Hypertension Research

Review

Pleiotropic Actions of Aldosterone and the Effects of Eplerenone, a Selective Mineralocorticoid Receptor Antagonist

Yoshiyu TAKEDA

2004Volume 27Issue 11 Pages 781-789
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.781

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Aldosterone plays an important role in the pathogenesis of cardiovascular and renal disease that is independent of angiotensin II. Mineralocorticoid receptors are expressed in nonepithelial tissues such as the heart and blood vessels. Although mineralocorticoid receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific mineralocorticoid receptor antagonist, spironolactone, have limited its usefulness in the treatment of cardiovascular diseases. This review exmanines the expanding role of aldosterone, including its broad spectrum of non-classical effects, and the recent clinical and experimental trials with the selective mineralocorticoid receptor antagonist, eplerenone. (Hypertens Res 2004; 27: 781-789)

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Role of Interstitial ATP and Adenosine in the Regulation of Renal Hemodynamics and Microvascular Function

Akira NISHIYAMA, Matlubur RAHMAN, Edward W. INSCHO

2004Volume 27Issue 11 Pages 791-804
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.791

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The role of adenosine in the regulation of renal hemodynamics and function has been studied extensively; however, another purine agent, ATP, is also gaining recognition for its paracrine role in the kidney. Adenosine and ATP bind to specific membrane-bound P1 and P2 purinoceptors, respectively, and initiate a variety of biological effects on renal microvascular tone, mesangial cell function, and renal epithelial transport. The purpose of this review is to summarize the potential roles of interstitial ATP and adenosine as regulators of renal hemodynamics and microcirculation. In vitro blood-perfused juxtamedullary nephron preparation was used to assess the roles of ATP and adenosine in the regulation of renal microvascular tone. This approach mimics the adventitial exposure of renal microvascular smooth muscle to ATP and adenosine synthesized locally and released into the interstitial fluid. ATP selectively vasoconstricts afferent but not efferent arterioles via P2X and P2Y receptors, whereas, adenosine vasoconstricts both vascular segments via activation of adenosine A₁ receptors. Furthermore, selective P2X and P2Y receptor stimulation increases intracellular calcium concentration in vascular smooth muscle cells that are freshly isolated from the preglomerular microvasculature. These data support the hypothesis that interstitial ATP plays a critical role in the control of renal microvascular function through mechanisms that are independent of adenosine receptors. We have recently developed a renal microdialysis method to determine the dynamics of ATP and adenosine levels in the renal cortical interstitium. In this review, we also summarize current knowledge pertaining to the alterations in renal interstitial ATP and adenosine in some pathophysiological conditions. (Hypertens Res 2004; 27: 791-804)

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Original Articles

Clinical studies

Predictors of Controlled Ambulatory Blood Pressure in Treated Hypertensive Patients with Uncontrolled Office Blood Pressure

Ayumu ONO, Toshiro FUJITA

2004Volume 27Issue 11 Pages 805-811
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.805

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Although some treated hypertensive patients have controlled 24-h ambulatory blood pressure (ABP) despite their uncontrolled office blood pressure (BP), the factors relating to the control of 24-h ABP remain unknown. We conducted a study to assess 24-h ABP and its association with other cardiovascular risk factors, including echocardiographic left ventricular hypertrophy (LVH), in elderly hypertensive patients (n =41) with uncontrolled office BP (>140/90 mmHg) during long-term medication. Although a majority of the patients had isolated elevation of office systolic BP (SBP), there was no significant relationship between office SBP and 24-h SBP, and about half of the patients had controlled 24-h ABP (125±8/69±6 mmHg). Patients with controlled 24-h ABP (125±8/69±6 mmHg) had similar office BP (150±6/77±5 vs. 150±7/79±7 mmHg), but lower left ventricular mass index (LVMI) (123±34 vs. 156±34 g/m²) and body mass index (BMI) (24.4±2.1 vs. 26.4±3.6 kg/m²) compared with those with uncontrolled 24-h ABP (149±13/78±7 mmHg). Multivariate analysis showed that LVMI and BMI were independently associated with controlled 24-h ABP, and the control status of 24-h ABP was highly dependent on the presence of LVH and obesity. Therefore, absence of LVH and obesity may be useful for predicting the level of control of 24-h ABP in treated patients whose office BP is uncontrolled without ABP measurements. (Hypertens Res 2004; 27: 805-811)

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Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Polymorphism Is Not Associated with Essential Hypertension and Type 2 Diabetes Mellitus in Chinese Population

Shufeng CHEN, Weili YAN, Jianfeng HUANG, Wenjie YANG, Dongfeng GU

2004Volume 27Issue 11 Pages 813-820
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.813

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To investigate whether variations in the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) are associated with essential hypertension and type 2 diabetes in a Chinese population. A case-control study design was applied in a Chinese population. Two single nucleotide polymorphisms (SNPs), +1302G>A and G482S, in the PGC-1α gene were genotyped and compared between 494 unrelated Chinese subjects with essential hypertension and type 2 diabetes and 555 normal control subjects with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. These two polymorphisms were in highly significant linkage disequilibrium with each other (p <0.0001). The frequency of the 482S allele was 42.9% in the Chinese population, which was similar to the frequency in the Japanese population (43.7%), but much higher than those of Caucasian populations (30.8% to 38.1%). There were no associations of the G482S and +1302G>A polymorphisms and haplotype combinations with essential hypertension and type 2 diabetes. In addition, no associations were found between these two polymorphisms and blood pressure. In conclusion, these results indicated that these two variations in the PGC-1α gene might not contribute to the risk of hypertension and type 2 diabetes in the Chinese population studied here. (Hypertens Res 2004; 27: 813-820)

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The Thiazide-Sensitive Na⁺-Cl^- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Tetsutaro MATAYOSHI, Kei KAMIDE, Shin TAKIUCHI, Masayoshi YOSHII, Yosh ...

2004Volume 27Issue 11 Pages 821-833
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.821

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The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4±9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs. (Hypertens Res 2004; 27: 821-833)

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Hyperuricemia as a Predictor of Hypertension in a Screened Cohort in Okinawa, Japan

Kazufumi NAGAHAMA, Taku INOUE, Kunitoshi ISEKI, Takashi TOUMA, Kozen K ...

2004Volume 27Issue 11 Pages 835-841
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.835

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Several epidemiological studies have shown a positive association between serum uric acid levels and the risk of hypertension. However, subjects in these studies were mostly men, or were incompletely examined for lifestyle-related variables. We prospectively examined the relation between hyperuricemia and the risk of developing hypertension with consideration for alcohol consumption and smoking habits in a large screened cohort of men and women. A total of 4,489 individuals (2,927 men and 1,562 women) who did not have hypertension and were not currently using antihypertensive medication were examined at the Okinawa General Health Maintenance Association in 1977. Subjects were re-examined in 2000. Hyperuricemia was defined as a serum uric acid level ≥7.0 mg/dl in men and ≥6.0 mg/dl in women. Hypertension was defined as systolic blood pressure (SBP) ≥140 mmHg, and/or diastolic blood pressure (DBP) ≥90 mmHg. A total of 289 subjects (201 men and 88 women) were hypertensive (SBP ≥140 mmHg, and/or DBP ≥90 mmHg) in 2000. Multivariate analysis was performed for development of hypertension in hyperuricemic subjects, adjusted for age, family history of hypertension, alcohol consumption, cigarette smoking, obesity, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein cholesterol, and diabetes mellitus. The adjusted odds ratio (95% confidence interval) in men was 1.48 (1.08-2.02) and in women was 1.90 (1.03-3.51) (p <0.05, respectively). The results showed hyperuricemia to be a new predictor of hypertension development in both men and women. (Hypertens Res 2004; 27: 835-841)

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Applicability of the Stages of Change Model for Analyzing Fruit and Vegetable Intake in Relation to Urinary Potassium Excretion: Baseline Results from the High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) Study

Junko TAMAKI, Katsushi YOSHITA, Yuriko KIKUCHI, Toru TAKEBAYASHI, Naga ...

2004Volume 27Issue 11 Pages 843-850
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.843

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The Stages of Change model evaluates and conceptualizes attempts to alter particular behavior patterns. To investigate the validity of this model for assessing fruit and vegetable intake, we examined the association between the stage of change in fruit and vegetable intake and urinary potassium excretion. The data were from baseline surveys taken in 1999 and 2000 from the High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study in Japan. This was a non-randomized control trial at 12 worksites in Japan and aimed to decrease cardiovascular risk factors. Cross-sectional analysis was performed using data from 6,774 participants (5,364 men and 1,410 women). We used three categories of the model: precontemplation or contemplation (P/C), indicating no commitment to change; preparation (P), indicating readiness to change behavior but not actually doing so; and action or maintenance (A/M), indicating an actual change in behavior. Urinary potassium excretion was estimated from the potassium and creatinine concentrations in spot urine samples. Multivariate analysis indicated that urinary potassium excretion in the A/M stage was 1.65 mmol/day more than in the P stage, and 1.44 mmol/day more than in the P/C stage for men (p <0.05, respectively). For women, urinary potassium excretion in the A/M stage was 1.26 mmol/day more than in the P/C stage (p <0.05) and 1.04 mmol/day more than in the P stage, although the latter result lacked statistical significance (p =0.08). This study supports the potential value of the Stages of Change model for increasing fruit and vegetable intake in the design of dietary intervention programs. (Hypertens Res 2004; 27: 843-850)

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Reproducibility of Arterial Stiffness Indices (Pulse Wave Velocity and Augmentation Index) Simultaneously Assessed by Automated Pulse Wave Analysis and Their Associated Risk Factors in Essential Hypertensive Patients

Yoshio MATSUI, Kazuomi KARIO, Joji ISHIKAWA, Kazuo EGUCHI, Satoshi HOS ...

2004Volume 27Issue 11 Pages 851-857
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.851

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Arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) and the augmentation index (AIx) are widely used as arterial stiffness indices. We studied the reproducibility of these indices and their association with cardiovascular risk factors in hypertensives. We measured brachial blood pressure (BP), brachial-ankle PWV (baPWV) and carotid AIx (cAIx) twice (at the baseline and 4 weeks after the baseline) using an automatic device in 103 hypertensives. The mean intraobserver-intersession difference was 29.0 cm/s with an SD of 201.6 cm/s for baPWV, and 0.5% with an SD of 5.9% for cAIx, and the Bland-Altman plots demonstrated the good reproducibility of baPWV and cAIx. Both baPWV and cAIx (the average of the 1st and the 2nd measurements) were significantly correlated with age, systolic BP (SBP), and pulse pressure (all, p <0.005); however, these factors were not correlated with each other (r =0.06, NS). cAIx was correlated with height, heart rate (HR), total cholesterol, and low density lipoprotein cholesterol (LDL-C) (all, p <0.05). In multiple regression analysis, age, SBP, and HR emerged as significant independent predictors of baPWV (adjusted R²=0.43, p <0.0001), while height, SBP, HR, and LDL-C emerged as significant independent predictors of cAIx (adjusted R²=0.58, p <0.0001). Both PWV and AIx measured using an automatic device were fairly reproducible, and their associated risk factors appeared to be different. Automated simultaneous measurement of these arterial stiffness indices may be useful for risk stratification of hypertensives. (Hypertens Res 2004; 27: 851-857)

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Efficacy of a Multicomponent Program (Patient-Centered Assessment and Counseling for Exercise plus Nutrition [PACE+ Japan]) for Lifestyle Modification in Patients with Essential Hypertension

Shin-ichiro MIURA, Yukio YAMAGUCHI, Hidenori URATA, Yuki HIMESHIMA, No ...

2004Volume 27Issue 11 Pages 859-864
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.859

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With conventional lifestyle modification programs, it can be difficult for hypertensive individuals to modify their lifestyles and maintain the changes. We assessed whether a multicomponent program (patient-centered assessment and counseling for exercise plus nutrition [PACE+ Japan]) based on behavior theory and social cognitive theory would be effective for treating patients with essential hypertension. We examined 57 outpatients aged 62±10 years with essential hypertension irrespective of antihypertensive drug treatment. Participants were randomly divided into two groups: 1) a PACE+ Japan follow-up group (n =18), who were given an action-plan sheet and systemic health counseling by a physician and counselor every 4 weeks for 24 weeks, and 2) a PACE+ Japan-only group (n =20), who were given an action-plan sheet but did not receive counseling. An age- and sex-matched control group (n =19) was also selected. The decrease in systolic blood pressure (SBP) (ΔSBP=SBP at 24 weeks minus that at 0 weeks) in the PACE+ Japan follow-up group was significantly greater than that in the control group. In addition, the Δpercentage of Fat (%Fat) and Δurinary sodium extraction (U-Na) in the PACE+ Japan follow-up group were significantly greater than those in the control group. With regard to changes in total energy expenditure, exercise energy expenditure and total energy intake between 0 weeks and 24 weeks, significant improvements were observed for the PACE+ Japan follow-up group. ΔU-Na was determined to significantly predict ΔSBP as assessed by stepwise selection. In addition, the partial correlation coefficient of ΔSBP with ΔU-Na was 0.361 (p =0.011) as assessed by a multiple regression analysis. Therefore, PACE+ Japan follow-up counseling was associated with a reduction in SBP, which in turn was associated with reduction in U-Na. This new program may be effective for reducing blood pressure in hypertensives. (Hypertens Res 2004; 27: 859-864)

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Experimental studies

Effects of Bradykinin on Cardiovascular Remodeling in Renovascular Hypertensive Rats

Yasuyuki TANAKA, Makoto NAGAI, Taro DATE, Takuya OKADA, Yuichi ABE, Sh ...

2004Volume 27Issue 11 Pages 865-875
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.865

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Angiotensin converting enzyme (ACE) inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin (BK). They prevent not only hypertension but also cardiac hypertrophy and fibrosis. An increase in BK level stimulates the expression of nitric oxide (NO) synthase (NOS) and induces prostaglandins, both of which are powerful vasodilator factors. The direct effect of BK against cardiac hypertrophy is still unclear. This study was performed to examine the cardioprotective effects of BK in hypertrophic models. Renovascular hypertensive (RHT) rats were treated with BK (1,000 ng/kg/day), BK+D-arginyl-[Hyp³, Thi⁵, D-Tic⁷, Oic⁸]-bradykinin (HOE140) (a BK B₂ receptor antagonist), and BK+N^ω-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor) for 3 weeks. Blood pressure was measured and echocardiographic analysis performed during the treatment. Histological data were analyzed to confirm the hypotrophic effect of BK. Treatment with BK improved cardiac remodeling, reducing both the heart weight/body weight ratio and the left ventricular wall thickness. However, co-treatment with HOE140 or L-NAME reversed the anti-hypertrophic action of BK. In particular, cardiac fibrosis or perivascular fibrosis, along with collagen accumulation, were inhibited by treatment with BK, while HOE140 and L-NAME counteracted these changes. In addition, expressions of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP), which are markers of cardiac abnormalities, were down-regulated by treatment with BK. These effects were reversed by co-treatment with HOE140 and L-NAME. Together, these results indicate that BK directly inhibits the progression of cardiac hypertrophy and cardiac fibrosis due to NO release via the BK B₂ receptor. The BK-NO pathway may play an important role in the progression of cardiac remodeling. (Hypertens Res 2004; 27: 865-875)

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Calcium Antagonist Reduces Oxidative Stress by Upregulating Cu/Zn Superoxide Dismutase in Stroke-Prone Spontaneously Hypertensive Rats

Seiji UMEMOTO, Masakazu TANAKA, Shinji KAWAHARA, Makoto KUBO, Kyoko UM ...

2004Volume 27Issue 11 Pages 877-885
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.877

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Recent studies have suggested that the calcium antagonists have an antiatherogenic antioxidant property. The effects of the calcium antagonists on reactive oxygen species (ROS)-related enzymes, however, remain unknown. We hypothesized that the calcium antagonists inhibit oxidative stress in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) through the ROS-scavenging enzymes known as superoxide dismutases (SODs). Male 12-week-old Wister-Kyoto rats (WKY) and SHRSP were used for the study. SHRSP were randomized and treated for 6 weeks with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). NAD(P)H oxidase activity was measured by a luminescence assay, and SOD activity was measured spectrophotometrically. Protein expressions were analyzed by immunoblots. Both drugs showed equipotent effects on systolic blood pressure, left ventricular hypertrophy and fibrosis, the wall-to-lumen ratio, the manganese SOD activity, ROS, and the endothelial NO synthase expression in the SHRSP hearts. Furthermore, amlodipine significantly restored copper/zinc-containing SOD (Cu/ZnSOD) expression and its activity in SHRSP hearts to a level equal to that of WKY more effectively than did enalapril (p <0.05), whereas enalapril downregulated NAD(P)H oxidase activity more than did amlodipine (p <0.05) in the SHRSP hearts. Furthermore, amlodipine restored Cu/ZnSOD expression and its activity in SHRSP hearts to a level equal to that in WKY hearts, and this restoration was significantly more effective than that by enalapril (p <0.05); on the other hand, enalapril induced a greater downregulation of NAD(P)H oxidase activity in SHRSP hearts than did amlodipine (p <0.05). Thus, amlodipine may inhibit vascular remodeling and oxidative stress in the SHRSP heart by efficiently upregulating Cu/ZnSOD, suggesting that the calcium antagonist may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension. (Hypertens Res 2004; 27: 877-885)

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Hepatocyte Growth Factor Stimulates Nitric Oxide Production through Endothelial Nitric Oxide Synthase Activation by the Phosphoinositide 3-Kinase/Akt Pathway and Possibly by Mitogen-Activated Protein Kinase Kinase in Vascular Endothelial Cells

Akira URUNO, Akira SUGAWARA, Hiroshi KANATSUKA, Shuji ARIMA, Yoshihiro ...

2004Volume 27Issue 11 Pages 887-895
Published: 2004
Released on J-STAGE: April 12, 2005

DOIhttps://doi.org/10.1291/hypres.27.887

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Hepatocyte growth factor (HGF) has recently been the focus of attention due to its angiogenic effects, which are similar to those of vascular endothelial growth factor (VEGF); because of these effects, HGF is considered to be a novel therapeutic agent against vascular disorders, including atherosclerotic angiopathies. Although nitric oxide (NO), which is derived from vascular endothelial cells (ECs), is also involved in angiogenesis, little is known regarding the interactions between HGF and NO. We therefore examined the effects of HGF on NO production as well as endothelial NO synthase (eNOS) phosphorylation, and investigated their mechanisms. In bovine aortic ECs, HGF induced a rapid (5 min) increase of NO production measured by diaminofluorescein-2 diacetate. Moreover, HGF rapidly (2.5 min) stimulated eNOS phosphorylation (Ser-1179) as determined by Western immunoblot analyses. Both of these effects were almost completely suppressed by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and were partially suppressed by the mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor U0126. HGF also stimulated Akt phosphorylation (Ser-473), which was completely suppressed by LY294002 and was partially suppressed by U0126. Moreover, HGF stimulated extracellular signal-regulated kinase 1/2 phosphorylation (Thr-202/Tyr-204), which was completely suppressed by U0126 and was partially suppressed by LY294002. Taken together, these results indicate that HGF not only phosphorylates eNOS through the PI3K/Akt pathway, but also partially through the MAPK pathway, and that these two pathways may interact. Compared with VEGF, HGF was more potent in both NO production and eNOS phosphorylation. Our study thus demonstrates a novel activity of HGF—the stimulation of NO production—which occurs via eNOS phosphorylation that may in turn be mediated by cross-talk between the PI3K/Akt and MAPK pathways. (Hypertens Res 2004; 27: 887-895)

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