Hypertension Research

Original Articles

Clinical studies

Association of the GNAS1 Gene Variant with Hypertension Is Dependent on Alcohol Consumption

Yusen CHEN, Jun NAKURA, Jing-ji JIN, Zhihong WU, Miyuki YAMAMOTO, Mich ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 439-444
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.439

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The β-adrenoceptor (β-AR)-stimulatory guanine nucleotide-binding (Gs) protein system has been shown to play important roles in the cardiovascular system. The gene encoding the α-subunit of Gs proteins (GNAS1) is a candidate genetic determinant for hypertension. Because alcohol consumption is known to affect blood pressure partly through the β-AR-Gs protein system, we examined the possible interaction between GNAS1 T393C polymorphism and drinking status in the association with hypertension in the present study. As a result, a non-significant but reasonable trend supporting the presence of an interaction was shown (p =0.076). In line with this trend, the T393C polymorphism significantly interacted with drinking status in the association with systolic blood pressure (p =0.028). Moreover, supporting the presence of an interaction, T allele carriers consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than CC homozygotes in non-drinkers and light drinkers. In contrast, CC homozygotes consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than T allele carriers in moderate to heavy drinkers. The present study also showed a significant interaction between the T393C polymorphism and drinking status in the association with pulse pressure (p =0.026), reflected by a significant association between the T393C polymorphism and pulse pressure in moderate to heavy drinkers (p =0.026). These findings may be helpful in conducting further molecular and biological studies on the relationship among the effects of alcohol, the β-AR-Gs protein system, and hypertension. (Hypertens Res 2003; 26: 439-444)

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A 17-Year Follow-Up Study of Hypertensive and Normotensive Male University Students in Japan

Terukazu KAWASAKI, Keiko UEZONO, Miho SANEFUJI, Hiroko UTSUNOMIYA, Tak ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 445-452
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.445

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The aim of the present study was to determine the disease course of hypertensive male university students followed for 8 to 26 years (average, 17 years) after graduation. Subjects were classified into two groups. 1) A hypertensive group (H-group) consisting of 338 conclusively hypertensive male students followed from 1973 to 1990 at the Institute of Health Science, Kyushu University. Their ages ranged from 20 to 27 years, and all had high blood pressure (BP) of 140 mmHg or greater in systole (SBP) and/or 90 mmHg or greater in diastole (DBP) at a regular health check. This was confirmed by BP measurements for 3 days within 1 week. 2) A normotensive control group (N-group) consisting of 732 normotensive students (110-124 SBP/60-74 mmHg DBP) for whom faculty, age, sex, height, weight, and examination period were matched to the H-group as closely as possible. In 1997, each subject was sent a questionnaire with items on height, weight, sitting BP, pulse rate, family history of hypertension, lifestyle habits (such as drinking and smoking), stress and personality type. Completing the questionnaire were 177 (52.4%) of the H-group and 206 (28.1%) of the N-group subjects. Hypertension continued in 44.6% of the H-group subjects, whereas 9.2% of the N-group subjects became hypertensive. The rate of hypertension at the end of the investigation was significantly higher in those subjects who had a family history of hypertension than in those who did not. Weight gain (+15.1%) was the highest in H-group subjects who were initially normotensive. These subjects showed a significantly higher incidence of smoking and drinking than the other subjects. These results confirmed lifestyle to be one of the most important factors in keeping BP normal throughout life and also suggested that fundamental health education should be introduced at an early age. (Hypertens Res 2003; 26: 445-452)

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Low-Dose Candesartan Cilexetil Prevents Early Kidney Damage in Type 2 Diabetic Patients with Mildly Elevated Blood Pressure

Satoru MURAYAMA, Tsutomu HIRANO, Taro SAKAUE, Kenta OKADA, Reiko IKEJI ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 453-458
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.453

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To determine the effect of a low-dose angiotensin receptor blocker, candesartan, on early kidney damage associated with diabetes. Fifty-two patients with type 2 diabetes with normo- and microalbuminuria participated in this study. Nineteen patients with high-normal and mildly high blood pressure received low-dose candesartan cilexetil at 4 mg daily (candesartan group), and 33 patients did not receive candesartan (control group). Blood pressure, urinary excretion of albumin, transferrin, and type IV collagen (expressed as urinary creatinine index) and plasma parameters were determined at baseline and at 2, 6, 12 and 18 months after the start of candesartan therapy. Baseline urinary albumin, transferrin, and type IV collagen excretions was similar in the control and candesartan groups. The higher baseline systolic blood pressure was decreased by candesartan treatment to a level similar to that in the control group, such that blood pressure was comparable between the control and candesartan groups during the run-in period. In the control group, urinary albumin excretion was significantly increased at 18 months when compared with baseline, while urinary albumin excretion did not increase in the candesartan group throughout the study. Urinary transferrin excretion was significantly increased at 6, 12, and 18 months when compared with baseline in the control group, while it did not increase in the candesartan group during the study. In both groups, urinary type IV collagen excretion did not change significantly during the study. Hemoglobin A1c, serum urea nitrogen, creatinine, albumin, and lipids were comparable between the two groups throughout the study. In conclusion, low-dose candesartan can prevent early kidney damage in type 2 diabetic patients with mildly higher blood pressure independently of its hypotensive action. (Hypertens Res 2003; 26: 453-458)

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Variation near the Region of the Lipoprotein Lipase Gene and Hypertension or Blood Pressure Levels in Chinese

Wenjie YANG, Jianfeng HUANG, Dongliang GE, Cailiang YAO, Xiufang DUAN, ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 459-464
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.459

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Essential hypertension (EH) is a common late-onset disease that exhibits complex genetic heterogeneity. Human lipoprotein lipase (LPL) is a rate-limiting enzyme that regulates the catabolism of triglycerides (TG) and chylomicrons (CM). Since dyslipidemia is a common finding in hypertensive patients, the LPL gene is a logical candidate gene that could contribute to the development of hypertension. Using linkage analysis in 148 Chinese hypertensive families, we identified a region of linkage with systolic blood pressure (SBP) and diastolic blood pressure (DBP) that consisted of a 10.6-cM interval defined by markers D8S1145, D8S261, and D8S282 on chromosome 8, which maps between 31 to 41.6 cM from the 8p-telomere contained LPL gene, with statistically significant p values for the marker D8S261 (p =0.0021 for SBP, and p =0.0395 for DBP). In the qualitative-trait linkage analysis, evidence for linkage between the marker D8S1145 and EH was found (p =0.0286). The transmission/disequilibrium test (TDT/S-TDT) also supported a significant linkage-disequilibrium of the allele 3 of D8S261 with EH (χ²=8.643, p <0.01). Furthermore, the marker neurofilament light polypeptide (NEFL) (11 cM centromeric to the LPL gene) appeared to be in linkage with SBP and DBP (p =0.0329 for SBP; p =0.0319 for DBP). Additionally, two flanking markers for LPL, D8S511 (9.5 cM telomeric to the LPL gene) and D8S560 (3.2 cM centromeric to the LPL gene), also showed significant linkage with EH (p =0.0036 for D8S511; p =0.0115 for D8S560). Previous knowledge about the physiological involvement of LPL in blood pressure regulation and the present findings of variation near the LPL gene support the proposition that a region near the LPL gene or the LPL gene itself might contribute to the individual blood pressure variation in Chinese. (Hypertens Res 2003; 26: 459-464)

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Risk Factors for the Progression of Early Carotid Atherosclerosis in a Male Working Population

Koji FUJII, Isao ABE, Yusuke OHYA, Yuko OHTA, Hisatomi ARIMA, Takashi ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 465-471
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.465

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Increased intima-media thickness (IMT) of the carotid artery may represent early atherosclerosis. Although several studies have evaluated risk factors for carotid IMT, only limited information is available concerning risk factors for the progression of carotid IMT. The present study was designed to determine risk factors for the progression of carotid IMT in a male working population. Male employees of a regional transport company (n =220, 50.9±4.4 years) underwent baseline physical and laboratory examinations, and ultrasonographic assessment of the maximum common carotid IMT between 1992 and 1994, and they were reexamined 5 years later. In a multivariate analysis at baseline, carotid IMT was positively associated with age, diastolic blood pressure and total cholesterol, and negatively with high density lipoprotein (HDL) cholesterol. During the follow-up period, carotid IMT increased from 0.669±0.135 mm to 0.784±0.229 mm, or at a rate of 0.023 ±0.039 mm/year. In a multivariate regression analysis using baseline values of carotid IMT, age, body mass index, diastolic blood pressure, total cholesterol, HDL cholesterol and HbA1c as independent variables, the progression of carotid IMT was associated only with baseline total cholesterol. These findings suggest that in middle-aged men, although age, blood pressure, and total cholesterol were associated with baseline carotid IMT, total cholesterol level appeared to be the strongest determinant of the progression of carotid IMT, a result which underscores the importance of maintaining lower cholesterol levels to prevent early atherosclerosis. (Hypertens Res 2003; 26: 465-471)

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A Novel Variable Number of Tandem Repeat Polymorphism of the Renin Gene and Essential Hypertension

Buaijiaer HASIMU, Tomohiro NAKAYAMA, Yoshihiro MIZUTANI, Yoichi IZUMI, ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 473-477
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.473

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The aims of the present study were to find new genetic markers of essential hypertension (EH) and to investigate relationships between EH and polymorphisms of the renin gene. Using single strand conformation polymorphism, we discovered a new variable number of tandem repeat (VNTR) polymorphism in intron 7 that is 18 bp upstream from the boundary with exon 8. Nucleotide sequencing revealed that this VNTR polymorphism is a tandem repeat of the 4-nucleotide sequence TCTG. There were 6 alleles of this VNTR polymorphism, ranging from 7 repeats to 12 repeats. We analyzed the association between EH and this VNTR polymorphism. There was no significant difference in the overall distribution of this VNTR polymorphism between the EH and normotensive subjects. In summary, we discovered a novel VNTR polymorphism in the renin gene, and this polymorphism was not associated with EH. (Hypertens Res 2003; 26: 473-477)

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Circulating Thrombomodulin Levels Are Related to Latent Progression of Atherosclerosis in Hypertensive Patients

Yasuaki DOHI, Masuo OHASHI, Masaya SUGIYAMA, Hiroyuki TAKASE, Koichi S ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 6 Pages 479-483
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.479

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The present study was designed to test the hypothesis that circulating levels of thrombomodulin are elevated in patients with hypertension in proportion to the severity of the vascular damage. A cross-sectional study was carried out using a population consisting of 96 patients with essential hypertension without clinically evident cardiovascular disease (mean age: 65±10 years) and 99 healthy normotensive control subjects (64±9 years). Blood was sampled and serum concentrations of soluble thrombomodulin were measured using an enzyme immunoassay method. We calculated the ratio of the concentration of thrombomodulin to that of creatinine, because soluble thrombomodulin is excreted by the kidney and the serum level of thrombomodulin was correlated with that of creatinine (p <0.05). The association between the ratio and other clinical variables was investigated. The ratio of the thrombomodulin to creatinine concentrations was higher in hypertensive (29.3±10.9) than in control subjects (24.4±5.9; p <0.0001). Systolic blood pressure was correlated with the ratio but the ratio showed no correlation with serum lipid levels when analyzed using data from all subjects. In hypertensive patients, the ratio correlated with the grade of sclerotic, but not hypertensive, changes in the fundus oculi (Scheie’s classification, p <0.001). Furthermore, the ratio correlated with brachial-ankle pulse wave velocity (p <0.001). However, no correlation was detected between the ratio and blood pressure. These results suggest that circulating levels of thrombomodulin are elevated in hypertensive patients as compared to normotensive subjects and that the thrombomodulin level may be a molecular marker of the latent progression of atherosclerosis in hypertensive patients. (Hypertens Res 2003; 26: 479-483)

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Experimental studies

Effects of Angiotensin II Receptor Antagonists on Insulin Resistance Syndrome and Leptin in Sucrose-Fed Spontaneously Hypertensive Rats

Mamoru UMEDA, Tsugiyasu KANDA, Masami MURAKAMI

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 6 Pages 485-492
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.485

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In order to investigate the usefulness of angiotensin II type 1 receptor (AT₁) antagonists (ARA) in the treatment of hypertension with insulin resistance syndrome, we studied the effects of a high dose sucrose diet and ARA on insulin sensitivity, plasma lipids, and leptin in spontaneous hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). SHR and WKY were divided into three groups and treated for 12 weeks: those fed a standard chow, those given a sucrose-rich chow or those given a sucrose-rich chow and ARA. While in SHR the weight of both subcutaneous and mesenteric adipose tissue was greater in the sucrose-rich chow fed animals than in the standard chow fed animals, ARA treatment significantly decreased the weights of both subcutaneous and mesenteric adipose tissue. ARA treatment decreased free fatty acid and triglyceride in SHR, and increased high density lipoprotein cholesterol in SHR and WKY. Homeostasis model assessment-insulin resistance (HOMA-IR) index, plasma levels of leptin, and leptin mRNA in mesenteric adipose tissue were significantly greater in the sucrose-rich chow fed animals than in the standard chow fed animals, and significantly lower in the ARA-treated sucrose-rich chow fed animals than in the sucrose-rich chow fed animals in both SHR and WKY. ARA improved insulin resistance, and reduced plasma leptin and leptin mRNA in adipose tissue. These results suggest that the improvement of insulin resistance by ARA may be attributed, at least in part, to the reduction of adipose tissue weight. It is concluded that ARA is useful in the treatment of patients with hypertension and concomitant insulin resistance syndrome. (Hypertens Res 2003; 26: 485-492)

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Transmural Pressure Control of Prorenin Processing and Secretion in Diabetic Rat Juxtaglomerular Cells

Nobuhisa HIROTA, Atsuhiro ICHIHARA, Yukako KOURA, Yuko TADA, Matsuhiko ...

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 6 Pages 493-501
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.493

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In diabetic patients, the elevation of plasma prorenin levels or arterial pressure is correlated with the severity of diabetic nephropathy. This study was designed to assess the effects of transmural pressure on prorenin regulation in juxtaglomerular (JG) cells from diabetes rats. The JG cells, harvested from rats intraperitoneally injected with streptozotocin 7 (early-diabetic) or 28 (late-diabetic) days previously, were exposed to atmospheric pressure (AP) and AP+40 mmHg for 12 h, and the renin secretion rate (RSR), prorenin secretion rate (PRSR), active renin content (ARC), prorenin content (PRC), and total renin content (TRC) were determined. Exposure of control JG cells to AP+40-mmHg significantly decreased RSR, PRSR, and ARC and significantly increased PRC without affecting TRC, suggesting the occurrence of pressure-mediated inhibition of prorenin processing and secretion. Exposure of early-diabetic and late-diabetic cells to AP+40-mmHg significantly decreased ARC and significantly increased PRC without affecting RSR, PRSR, or TRC. The changes in ARC and PRC were similar in the control and early-diabetic cells, but greater changes were observed in late-diabetic cells. However, when streptozotocin-treated rats were continuously treated with insulin (9 U/kg/day), the transmural pressure control of prorenin in JG cells was similar to that observed in the JG cells from control rats. In late-diabetic cells, treatment with a phospholipase C inhibitor did not alter the pressure control of ARC or PRC; however, treatment with a phospholipase D inhibitor did inhibit the changes in ARC and PRC with transmural pressure. Thus, pressure-mediated inhibition of prorenin secretion from JG cells has already been impaired in early diabetes. Pressure-induced inhibition of prorenin processing in JG cells via phospholipase D-dependent pathways is enhanced in late diabetes. (Hypertens Res 2003; 26: 493-501)

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Nifedipine Upregulates Manganese Superoxide Dismutase Expression in Vascular Smooth Muscle Cells via Endothelial Cell-Dependent Pathways

Keisuke FUKUO, Jin YANG, Takashi SUZUKI, Taeko KAIMOTO, Yukihiro TAKEM ...

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 6 Pages 503-508
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.503

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Calcium antagonists normalize endothelial dysfunction and improve the clinical outcome in patients with hypertension. However, the mechanism underlying these beneficial effects remains to be elucidated. Here, we show that the calcium antagonist nifedipine upregulates the expression of manganese superoxide dismutase (Mn SOD), an endogenous antioxidant enzyme, in vascular smooth muscle cells (VSMC) via cellular interactions between VSMC and endothelial cells (EC). Nifedipine induced upregulation of Mn SOD activity and expression in VSMC when cocultured with EC but not when cultured individually. N^G-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Mn SOD expression induced by nifedipine. Additionally, N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine, a NO donor, reversed this inhibition by L-NMMA, indicating that NO may be involved in the mechanism underlying the nifedipine-induced upregulation of Mn SOD in VSMC. Preincubation of VSMC with Mn SOD antisense oligodeoxyribonucleotides (ODN) blocked the suppressive effects of nifedipine on DNA synthesis in VSMC cocultured with EC, whereas sense ODN had no effect. We conclude that the calcium antagonist nifedipine induces upregulation of Mn SOD expression in VSMC via NO derived from EC. This finding may provide some insight into the mechanism underlying the beneficial effects of calcium antagonists in patients with hypertension. (Hypertens Res 2003; 26: 503-508)

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Case Report

A Case of Exercise-Induced Acute Renal Failure in a Patient with Idiopathic Renal Hypouricemia Developed during Antihypertensive Therapy with Losartan and Trichlormethiazide

Osamu ITO, Yutaka HASEGAWA, Kazuto SATO, Hideaki MITSUI, Fumiaki YUDA, ...

Article type: Case Report
2003 Volume 26 Issue 6 Pages 509-513
Published: 2003
Released on J-STAGE: December 31, 2003

DOIhttps://doi.org/10.1291/hypres.26.509

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Exercise-induced acute renal failure (ARF) developed in a 45-year-old man during antihypertensive therapy with losartan and trichlormethiazide. The antihypertensive therapy was stopped and marked hypouricemia became apparent during improvement of his renal function. The daily urinary excretion of uric acid was normal and an increased fractional excretion of uric acid was observed. Renal biopsy revealed that the kidney was recovering from acute tubular necrosis with interstitial fibrosis. Based on the results of pyrazinamide and benzbromarone tests, we classified this case as one of presecretory reabsorption defect of uric acid. Antihypertesive therapy with benidipine and candesartan was initiated, and the patient has not had any ARF episodes since. Because idiopathic renal hypouricemia can be associated with exercise-induced ARF and chronic renal dysfunction, careful antihypertensive therapy and follow-up evaluation of renal function might be necessary for hypertensive patients with idiopathic renal hypouricemia. (Hypertens Res 2003; 26: 509-513)

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