Hypertension Research

Original Articles

Clinical studies

Lipoprotein Lipase Gene Polymorphisms and Blood Pressure Levels in the Northern Chinese Han Population

Biao LI, Dongliang GE, Yuelan WANG, Weiyan ZHAO, Xiaoyang ZHOU, Dongfe ...

2004 Volume 27 Issue 6 Pages 373-378
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.373

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The lipoprotein lipase (LPL) gene has been investigated extensively in linkage studies and in studies of its association with lipid profiles and coronary artery disease (CAD), and this gene has also been reported to have an association with hypertension. In our previous linkage study on 148 Chinese hypertensive families, the regions at or near the LPL gene were found to be associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Thus the LPL gene is a logical candidate gene for involvement in the underlying cause of essential hypertension (EH). In the present study, we identified 22 sequence variants by directly sequencing 10 exons and flanking regions of the LPL gene, and investigated the occurrence of 3 of these variants, IVS4-214C>T, 7754C>A and S447X, in a case-control study including 501 normotensive (NT) subjects and 497 EH subjects. In males, the frequencies of the genotypes of each of the 3 variants did not differ significantly between the NT and EH groups. Among the EH group in females, ANCOVA revealed no significant difference in blood pressure levels according to the 7754C>A genotype. However, in female, the distribution of the 7754C>A genotype and the frequency of the A allele of 7754C>A differed significantly between the NT and EH groups (p =0.032 and p =0.027, respectively) with 0.78 (95% confidence interval (CI): 0.56 to 1.07; p =0.12) of odds ratio for the A allele. Moreover, haplotype analysis revealed that T-A-C and T-C-G haplotypes (in the order of IVS4-214C>T, 7754C>A and S447X) were statistically more frequent in the NT group than in the EH group in females and males, respectively. Our indivisual single nucleotide polymorphism (SNP) analysis did not provide substantial evidence of an association between polymorphisms in the LPL gene and hypertension status and/or blood pressure levels in this cohort, but the more powerful haplotypes analysis suggested an association between the LPL gene and hypertension. (Hypertens Res 2004; 27: 373-378)

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Comparison between Cilnidipine and Amlodipine Besilate with Respect to Proteinuria in Hypertensive Patients with Renal Diseases

Shunichi KOJIMA, Mikio SHIDA, Hiroyuki YOKOYAMA

2004 Volume 27 Issue 6 Pages 379-385
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.379

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Unlike other dihydropyridine calcium channel blockers (CCBs), cilnidipine has been reported to exert an N-type calcium-channel-blocking activity and to reduce sympathetic hyperactivity. This study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria. Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62±2 years) who had been maintained on CCBs for more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients). CCBs were increased in dosage or other drugs were added until blood pressure decreased below 140/90 mmHg, but no inhibitors of the renin-angiotensin (RA) system were added or changed in dosage. Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum β₂-microglobulin were determined. The amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group. The rate of increase in proteinuria at 12 months was 87% (95% confidence interval (CI) -10 to 184) of the baseline value with amlodipine and 4% (95% CI -69 to 77) of baseline with cilnidipine, a significant intergroup difference (p <0.05). The mean blood pressure remained in the 96-99 mmHg range until 12 months after randomization, showing no significant difference between the two groups. The cilnidipine group showed an increase in serum Cr levels (baseline vs. 12 months, 1.36±0.20 vs. 1.50±0.23 mg/dl, p <0.01). Overall, an inverse correlation existed between the changes in Cr and proteinuria (r =-0.477, p <0.01). These results suggest that cilnidipine results in a greater suppression of the increase in proteinuria and greater reduction in glomerular filtration rate than amlodipine, and that these effects are similar between cilnidipine and RA inhibitors. However, additional large-cohort and longer-term studies will be needed to clarify whether cilnidipine is superior to other CCBs in maintaining renal function. (Hypertens Res 2004; 27: 379-385)

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Association of QT Interval with Blood Pressure in 80-Year-Old Subjects

Kiyoshi MATSUMURA, Yutaka TAKATA, Toshihiro ANSAI, Shuji AWANO, Tadami ...

2004 Volume 27 Issue 6 Pages 387-391
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.387

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Few data are available on the association between the prolonged heart rate-adjusted QT (QTc) interval and high blood pressure in elderly individuals, particularly in subjects over 80 years old. The aim of the present study was to determine the association between the QTc interval and blood pressure in 80-year-old subjects. This study was part of the 8020 Data Bank Survey, which was designed to collect the baseline data of systemic and dental health conditions in 80-year-old subjects. We studied the cross-sectional association of the QTc interval with blood pressure in 642 Japanese (257 men and 385 women), all 80 years old. Mean systolic blood pressure (SBP) rose from 146.0 mmHg in the first quartile of QTc interval to 149.1 mmHg in the second, 154.6 mmHg in the third, and 152.3 mmHg in the fourth quartile (test for trend, p =0.008). Mean diastolic blood pressure (DBP) also rose from 76.9 mmHg in the first quartile of QTc interval to 77.7 mmHg in the second, 81.8 mmHg in the third, and 79.0 mmHg in the fourth quartile (test for trend, p =0.003). We performed multiple regression analysis, controlling for factors known to influence the QTc intervals—e.g., SBP, heart rate, sex, and left ventricular hypertrophy assessed by the voltage amplitudes recorded in the precordial leads of the electrocardiogram. The association between the QTc interval and SBP was highly statistically significant in all analyses. These results show that SBP by itself may influence the QTc interval in very old subjects. (Hypertens Res 2004; 27: 387-391)

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Sodium Intake and Cardiac Sympatho-Vagal Balance in Young Men with High Blood Pressure

Osamu TOCHIKUBO, Kiyoko NISHIJIMA

2004 Volume 27 Issue 6 Pages 393-398
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.393

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We have previously reported that a high sodium intake increases sleep-time blood pressure (BP) in young men. However, there are cases in which this relation does not apply. To account for them, we investigated the relation between sodium intake and cardiac sympatho-vagal balance (SVB) in young men with high BP. Sodium intake was estimated from the amount of urinary sodium excretion over 1 week. Twenty-four-hour (24-h) urinary sodium excretion (Salt₂₄), 24-h ambulatory BP and ECG were obtained on the last day of the observation period. As an index of sodium intake, the expression ln(Salt₂₄/Cr₂₄) (Cr₂₄, 24-h urinary creatinine excretion) was used. From power-spectral analysis of ECG-RR intervals during sleep, we obtained the LF/HF ratio between the low-frequency component (LF) and the high frequency component (HF) and used it as an index of SVB. The subjects were male medical students divided into a normal BP group (N-group; n =103) and a high BP group (H-group; n =26, 24-h BP>125/75 mmHg). Mean ln(Salt₂₄/Cr₂₄) and LF/HF in the H-group were significantly higher than those in the N-group (LF/HF: 1.86±0.44 [SD] vs. 1.37±0.30, p <0.001). The calculated discriminant function (D) for the H-group and N-group was D =1.6x+5y-11, where x is ln(Salt₂₄/Cr₂₄) and y is LF/HF. This formula (D) resulted in high discriminant predictive accuracy (82%) between the groups. If D =0 (the value of the cut-off line determining separation of the groups), the relation y =-0.32x+2.2 (negative relation between y and x) was obtained. These results suggest that excessive sodium intake in combination with accentuated SVB (LF/HF) increases BP in young men. (Hypertens Res 2004; 27: 393-398)

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Experimental studies

Renal Protective Role of Bradykinin B1 Receptor in Stroke-Prone Spontaneously Hypertensive Rats

Makoto HAGIWARA, Hideyuki MURAKAMI, Nobuyuki URA, Jun AGATA, Hideaki Y ...

2004 Volume 27 Issue 6 Pages 399-408
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.399

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The kallikrein-kinin system plays important roles in blood pressure regulation, metabolism of electrolytes and organ protection. Although the bradykinin B2 receptor (B2R) has been reported to be involved in most of these effects, a role of the bradykinin B1 receptor (B1R) has also been noted recently. The aim of this study was to determine the role of renal B1R in stroke-prone spontaneously hypertensive rats (SHR-SP). Sixteen-week-old SHR-SP and Wistar Kyoto rats (WKY) as a control were used in the experiments. A high level of B1R mRNA was detected in SHR-SP, while the expression in WKY was almost undetectable. Immunohistochemistry revealed a B1R protein in the renal tubules and glomeruli in SHR-SP. The acute injection of a B1R agonist into SHR-SP increased urinary NO_x excretion to a level up to 5-fold higher than that in the SHR-SP treated with vehicle. The infusion of B1R antagonist for 4 weeks resulted in a significant elevation of blood pressure and urinary albumin excretion and a decrease in urinary NO_x excretion in SHR-SP. The administration of B1R antagonist resulted in renal interstitial and glomerular fibrosis in SHR-SP. Moreover, the expressions of transforming growth factor (TGF) β1 protein and collagen III mRNA in SHR-SP treated with B1R antagonist were significantly higher than those of SHR-SP treated with a vehicle. The expression and phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38, but not c-Jun N-terminal kinase (JNK), were significantly increased in the SHR-SP treated with B1R antagonist. These results indicated that renal B1R might be over-expressed in a high blood pressure condition, and that this up-regulated B1R may play an important role in renal protection by inhibiting renal fibrosis via an increase of NO production and a suppression of TGFβ1 expression and mitogen-activated protein kinase (ERK and p38) phosphorylation. (Hypertens Res 2004; 27: 399-408)

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Endothelin-1 Gene Expression in Endothelial Cells Is Potently Inhibited by a Vasodilator, Dilazep

Balaram SHRESTHA, Chiaki HIDAI, Hiromi IKEDA, Masako OKADA-OHNO, Hiros ...

2004 Volume 27 Issue 6 Pages 409-415
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.409

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Endothelin-1 (ET-1) is considered to be involved in various cardiovascular and renal disorders. The objective of this study was to investigate whether a vasodilator and antiplatelet agent, 1,4-bis[3-(3,4,5-trimethoxybenzoyloxy) propyl]perhydro-1,4-diazepine dihydrochloride monohydrate (dilazep, DZ), has an ET-1-inhibiting effect in vitro. Bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) pretreated with fetal calf serum were treated with DZ and preproET-1 (PpET-1) transcription was evaluated by Northern blot analysis. ET-1 peptide release in culture medium was evaluated by radioimmunoassay. The effect of DZ on the ET-1 promoter/enhancer apparatus was evaluated in transfection experiments using -5 kb ET-1 promoter/enhancer constructs. Modest inhibition of PpET-1 gene transcription was detected after 30 min of DZ treatment (0.56±0.19 vs. 1 , p <0.01) and more marked inhibition was seen at 24 h (0.04±0.04 vs. 1, p <0.0001). ET-1 peptide release was suppressed strongly after 3 h (382.5±2.9 vs. 673.5±74.5 pg/ml, p <0.001) and 24 h (38.8±9.8 vs. 5,075±52.0 pg/ml, p <0.0001). DZ potently inhibited PpET-1 transcription in a concentration-dependent manner (0.42±0.18 vs. 1, p <0.001, at 100 μmol/l). DZ suppressed PpET-1 transcription in confluent HUVEC at 3 h (0.41±0.11 vs. 1, p <0.0001). DZ strongly inhibited PpET-1 transcription after 1 h of thrombin (TH) treatment (0.30±0.01 vs. 1.51±0.03, p <0.0001). Transfection experiments using the 5 kb ET-1 promoter-luciferase plasmid revealed that DZ strongly suppressed ET-1 promoter activity by 99% (p <0.01). DZ potently inhibited ET-1 gene expression at the transcription level in serum- or TH-treated endothelial cells. (Hypertens Res 2004; 27: 409-415)

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Expression of Peroxisome Proliferator-Activated Receptor Isoform Proteins in the Rat Kidney

Kazunori SATO, Akira SUGAWARA, Masataka KUDO, Akira URUNO, Sadayoshi I ...

2004 Volume 27 Issue 6 Pages 417-425
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.417

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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors mediating ligand-dependent transactivation. Among the 3 isoforms, PPAR-α is involved in lipid metabolism in the liver, while PPAR-γ(-γ1 and -γ2) is involved in adipocyte differentiation. Recently, PPARs have been suggested to be involved in renal electrolyte metabolism as well as atherosclerosis. PPAR-α is known to regulate cytochrome P450 gene expression, and may possibly affect sodium retention in the kidney. Moreover, PPAR-γ is involved in the transcription regulation of blood pressure regulatory genes, including thromboxane and angiotensin II type 1 receptors. In the kidney, although expression of PPARs has been reported, detailed immunohistochemical analyses have not been performed. We here generated isoform-specific anti-PPAR antibodies to localize their proteins in the kidney. Anti-PPAR antibodies were raised against synthetic peptides. Their isoform specificity was confirmed by immunoblot analyses, immunoprecipitations, and antibody supershift experiments by electrophoretic mobility shift assay. We therefore studied the protein expression of PPARs in the kidney of adult Sprague-Dawley rats using these antibodies. Immunoblot analyses demonstrated protein expression of PPAR-α and -γ1, but not of -γ2, in the kidney nuclear extracts. Immunohistochemical analyses demonstrated that both PPAR-α and -γ1 proteins were widely expressed in the nuclei of mesangial and epithelial cells in glomeruli, proximal and distal tubules, the loop of Henle, medullary collecting ducts, and intima/media of renal vasculatures. PPAR-α and -γ1 proteins are thus widely expressed along the nephron segments, and may affect gene expression at these segments. Further studies will be needed to identify additional target genes for PPARs along the nephron segments. (Hypertens Res 2004; 27: 417-425)

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Effects of Angiotensin II Type 1 Receptor Antagonist on Pressor Responses to Pulsatile Compression of the Rostral Ventrolateral Medulla in Rats

Hidenori KIDO, Susumu SASAKI, Atsuhiko OGUNI, Sanae HARADA, Satoshi MO ...

2004 Volume 27 Issue 6 Pages 427-432
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.427

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The rostral ventrolateral medulla (RVLM) is known to be a major center regulating sympathetic and cardiovascular activities. A possible association between neurovascular compression of the RVLM and essential hypertension has been indicated. The present study was performed to determine the role of angiotensin II (AngII) in the pressor and sympathetic responses to pulsatile compression of the RVLM. To determine the role of glutamate and AngII in the RVLM, L-glutamate (Glu) 2 nmol or AngII 100 pmol was injected into the RVLM with or without RVLM pretreatment of kynurenate (Glu receptor antagonist) 3 nmol, candesartan (AngII type 1 (AT1) receptor antagonist) 2 nmol, or PD123319 (AngII type 2 (AT2) receptor antagonist) 1 nmol in anesthetized Wistar rats. In addition, to determine the role of glutamate and AngII in the pressor and sympathetic effects to the RVLM compression, kynurenate, candesartan, or PD123319 was locally injected before pulsatile compression of the RVLM. Finally, to determine the effects of peripherally administered AngII antagonists in these pressor and sympathetic excitatory responses, candesartan 0.25 μmol or PD123319 0.05μmol was intravenously injected before pulsatile compression of the RVLM. Glu injected into the RVLM significantly increased mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (SNA), and these effects were reduced by RVLM pretreatment with kynurenate, but were unaffected by candesartan or PD123319. AngII injected into the RVLM and pulsatile compression of the RVLM also increased MAP and SNA. However, in contrast with Glu injections, these effects were reduced by RVLM pretreatment with candesartan or kynurenate, but were unaffected by PD123319. Pressor and sympathetic excitatory responses to RVLM compression were reduced by intravenous pretreatment with candesartan but not with PD123319. These results indicate that, upon pulsatile compression of the RVLM, AngII may activate RVLM neurons via AT1 receptors and stimulate Glu release to thereby elicit sympathetic activation and pressor effects. Candesartan may exert its hypotensive effect at least in part by affecting the RVLM neurons to reduce sympathetic outflow induced by pulsatile compression of the RVLM. (Hypertens Res 2004; 27: 427-432)

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Dual Effects of Endothelin-1 (1-31): Induction of Mesangial Cell Migration and Facilitation of Monocyte Recruitment through Monocyte Chemoattractant Protein-1 Production by Mesangial Cells

Keisuke ISHIZAWA, Masanori YOSHIZUMI, Koichiro TSUCHIYA, Hitoshi HOUCH ...

2004 Volume 27 Issue 6 Pages 433-440
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.433

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We previously found that human chymase selectively cleaves big endothelin-1 (ET-1) at the Tyr³¹-Gly³² bond and produces 31-amino acid endothelins, ET-1 (1-31), without any further degradation products. In this study, we investigated the effect of ET-1 (1-31) on the migration of cultured rat mesangial cells (RMCs) and on cells of the human monocytic cell line, THP-1. In addition, we examined the interaction between RMCs and THP-1 cells using conditioned media from ET-1 (1-31)-stimulated RMCs. ET-1 (1-31) caused an increase in RMC migration in a concentration-dependent manner, and the degree of increase was similar to those by ET-1 and angiotensin II (AII). The ET-1 (1-31)-induced increase in RMC migration was inhibited by BQ123, an endothelin ET_A receptor antagonist, but not by BQ788, an endothelin ET_B receptor antagonist. ET-1 (1-31) alone did not cause significant migration of THP-1 cells. However, significant recruitment of THP-1 cells was observed with conditioned media taken from ET-1 (1-31)-stimulated RMCs. The conditioned media-induced migration of THP-1 cells was inhibited by BQ123, but not by BQ788. Western blotting analysis of the lysate of RMCs revealed that the expression of monocyte chemoattractant protein-1 (MCP-1) protein in RMCs was increased by treatment with ET-1 (1-31). The addition of neutralizing antibody for MCP-1 to the medium inhibited the migration of THP-1 cells induced by conditioned media from ET-1 (1-31)-stimulated RMCs. These findings suggest that ET-1 (1-31) play a role in glomerulonephritis (GN) via dual effects that directly cause the migration of mesangial cells (MCs) and may be responsible for the recruitment of mononuclear cells mediated through the activation of MCs. Since human chymase has been reported to be involved in glomerular disease, ET-1 (1-31) may be among the mediators. (Hypertens Res 2004; 27: 433-440)

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Case Report

Efficacy of Candesartan in the Treatment of Migraine in Hypertensive Patients

Kiyoshi OWADA

2004 Volume 27 Issue 6 Pages 441-446
Published: 2004
Released on J-STAGE: August 01, 2005

DOIhttps://doi.org/10.1291/hypres.27.441

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Triptans are usually administered for migraine, but cannot be given to patients with malfunctioning cardiac or cerebral vascular systems, which commonly accompany hypertension. This article focuses on 8 cases in which treatment with candesartan was successful in reducing both the incidence and severity of headache in hypertensive patients with migraine. The cases reported in this article showed a mean improvement in Migraine Disability Assessment score from 29.4 to 9 points and in blood pressure from 154.9/90.4 to 129.5/81.9 mmHg, suggesting that candesartan is an extremely attractive option for the treatment of migraine. Although recent studies have reported the efficacy of candesartan for treating migraine, there has been no description of its potential advantages over other prophylactic drugs. The present study included patients who could not tolerate triptans for whom triptans were contraindicated, several patients for whom other migraine prophylactic drugs showed little or no effect, and one patient for whom candesartan was prescribed initially for hypertension, but was also found to be therapeutic for migraines. Thus candesartan is considered to be a unique, attractive choice of prophylactic agent for migraine complicated by hypertension. (Hypertens Res 2004; 27: 441-446)

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