pulse wave velocity

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