Hypertension Research

Original Articles

Clinical studies

CYP11B2 Polymorphisms and Home Blood Pressure in a Population-Based Cohort in Japanese: the Ohasama Study

Mitsunobu MATSUBARA, Tomomi SATO, Takuya NISHIMURA, Michiko SUZUKI, Ma ...

2004 年27 巻1 号 p. 1-6
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.1

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Genetic polymorphisms of the aldosterone synthase gene (CYP11B2) have been major targets of studies into the genetic factors involved in hypertension. We have identified three genetic variants of CYP11B2, -344C/T at the promoter region, a conversion in intron 2 from the CYP11B2 sequence to the CYP11B1 sequence, and R173K in exon 3, in the Japanese population. -344C/T and R173K were in complete linkage disequilibrium in CYP11B2, and -344C/T was in strong, but not complete, linkage disequilibrium with the polymorphism in intron 2. Thus, two genetic polymorphisms, -344C/T and the gene conversion in intron 2, were investigated in association with home blood pressure (BP) values and clinical parameters in 1,242 subjects aged 40 and over in Ohasama, a rural Japanese community. Hypertension was defined as being treated with antihypertensive medication and/or having home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The results demonstrated that the -344T allele was significantly associated with increased prevalence of hypertension (p =0.015 in multiple logistic regression analysis, adjusted by age, gender, BMI, and smoking status), though BP level was unaltered. This allele was also significantly related to the prevalence of cardiovascular diseases in the older population (60 ≤ age, p =0.014). The resting polymorphism, a gene conversion in CYP11B2 intron 2, was not associated with any clinical parameters. Therefore, -344C/T polymorphism in CYP11B2 was considered an independent genetic factor possibly associated with hypertension or atherosclerotic diseases in the Japanese population. (Hypertens Res 2004; 27: 1-6)

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Blunted Response of the Renin-Angiotensin System and Nitric Oxide Synthesis Related to Sodium Sensitivity in Immunoglobulin A Nephropathy

Yoshio KONISHI, Takashi MORIKAWA, Takanori YASU, Kae TERAMOTO, Noriyuk ...

2004 年27 巻1 号 p. 7-13
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.7

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Sodium sensitivity of blood pressure appears before hypertension in immunoglobulin A nephropathy, as glomerulosclerosis and interstitial damage progress. To find whether this sensitivity is related to NO and the renin-angiotensin system, we examined 39 such patients without hypertension after they followed a diet with an ordinary sodium level for 1 week and a sodium-restricted diet for 1 week, in random order. Patients were divided into two groups at the median of their sodium sensitivity index (<0.040, n =19; ≥0.040 mmHg/mEq per day, n =20), calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linkage of two datum points obtained during the different diets. Urinary excretion of NO_X (NO₂ and NO₃), plasma renin activity, and serum aldosterone were measured. NO_X was higher in the low-index group than in the high-index group with the ordinary sodium level, but not during sodium restriction. NO_X was correlated negatively and significantly with the index with the ordinary sodium level (ρ =-0.406), but correlation in changes during sodium loading was not significant (ρ =-0.195). Changes in plasma renin activity and serum aldosterone during sodium restriction were greater in the low-index group than in the high-index group. The changes in renin activity and aldosterone were correlated negatively and significantly with the index (ρ=-0.573 and -0.499, respectively). These results indicate that impairment of NO synthesis and a blunted response of the renin-angiotensin system are attributable to the altered sodium sensitivity of blood pressure in patients with immunoglobulin A nephropathy. (Hypertens Res 2004; 27: 7-13)

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Effects of Bedtime vs. Morning Administration of the Long-Acting Lipophilic Angiotensin-Converting Enzyme Inhibitor Trandolapril on Morning Blood Pressure in Hypertensive Patients

Toshio KURODA, Kazuomi KARIO, Satoshi HOSHIDE, Toru HASHIMOTO, Yutaro ...

2004 年27 巻1 号 p. 15-20
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.15

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Cardiovascular events occur most frequently in the morning. To study the effects of the long-acting lipophilic angiotensin-converting enzyme (ACE) inhibitor trandolapril on morning blood pressure (BP), we performed ambulatory BP monitoring (ABPM) before and after administration of trandolapril just before going to bed (bedtime-administered group: n =17) or in the morning (morning-administered group: n =20) in 37 hypertensive patients. Both sets of ABPM data were available in 30 patients. The 24-h systolic BP (SBP) levels were significantly decreased by 7.2 mmHg in the morning-administered group (p =0.02) and by 5.2 mmHg in the bedtime-administered group (p =0.04). In the bedtime-administered group, prewaking SBP (the average of the 2-h SBP values just before waking) and morning SBP (the average of the 2-h SBP values just after waking) were significantly decreased by 11 mmHg (p =0.005) and by 8.4 mmHg (p =0.03), respectively. On the other hand, in the morning-administered group, the reduction of prewaking SBP (3.9 mmHg, n.s.) and morning SBP (6.6 mmHg, n.s.) did not reach the level of statistical significance. However, the differences in the reductions of prewaking and morning SBPs between the two groups were not statistically significant. There was no additional reduction of the nighttime lowest BP in either administration group. In conclusion, bedtime administration of the long-acting ACE inhibitor trandolapril seems to be a safe and effective means of controlling morning BP in hypertensive patients without an excessive fall in nocturnal BP. (Hypertens Res 2004; 27: 15-20)

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Renoprotective Effect of Losartan in Comparison to Amlodipine in Patients with Chronic Kidney Disease and Hypertension—a Report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) Study

Yasuhiko IINO, Matsuhiko HAYASHI, Tetsuya KAWAMURA, Tatsuo SHIIGAI, Ya ...

2004 年27 巻1 号 p. 21-30
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.21

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A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with ≥2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control. (Hypertens Res 2004; 27: 21-30)

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Association between Hypertension and the α-Adducin, β1-Adrenoreceptor, and G-Protein β3 Subunit Genes in the Japanese Population; the Suita Study

Keisuke SHIOJI, Yoshihiro KOKUBO, Toshifumi MANNAMI, Nozomu INAMOTO, H ...

2004 年27 巻1 号 p. 31-37
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.31

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This study focused on 3 genetic polymorphisms that have previously been implicated in hypertension: the α-adducin (ADD1/Gly460Trp), β1-adrenoreceptor (ADRB1/Arg389Gly), and G-protein β3 subunit (GNB3/C825T) gene polymorphisms. We determined genetic variants using the TaqMan system in a large cohort representing the general population in Japan (867 males, 1,013 females). Logistic analysis indicated that the ADD1/ G460W polymorphism was associated with hypertension in female subjects. The odds ratio of the WW genotype for hypertension was 1.53 (95%CI, 1.12-2.08) over the WG+GG genotype (p =0.0070, p corrected (p_c) =0.0420 corrected by the Bonferroni method). The ADRB1/R389G polymorphism tended to be associated with hypertensive status in male subjects (p =0.0117, p_c =0.0702). The odds ratio of the GG genotype for hypertension was 0.38 (95%CI, 0.167-0.780) over the RR+RG genotype. The GNB3/C825T polymorphism was not associated with hypertensive status in either male or female subjects. The present results do not agree with those in previous reports. Almost all common variants may have only a modest effect on common diseases, and a single study even employing 1,880 subjects may lack the statistical power to detect a real association. Accordingly, it will be necessary to verify the association between these three genes and hypertension using a larger number of subjects from the Suita cohort or another population. (Hypertens Res 2004; 27: 31-37)

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Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Modulates Coronary Release of Tissue Plasminogen Activator in Response to Bradykinin

Naoto OHIRA, Tetsuya MATSUMOTO, Shinji TAMAKI, Hiroyuki TAKASHIMA, Yas ...

2004 年27 巻1 号 p. 39-45
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.39

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The aim of this study was to assess the relationship between the angiotensin converting enzyme gene (ACE) genotype and endothelium-dependent coronary vasomotor and fibrinolytic activity. The ACE DD genotype has been reported to be a risk factor for myocardial infarction. However, the mechanism is unknown. The fibrinolytic and renin-angiotensin systems are linked via ACE at the vascular beds. We studied 73 patients (II: n =24; ID: n =37; DD: n =12) who underwent diagnostic cardiac catheterization. Graded doses of bradykinin (BK) (0.2, 0.6, 2.0μg/min) and acetylcholine (30,100μg/min) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by measuring Doppler flow velocity. Blood samples were taken from the aorta (Ao) and the coronary sinus (CS). Coronary release of tPA antigen was determined as a CS-Ao gradient×CBF×[(100-hematocrit) / 100]. ACE genotypes were determined using polymerase chain reaction. The ACE genotype did not appear to affect coronary macro- and microvascular responses induced by BK or acetylcholine. Coronary tissue plasminogen activator (tPA) release induced by BK was depressed in subjects with the ACE DD genotype. ACE levels in the DD genotype were significantly higher than those in the ID or II genotype. In all of the subjects, there was a significant negative correlation between the serum level of ACE activity and net coronary tPA release in response to BK at 0.6μg/min. In conclusions, the DD genotype of the ACE gene impairs the coronary release of tPA induced by BK. (Hypertens Res 2004; 27: 39-45)

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Left Ventricular Hypertrophy Is Associated with Arterial Stiffness and Vascular Calcification in Hemodialysis Patients

Kosaku NITTA, Takashi AKIBA, Keiko UCHIDA, Shigeru OTSUBO, Yuriko OTSU ...

2004 年27 巻1 号 p. 47-52
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.47

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Left ventricular hypertrophy (LVH) is the most frequent cardiac abnormality in patients with end-stage renal disease (ESRD). Recent studies have shown that arterial stiffness is associated with mediacalcinosis in these patients. However, whether arterial stiffness and vascular calcification are associated with the LVH in patients with ESRD has not been well established. Forty-nine patients on chronic hemodialysis participated in this study. 1) To better understand the mechanism underlying the increased incidence of LVH, we studied the relation between LVH and each of arterial wall stiffness, aortic calcification, and numerous clinical parameters in 49 patients on chronic hemodialysis. 2) To evaluate the contribution of arterial stiffness and arterial calcification to LVH in hemodialysis patients, we performed the present clinical analysis on 49 patients on chronic hemodialysis. We used an automatic device to measure arterial pulse wave velocity (PWV) as an index of arterial wall stiffness. The aortic calcification index (ACI) was quantified morphometrically by CT scan. The left ventricular mass index (LVMI) was estimated by M-mode echocardiography. To understand the mechanism underlying the increased incidence of LVH, we examined the factors contributing to LVMI in these patients. The correlation between each of the study parameters and LVMI as an indicator of LVH was then examined.The LVMI value was correlated positively with PWV (r =0.439, p =0.0014), systolic blood pressure (r =0.421, p =0.0023), and ACI (r =0.467, p =0.0006). A stepwise linear regression analysis showed that PWV, systolic blood pressure, and ACI were independently associated with LVH in our subjects. These results suggest that LVH is associated with hypertension, increased arterial stiffness, and the extent of vascular calcification in hemodialysis patients, with vascular calcification being the most important contributor to the development of LVH. Alteration of pulsatile dynamics contributes to an increase in left ventricular load and thus is also related to the LVH in these patients. These results suggest that LVH is associated with hypertension, increased arterial stiffness, and the extent of vascular calcification in hemodialysis patients. Vascular calcification, which alters the pulsatile dynamics and thereby contributes to an increase in left ventricular load, is the most important contributor to the development of LVH in patients undergoing hemodialysis. (Hypertens Res 2004; 27: 47-52)

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High Sodium Intake Strengthens the Association between Angiotensinogen T174M Polymorphism and Blood Pressure Levels among Lean Men and Women: a Community-Based Study

Kazumasa YAMAGISHI, Hiroyasu ISO, Takeshi TANIGAWA, Renzhe CUI, Minako ...

2004 年27 巻1 号 p. 53-60
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.53

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Evidence on the effect of salt intake on the interaction between angiotensinogen (AGT) T174M polymorphism and high blood pressure is sparse. We therefore conducted a large population-based cross-sectional study of 2,823 men and women aged 30-74 in a Japanese farming community to examine associations between AGT polymorphism and blood pressure levels stratified by age (30-64 and 65-74), body mass index (BMI; median), and salt intake (median) estimated by 24-h urine collection and dietary questionnaire. Our a priori hypothesis is that individuals, particularly younger and non-overweight individuals, with the 174M allele have elevated blood pressure levels in response to higher sodium intake, and thus the association between T174M polymorphism and blood pressure is more evident among individuals with higher sodium intake than those with lower sodium intake. There were no differences in systolic or diastolic blood pressure levels (SBP or DBP) between the TT and TM+MM genotype groups overall. However, the mean difference in DBP between the TM+MM and TT groups was +1.0 mmHg in subjects of younger age (p =0.06), +1.7 mmHg in non-overweight subjects (BMI<23.5 kg/m², p =0.01), and +2.3 mmHg in younger and non-overweight subjects (p =0.002). Furthermore, among younger and non-overweight subjects, blood pressure differences were larger for those with higher urinary sodium excretion (+3.1 mmHg, p =0.03), those with a higher sodium/potassium excretion ratio (+4.1 mmHg, p =0.007), those with higher present sodium intake score (+3.0 mmHg, p =0.003), and those with higher past sodium intake score (+3.4 mmHg, p <0.001). In conclusion, AGT T174M polymorphism was associated with higher DBP levels in younger and non-overweight Japanese. This association was more evident among subjects with higher sodium intake. (Hypertens Res 2004; 27: 53-60)

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Experimental study

Regulation of Skeletal Muscle Peroxisome Proliferator-Activated Receptor γ Expression by Exercise and Angiotensin-Converting Enzyme Inhibition in Fructose-Fed Hypertensive Rats

Takayuki KAWAMURA, Kazunori YOSHIDA, Akira SUGAWARA, Makoto NAGASAKA, ...

2004 年27 巻1 号 p. 61-70
発行日: 2004年
公開日: 2004/07/30

DOIhttps://doi.org/10.1291/hypres.27.61

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The purpose of this study was to examine the effects of chronic exercise training and angiotensin-converting enzyme (ACE) inhibition on peroxisome proliferator-activated receptor γ (PPARγ) expression in fat and skeletal muscle in fructose-fed spontaneously hypertensive rats (SHR). SHR were fed a fructose-rich diet over 16 weeks of either exercise training (Ex group: 20 m/min, 0% grade, 60 min/day, 5 days/week), ACE inhibitor administration (TM group: temocapril, 10 mg/kg/day), or a combination of both treatments (TM+Ex group). The systolic blood pressure was reduced exclusively in the temocapril-treated groups. Serum leptin level was positively correlated with the ratio of epididymal fat weight to body weight (p <0.001). Exercise training significantly upregulated the PPARγ expression in all tissues, which was attenuated by temocapril. PPARγ expression was significantly upregulated in skeletal muscles in the Ex group, and temocapril administration attenuated this effect in the Ex+TM group. The level of PPARγ protein was significantly higher in the extensor digitorum longus muscle than in the soleus muscle. Both TM and Ex prevented the fructose diet-induced transitions of fiber type. These data suggested that PPARγ expression is tissue-specific, and that alterations in PPARγexpression in the skeletal muscle induced by either or both treatments may have contributed to reducing the fat mass via the regulation of metabolic homeostasis. Changes in muscle morphology were independent of PPARγ expression, and the higher proportion of type I fiber might also explain some of the beneficial impact of exercise and ACE inhibition on energy metabolism. (Hypertens Res 2004; 27: 61-70)

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