Hypertension Research

Original Articles

Clinical studies

Overweight, But Not Hypertension, Is Associated with SAH Polymorphisms in Caucasians with Essential Hypertension

Adam V. BENJAFIELD, Naoharu IWAI, Kazuhiko ISHIKAWA, William Y. S. WAN ...

2003 年 26 巻 8 号 p. 591-595
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.591

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The gene SAH (chromosome 16p12.3) is of interest in the etiology of human hypertension. In Caucasians a PstI restriction fragment length polymorphism (RFLP) of SAH has been correlated with body weight in individuals with hypertension. To extend this finding we carried out a case-control study of several recently identified polymorphisms in SAH: 1) an insertion/deletion of TTTAA at nucleotide -1037 in the promoter; 2) an insertion/deletion of two Alu like sequences in intron 1; and 3) an A→G variant in intron 12 located 7 bp upstream from exon 13. Subjects were 121 hypertensives with 2 hypertensive parents and 178 normotensives whose parents were both normotensive. All were Anglo-Celtic Caucasians and 51% of the hypertensives were overweight (body mass index (BMI)>25 kg/m²). The SAH promoter and intron 1 variants, but not the intron 12 or PstI RFLP, were in linkage disequilibrium (LD) (D′=100%, p <0.001). We found no association between any of the polymorphisms and hypertension. However, the frequency of the minor allele of the intron 1 polymorphism (0.20) was higher in overweight than in normal weight hypertensives (0.07) (p =0.013). This association was supported by the weak tracking of plasma lipid variables with this allele (p values=0.01-0.04), although these lost their statistical significance after correction for multiple comparisons. In conclusion, the present data offers support for variation in SAH having a role in predisposition to overweight in hypertensives. (Hypertens Res 2003; 26: 591-595)

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Time-Series Analysis of Systolic Blood Pressure Variation in Thirty-Three Uygur Centenarians in China

Hiroshi KAWAMURA, Yukio OZAWA, Medet JUMABAY, Hiromi MITSUBAYASHI, Yoi ...

2003 年 26 巻 8 号 p. 597-601
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.597

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The Uygur are reported to have an unusually long life expectancy. The purpose of this research was to perform a time-series analysis of systolic blood pressure (SBP) variations in the Uygur and clarify the role of blood pressure variation (BPV) in their longevity. A cross-sectional survey was carried out in Hotan. We investigated 133 clinically healthy elderly Uygur subjects and divided them into two groups: 1) 33 Uygur centenarians in Hotan (UCH; aged ≥100 years); and 2) 100 elderly Uygur in Hotan (UEH; aged 65-70 years). Blood pressure (BP) was monitored and analyzed with ambulatory BP monitoring. The frequency domain measures were obtained with the maximum entropy method. The mean 24-h SBP was higher in UCH than in UEH. The ratio of non-dipper type BPV was larger in the UCH than in UEH. The highest power spectral density occurred over a 12-h rather than a 24-h period in both UCH and UEH. Ultradian BPVs were more frequent in UCH than in UEH. The least square-fitting curves demonstrated that the maximum values, minimum values, and mean 24-h SBP values were higher in UCH than in UEH. The higher BP and greater number of ultradian BPVs in UCH may have been due to the greater energy expenditure for maintaining daily activities in this population. Factors such as meals, daytime naps, nocturnal micturition, decreased baroreceptor sensitivity, and arterial sclerosis may also have contributed to the higher ultradian BPVs. In conclusion, BPV in the 12-h is more dominant than in the 24-h in both UCH and UEH. BPVs in the 3-h and 4-h are more frequent in UCH than those in UEH. (Hypertens Res 2003; 26: 597-601)

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Microalbuminuria and Cardiovascular Events in Elderly Hypertensive Patients without Previous Cardiovascular Complications

Satoko NAKAMURA, Yuhei KAWANO, Takashi INENAGA, Hajime NAKAHAMA, Takes ...

2003 年 26 巻 8 号 p. 603-608
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.603

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To assist in the development of better treatments for elderly hypertensive patients, we studied the degree to which the baseline values of urinary albumin excretion (UAE) and other cardiovascular risk factors were predictive of cardiovascular complications in a cohort of elderly hypertensive patients. In 1994, we adopted 144 elderly hypertensive patients, who had been treated for more than 6 years at various clinics and more than 1 year at the National Cardiovascular Center, Osaka, Japan. They were divided into 2 groups: a NA group (n =111) with normoalbuminuria (UAE<30 mg/day) and an MA group (n =33) with microalbuminuria (UAE 30-300 mg/day). At baseline, the two groups were similar with respect to systolic and diastolic blood pressure (SBP/DBP), pulse pressure (PP), age, ratio of males to females, serum creatinine, uric acid, total cholesterol, fasting plasma glucose (FPG), and creatinine clearance (CCr). PP was calculated as SBP minus DBP. The efficacy of blood pressure (BP) control was similar in both groups during the 8-year follow up period; however, a total of 14 cardiovascular events occurred in the MA (6/33) and NA (8/111) groups, with the MA group showing the higher incidence rate by multiple logistic regression analysis (p <0.05). At 8 years of follow-up, PP and age were correlated with UAE (p <0.05, p <0.001). At the same time point, CCr was correlated with UAE at baseline (p <0.05). The results indicated that, in elderly hypertensive patients without previous cardiovascular complications, microalbuminuria can be a predictor of cardiovascular events irrespective of conventional BP control. (Hypertens Res 2003; 26: 603-608)

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Efficacy of Various Antihypertensive Agents as Evaluated by Indices of Vascular Stiffness in Elderly Hypertensive Patients

Takeshi TAKAMI, Minori SHIGEMASA

2003 年 26 巻 8 号 p. 609-614
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.609

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When observed in elderly hypertensive patients, increased pulse pressure (PP) and arterial stiffness are known to be independent risk factors for cardiovascular diseases. Increased systolic blood pressure (SBP) leads to left ventricular hypertrophy, while decreased diastolic blood pressure (DBP) results in decreased coronary circulation. It is known that increased arterial stiffness is the major cause of increased PP. Thus basic morbid states of cardiac failure or ischemic heart diseases are more likely to develop in elderly hypertensive patients with increased PP and arterial stiffness, and there is need of antihypertensive drugs that decrease these effects in elderly hypertensives. In this study, we compared the effects of an angiotensin-receptor blocker (ARB: valsartan), an angiotensin-converting enzyme inhibitor (ACE-I: temocapril), and long-acting Ca antagonists (L- and N-type Ca channel blocker: cilnidipine; and L-type Ca channel blocker: nifedipine CR) on PP and arterial stiffness measured by pulse wave velocity in elderly hypertensive patients for 3 months. The ARB yielded the largest reductions in PP and brachial-ankle pulse wave velocity (baPWV), followed by the ACE-I and L- and N-type Ca channel blocker, while the L-type Ca channel blocker yielded no improvement. The effects on arterial stiffness and PP thus varied among the drug characteristics. Although ARB achieved the largest reduction in baPWV, this decrease was not associated with any reductions in PP, SBP, DBP, or mean blood pressure, as were the baPWV-decreases achieved by the other drugs, suggesting that ARB may further reduce the risk of arteriosclerosis in elderly hypertensive patients by decreasing arterial stiffness in addition to its antihypertensive effect. (Hypertens Res 2003; 26: 609-614)

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Brachial-Ankle Pulse Wave Velocity as a Marker of Atherosclerotic Vascular Damage and Cardiovascular Risk

Akira YAMASHINA, Hirofumi TOMIYAMA, Tomio ARAI, Ken-ichi HIROSE, Yutak ...

2003 年 26 巻 8 号 p. 615-622
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.615

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The measurement of brachial-ankle pulse wave velocity (baPWV) is simple and applicable for general population studies. The present study was conducted to evaluate the applicability of baPWV for screening cardiovascular risk as well as for use as a marker of the severity of atherosclerotic vascular damage in a general population. baPWV was measured in a cross-sectional study involving two cohorts constituting a total of 10,828 subjects who underwent annual health screening check up examinations (6,716 males and 4,112 females; age 30 to 74 years). The Framingham risk score and Pocock’s score were obtained. Multivariate analysis demonstrated that baPWV was associated with both scores, independently from conventional atherosclerotic risk factors. The receiver-operator characteristic curve demonstrated that a baPWV of 14.0 m/s is useful for risk stratification by Framingham score and to discriminate patients with either stroke or coronary heart disease (n =143), but the likelihood ratios were less than 5.0. Logistic regression analysis demonstrated that a baPWV>14.0 m/s is an independent variable for the risk stratification by Framingham score and for the discrimination of patients with atherosclerotic cardiovascular disease. Thus, baPWV has potential as a new marker of cardiovascular risk and may be more useful than other conventional markers; in addition, baPWV is easy to obtain and serves as an indicator of either atherosclerotic cardiovascular risk or severity of atherosclerotic vascular damage; thus it is useful to screen the general population. While the discriminating powers are not sufficiently high, a cutoff value of 14.0 m/s serves to screen subjects, especially in middle-aged ones, of either gender. (Hypertens Res 2003; 26: 615-622)

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Experimental studies

Effects of Mitogen-Activated Protein Kinase Pathway and Co-Activator CREP-Binding Protein on Peroxisome Proliferator-Activated Receptor-γ-Mediated Transcription Suppression of Angiotensin II Type 1 Receptor Gene

Akira SUGAWARA, Kazuhisa TAKEUCHI, Akira URUNO, Masataka KUDO, Kazunor ...

2003 年 26 巻 8 号 p. 623-628
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.623

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Peroxisome proliferator-activated receptor (PPAR)-γ and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-γ suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the -58/-34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-γ function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-γ and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-γ-mediated AT1R gene transcription suppression. We observed that 1) PPAR-γ-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-γ-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-γ-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the -58/-34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-γ phosphorylation by the MAP kinase pathway may attenuate PPAR-γ-mediated AT1R gene transcription suppression through the inhibition of PPAR-γactivity; and 2) CBP may enhance the activity of the remaining Sp1 on the -58/-34 GC-box related element, resulting in a reduction in PPAR-γ-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-γ in AT1R gene transcription, probably leading to the progression of atherosclerosis. (Hypertens Res 2003; 26: 623-628)

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Acute Regulation of the Epithelial Sodium Channel Gene by Vasopressin and Hyperosmolality

Kenji MACHIDA, Hiroshi NONOGUCHI, Shiho WAKAMATSU, Hideki INOUE, Tatja ...

2003 年 26 巻 8 号 p. 629-634
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.629

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The amiloride-sensitive epithelial sodium channel (ENaC) plays a key role in sodium reabsorption in the collecting ducts. We examined ENaC mRNA distribution along the nephron and acute effects of vasopressin and hyperosmolality on ENaC mRNA expression. ENaCα,β, and γ mRNA expressions were observed in cortical, outer medullary and initial inner medullary collecting ducts (CCD, OMCD and iIMCD, respectively). ENaCα mRNA expression was also observed in medullary and cortical thick ascending limbs (MAL and CAL, respectively), while ENaCβ and γ mRNA expressions were not observed. Furthermore, ENaCα mRNA expression in MAL but not in collecting ducts was stimulated by acute exposure to arginine vasopressin (AVP), 8-(4-chlorophenylthio) (CPT)-cAMP and hyperosmolality. However, the physiological significance of these effects is not known, since ENaC protein is reported to be absent in MAL. These data suggest that ENaCα mRNA expression in MAL but not in collecting ducts is acutely regulated by AVP and hyperosmolality. The absence of stimulation of ENaCα mRNA expression in collecting ducts suggests the physiological significance of ENaCβ and γ mRNA for acute regulation by vasopressin. Determining the physiological significance of the acute effect of vasopressin in MAL will require further investigations. (Hypertens Res 2003; 26: 629-634)

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Renoprotective Effects of Benidipine in Combination with Angiotensin II Type 1 Receptor Blocker in Hypertensive Dahl Rats

Kozo YAO, Hitoshi SATO, Yasuhiro INA, Kazuo SUZUKI, Tetsuji OHNO, Shir ...

2003 年 26 巻 8 号 p. 635-641
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.635

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We examined the effects of the angiotensin II type 1 receptor blocker candesartan, the calcium channel blockers benidipine and amlodipine, hydralazine, and the combination of candesartan and benidipine or amlodipine on blood pressure and renal function in Dahl salt-sensitive (DS) hypertensive rats. Male DS rats (5 weeks of age) were fed a high-salt (8% NaCl) diet, resulting in hypertension accompanied by glomerular sclerosis and an increased urinary albumin excretion. Drugs were orally administered from 2 to 6 weeks after the start of the feeding. Although candesartan (1 or 10 mg/kg) had little effect on the blood pressure, benidipine (4 mg/kg), amlodipine (4 mg/kg) and hydralazine (5 mg/kg) had similar hypotensive effects. Benidipine, but not amlodipine, hydralazine, or candesartan, significantly inhibited the increase in the albuminuria and glomerular sclerosis. The combination of candesartan (1 mg/kg) and benidipine (4 mg/kg) lowered the levels of blood pressure and albuminuria more effectively than the combination of candesartan (1 mg/kg) and amlodipine (4 mg/kg). These results indicate that benidipine is effective in preventing the impairment of renal function in DS hypertensive rats, and suggest that additional benefits can be expected by combination therapy with benidipine and an angiotensin II type 1 receptor blocker. (Hypertens Res 2003; 26: 635-641)

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Impaired Ca²⁺ Handling in Perfused Hypertrophic Hearts from Dahl Salt-Sensitive Rats

Shingo SEKI, Makoto NAGAI, Hiroshi TAKEDA, Tatsuyuki ONODERA, Fumiko O ...

2003 年 26 巻 8 号 p. 643-653
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.643

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To clarify the correlation between intracellular Ca²⁺ dynamics and level of Ca²⁺-regulatory proteins, changes in Ca²⁺ handling and these proteins were investigated in a whole-heart experimental model of pressure-overload hypertrophy. We used 17-18-week-old male Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) fed a high-salt diet. We monitored the fura-2 fluorescence ratio, an index of cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i), using a Ca²⁺ analyzer in a retrograde perfused heart. Left ventricular pressure (LVP) and an electrocardiogram were simultaneously recorded. Ca²⁺ handling was assessed by exposing the hearts to 2 min of low-Na⁺ (70 mmol/l) perfusion to produce an increase in [Ca²⁺]_i (n =6), which was sensitive to Ni²⁺, a blocker of the Na⁺/Ca²⁺ exchanger (NCX). In another series, the hearts were stimulated at 2.5 to 5 Hz to determine the Ca²⁺-force-frequency relationship (n =6). DS rats showed marked cardiac hypertrophy without any signs of failure. The time-to-peak Ca²⁺ transient was prolonged in DS compared with that in DR during normal beating. During low-Na⁺ exposure, the time-to-peak diastolic [Ca²⁺]_i (TTP) and the decay-time from peak [Ca²⁺]_i (DT) were prolonged in DS compared with DR (TTP, 43.3±4.0 vs. 32.5±2.5 s, p <0.05; DT, 70.0±8.8 vs. 29.2±2.7 s, p <0.005). Following pretreatment with 10 mmol/l caffeine to inhibit sarcoplasmic reticulum (SR) function, TTP and DT were still prolonged in DS compared with DR (TTP, 64.2±9.7 vs. 37.0±5.8 s, p <0.05; DT, 55.8±12.6 vs. 26.0±5.7 s, p <0.05). The force (LVP)-frequency relationship was initially positive in DR but was negative at all times in DS (%LVP/2.5 Hz: DS, 90.3±2.0%; DR, 112.2±4.5%; p <0.05). Elevation of diastolic [Ca²⁺]_i (percent increase of baseline) was greater in DS than in DR with increased stimulation (5 Hz: DS, 80.7±6.7%; DR, 52.1±5.9%; p <0.05). In Western blot analysis, the protein level of NCX was equivalent, whereas that of SR Ca²⁺ ATPase (SERCA2) was significantly decreased in DS compared with DR. These results suggest that slowing of cellular Ca²⁺ mobilization and removal is related to impaired Ca²⁺ handling in late-phase cardiac hypertrophy. Both the activity of the NCX and that of the SR may be affected. The SR dysfunction may be associated with change in protein level of SERCA2. (Hypertens Res 2003; 26: 643-653)

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Eicosapentaenoic Acid Suppresses Basal and Insulin-Stimulated Endothelin-1 Production in Human Endothelial Cells

Keigo CHISAKI, Yukichi OKUDA, Seiji SUZUKI, Takashi MIYAUCHI, Masaaki ...

2003 年 26 巻 8 号 p. 655-661
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.655

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cis-Polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) are the major fatty acids contained in fish oil, and are known to affect the various physiological properties of cell membranes in humans. The present study investigated the effects of polyunsaturated fatty acids on endothelin-1 (ET-1) production in human umbilical vein endothelial cells (HUVECs) and on insulin activity. After addition of various concentrations of EPA, docosahexaenoic acid, arachidonic acid, or linoleic acid to a culture medium, the concentration of ET-1 was measured using ELISA, and that of ET-1 mRNA was determined by RT-PCR. The results showed that EPA had the strongest inhibitory effect (p <0.05) on both basal ET-1 production and ET-1 mRNA levels. In addition, insulin (1μmol/l) markedly increased ET-1 production, and EPA also significantly decreased the effect induced by insulin. Pretreatment with Ca²⁺ chelator EGTA (1 mmol/l), NOS inhibitor L-NAME (300μmol/l), or calmodulin antagonist W-7 (300μmol/l) inhibited NO production by EPA (100μmol/l), but these pretreatments had no effect on ET-1 production by EPA. These findings suggest that EPA reduces basal and insulin-enhanced ET-1 production by inhibiting ET-1 mRNA production. These effects of EPA may contribute to its vasorelaxant and anti-atherosclerotic effects. (Hypertens Res 2003; 26: 655-661)

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Case Report

A Case of Aldosterone-Producing Adrenocortical Adenoma Associated with a Probable Post-Operative Adrenal Crisis: Histopathological Analyses of the Adrenal Gland

Akira SUGAWARA, Kazuhisa TAKEUCHI, Takashi SUZUKI, Keiichi ITOI, Hiron ...

2003 年 26 巻 8 号 p. 663-668
発行日: 2003年
公開日: 2004/04/07

DOIhttps://doi.org/10.1291/hypres.26.663

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We describe a case of aldosterone-producing adrenocortical adenoma (APA) associated with a probable post-operative adrenal crisis possibly due to subtle autonomous cortisol secretion. The patient was a 46-year-old female who suffered from severe hypertension and hypokalemia. CT and MRI scans revealed a 2-cm diameter adrenal mass. The patient’s plasma aldosterone level was increased, and her plasma renin activity was suppressed, both of which findings were consistent with APA. Cushingoid appearance was not observed. Morning and midnight serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were all within the normal range. Her serum cortisol level was suppressed to 1.9μg/dl as measured by an overnight 1-mg dexamethasone suppression test, but was incompletely suppressed (2.7μg/dl) by an overnight 8-mg dexamethasone suppression test. In addition, adrenocortical scintigraphy showed a strong uptake at the tumor region and a complete suppression of the contra-lateral adrenal uptake. After unilateral adrenalectomy, she had an episode of adrenal crisis, and a transient glucocorticoid replacement improved the symptoms. Histopathological studies demonstrated that the tumor was basically compatible with APA. The clear cells in the tumor were admixed with small numbers of compact cells that expressed 17α-hydroxylase, suggesting that the tumor was able to produce and secrete cortisol. In addition, the adjacent non-neoplastic adrenal cortex showed cortical atrophy, and dehydroepiandrosterone sulfotransferase immunoreactivity in the zonae fasciculata and reticularis was markedly diminished, suggesting that the hypothalamo-pituitary-adrenal (HPA) axis of the patient was suppressed due to neoplastic production and secretion of cortisol. Together, these findings suggested that autonomous secretion of cortisol from the tumor suppressed the HPA axis of the patient, thereby triggering the probable post-operative adrenal crisis. Post-operative adrenocortical insufficiency should be considered in clinical management of patients with relatively large APA, even when physical signs of autonomous cortisol overproduction are not apparent. (Hypertens Res 2003; 26: 663-668)

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