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Masaru SHOJI, Shoji TSUTAYA, Jun SHIMADA, Keiya KOJIMA, Takeshi KASAI, ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
1-3
Published: 2002
Released on J-STAGE: July 09, 2002
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There is an inherited paternal predisposition to hypertension. Y chromosome alphoid satellite variation was recently reported to be linked to diastolic blood pressure. To determine whether there is also a Y chromosome marker linked to hypertension, we investigated the prevalence of the Y chromosome Alu insertion polymorphism (YAP) at DYS287 and its association with hypertension in the Aomori population in the northern area of Honshu Island, Japan. YAP was present in 98 of 285 male residents and absent in the rest. The YAP prevalence in the present study would appear to suggest that the present study population represents the general male population in central Japan. Within the study population, there were 110 hypertensive subjects and 104 normotensive subjects. YAP frequency in the hypertensive subjects was not different from that in the normotensive subjects. These results suggest that the YAP is not likely to be a genetic-susceptibility factor for hypertension in the Aomori population. (Hypertens Res 2002; 25: 1-3)
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Norio KOMAI, Mitsuru OHISHI, Atsushi MORIGUCHI, Yoshihiro YANAGITANI, ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
5-10
Published: 2002
Released on J-STAGE: July 09, 2002
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Evaluation of atherosclerosis is important in the treatment of hypertension. To evaluate the preventive effects of a small amount of α-blockade, arterial and endothelial dysfunction were measured by noninvasive tests, i.e., pulse wave velocity, acceleration plethysmography and strain-gauge plethysmography, in patients with essential hypertension. Fifteen patients (65±3 years old) with essential hypertension (WHO stage I or II) were analyzed in this study. We performed noninvasive evaluations to measure aortic stiffness and endothelial dysfunction, in addition to measuring blood pressure, cholesterol profile, and levels of cells adhesion molecules and nitric oxide before and 6 and 12 months after the start of doxazosin treatment (1.0 mgfrasl;day). Blood pressure and heart rate did not significantly change during treatment. The pulse wave velocity index was significantly reduced both at 6 (7.72±0.23 m⁄s; p<0.05) and 12 (7.34±0.26 m⁄s; p<0.05) months after the start of treatment compared to the pretreatment level that at baseline. There was also a significant improvement in b⁄a after 12 months (-0.46±0.04; p<0.05) and in dfrasl;a after 6 months (-0.38±0.03; p<0.05) and 12 months (-0.39±0.03; p=0.05) compared to the pretreatment values. Moreover, reactive hyperemia evaluated by strain-gauge plethysmography after 6 months (1.34±0.11; p<0.05) and 12 months (1.49±0.16; p<0.05) was significantly improved compared to that before treatment, and NOX was significantly increased after 12 months (89.7±15.7 μmol⁄l; p<0.005). These data suggest that a low dose of doxazosin may play an important role in improving arterial stiffness and endothelial dysfunction without changing cardiac hemodynamics. (Hypertens Res 2002; 25: 5-10)
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Yuji FUKUDOME, Koji FUJII, Hisatomi ARIMA, Yusuke OHYA, Takuya TSUCHIH ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
11-18
Published: 2002
Released on J-STAGE: July 09, 2002
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Patients with primary aldosteronism show relatively high rates of hypertension after adrenalectomy, but the risk factors for postoperative hypertension remain unclear. Forty-six patients with primary aldosteronism (PA) who had undergone adrenalectomy between 1976 and 1998 were enrolled in this study. Follow-up information including blood pressure (BP) and cardiovascular complications was collected by means of correspondence or telephone contact. At discharge BP was normalized in 34 patients (72%); hypertension persisted in the remaining 12 patients, but BP control was significantly improved. The patients who remained hypertensive at discharge had longer durations of hypertension than did those with normalized BP. After an average follow-up period of 12.2 years, 16 of 34 BP-normalized patients (47%) had recurrent hypertension. Age at adrenalectomy, preoperative serum creatinine level and systolic blood pressure at discharge were significantly higher in patients with recurrent hypertension than in those without it. A multivariate logistic regression analysis revealed that only the level of serum creatinine was independently associated with the incidence of recurrent hypertension. Patients with serum creatinine of 0.9 mg⁄dl or greater had significantly higher rates of recurrent hypertension than those with lower values of serum creatinine. Cardiovascular complications occurred in 5 patients prior to the surgery and in 2 patients during the follow-up period. Although the severity of renal involvement is subclinical, renal damage may play an important role in the development of hypertension during a long period after adrenalectomy in patients with PA. (Hypertens Res 2002; 25: 11-18)
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Koichi HANADA, Osamu TOCHIKUBO, Tomohiko SHIGEMASA, Kazuo KIMURA, Sato ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
19-24
Published: 2002
Released on J-STAGE: July 09, 2002
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Left ventricular mass (LVM) as assessed by magnetic resonance imaging (MRI, LVMMRI) and electrocardiographic (ECG) voltage reflect different pathological features. We hypothesized that ECG voltage is related to the electrical potential of cardiac muscle cells (electrical LVM) and to anatomical LVM as evaluated by MRI, and that the divergence between electrical LVM and anatomical LVM reflects the degree of myocardial damage. Because adipose tissue has high electrical resistance, we previously found a very strong correlation between body-fat-corrected mean ECG voltage (Vfm) and LVM as estimated by echocardiography in patients with essential hypertension. In this study we compared LVMMRI, Vfm, the ratio of Vfm×102⁄LVMMRI, and the results of 99mTc tetrofosmin scintigraphy in patients with and without myocardial infarction (MI). We studied 33 patients without MI and 26 patients with MI. Vfm significantly correlated with LVMMRI in patients without MI (r=0.71, p<0.01). The ratio of Vfm×102⁄LVMMRI apparently reflected the relation between electrical LVM and anatomical LVM. Vfm×102⁄LVMMRI in patients with MI was smaller than that in patients without MI (0.98±0.28 vs. 1.42±0.29, p<0.01). Vfm×102⁄LVMMRI decreased as 99mTc score increased (r=-0.66, p<0.01). Our results indicate that Vfm is a useful index of electrical LVM and that Vfm×102⁄LVMMRI reflects the electrical potential of the viable myocardium in total anatomical LVM. (Hypertens Res 2002; 25: 19-24)
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Junko YAMAMOTO, Shigeru KAGEYAMA, Masami NEMOTO, Takashi SASAKI, Tatsu ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
25-29
Published: 2002
Released on J-STAGE: July 09, 2002
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We investigated the relationship between peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala substitution and insulin resistance in subjects with normal insulin secretory capacity, since it has been reported that PPARγ may affect not only insulin resistance but also insulin secretion. We examined 81 Japanese male patients with untreated essential hypertension using the glucose clamp technique. We found 77 subjects with Pro⁄Pro and 4 subjects with Pro⁄Ala genotype, and the glucose disposal rate was not significantly different between the two groups. Fasting plasma glucose, fasting immunoreactive insulin, total cholesterol, HDL cholesterol, and triglyceride were not significantly different between the two groups. There were also no significant differences between groups in homeostasis model assessment of insulin resistance (HOMA-R) values, area under the curve (AUC) for plasma glucose, or AUC for IRI in 75 g OGTT. Because insulin sensitivity is likely to be determined by polygenic factors, we also investigated β3 adrenergic receptor Trp64Arg polymorphism as a possible determinant of insulin resistance. In conclusion, no significant association was observed between PPARγ2 substitution and insulin sensitivity in the present cohort of Japanese hypertensive patients. (Hypertens Res 2002; 25: 25-29)
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Katsuhiko KOHARA, Yasuharu TABARA, Yoshikuni YAMAMOTO, Michiya IGASE, ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
31-39
Published: 2002
Released on J-STAGE: July 09, 2002
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Plasma levels of soluble forms of cellular adhesion molecules (CAMs) and their relationships with carotid intima-media thickness (IMT) were investigated in community residents. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA in 200 community residents in Japan. Carotid IMT showed a weak but significant positive correlation with the plasma levels of both sICAM-1 (r=0.175, p=0.013) and sVCAM-1 (r=0.19, p=0.0075). Gene polymorphisms of angiotensin converting enzyme (ACE) insertion⁄deletion (I⁄D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C and apolipoprotein E (apoE) were determined for each subject. The plasma level of sVCAM-1 tended to be lower in subjects with the ACE DD genotype than in those with the ACE ID and II genotypes (373±94, 421±133, 443±135 ng⁄ml, respectively, p=0.056). However, there were no genotype-specific differences in the plasma levels of soluble forms of CAMs for the other genes examined. In a separate analysis, the plasma level of sICAM-1 was significantly associated with carotid IMT in ACE D carriers (ID + DD) (r=0.28, p=0.002), AGT M carriers (MT + MM) (r=0.32, p=0.0045), and subjects with apoE4 (r=0.35, p=0.036). In contrast, the plasma level of sVCAM-1 showed significant positive correlations with carotid IMT in subjects with the ACE II genotype (r=0.33, p=0.0027) or AGT TT genotype (r=0.22, p=0.015), and subjects with apoE E2⁄E3 or E3⁄E3 (r=0.16, p=0.043). Stepwise regression analysis showed that plasma sVCAM-1 was independently associated with carotid IMT in subjects with the ACE II genotype or apoE4 genotype. Similarly, the plasma level of sICAM-1 was independently associated with carotid IMT in AGT M carriers. These findings suggest that genetic background could be involved in the association between plasma CAMs and atherosclerosis. (Hypertens Res 2002; 25: 31-39)
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Naofumi IKEDA, Hiromichi SUZUKI, Kenshi MORIWAKI, Souichi SUGAHARA, Yo ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
41-48
Published: 2002
Released on J-STAGE: July 09, 2002
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Both in CHF (congestive heart failure) and CRI (chronic renal insufficiency), blood pressure reduction is beneficial for preservation of cardiac and renal function. However, it is uncertain how much blood pressure reduction is appropriate in patients with both CHF and coexisting CRI. In the present study, we examined whether intensive blood pressure reduction is more beneficial in these patients than the usually accepted level of reduction. Thirty-five men and 21 women of average age 63±5 years suffering from both CHF and CRI were selected from 316 patients attending the Kidney Disease Center of Saitama Medical School Hospital. All participants had an ejection fraction (EF) of less than 55% as determined by echocardiography. Renal function was evaluated by 24-h creatinine clearance (GFR), and a GFR of less than 50 ml⁄min was regarded as indicating renal insufficiency. Patients were divided into 2 groups according to the target blood pressure: in group I, blood pressure (BP) was lowered to less than 120⁄75 mmHg and in group II, blood pressure was lowered to less than 130⁄80 but more than 121⁄76 mmHg. The daily doses of basic antihypertensive agents were amlodipine 5 to 20 mg, benazepril 2.5 to 5 mg, guanabenz 2 to 8 mg and furosemide 20 to 60 mg. At the end of a 2-year follow-up period, the BP in group I was controlled at the level of 118±4⁄73±3 mmHg with good maintenance of EF (46±4 to 60±4%) and GFR (44±4 to 40±3 ml⁄min). In group II, BP was maintained at 128±4⁄81±2 mmHg, accompanied by a reduction of EF (46±4 to 42±3%) and a significant reduction of GFR (44±3 to 35±3 ml⁄min). These results suggest that intensive blood pressure reduction might be beneficial in cases complicated by cardiorenal failure. (Hypertens Res 2002; 25: 41-48)
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Yoshio IWASHIMA, Takeshi HORIO, Setsuko KURODA, Shuichi TAKISHITA, Yuh ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
49-56
Published: 2002
Released on J-STAGE: July 09, 2002
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Since aldosterone is known to promote interstitial fibrosis in cardiac tissues, it is possible that aldosterone may influence cardiac structure and function. In the present study, we investigated whether plasma aldosterone concentration (PAC) is related to the distinct patterns of left ventricular (LV) geometry and LV diastolic function in treated essential hypertension. In 92 patients with chronically treated essential hypertension, two-dimensional and Doppler echocardiographic examinations were performed and LV inflow velocities were measured for evaluation of LV diastolic function. When patients were divided into four groups by the different LV geometric patterns, PAC in patients with eccentric hypertrophy was significantly higher than in those with concentric hypertrophy (15.2±2.1 vs. 10.0±0.7 ng⁄dl, p<0.01). However, the ratio of the peak velocity of early diastolic filling to that of atrial filling (E⁄A), an index of LV diastolic function, was significantly decreased in patients with concentric hypertrophy compared with those showing normal geometry. In the relationship between PAC and LV diastolic function, PAC was negatively correlated with E⁄A (r=-0.35, p<0.05) only in the subgroup with normal relative wall thickness (i.e., without the concentric change in LV geometry). A multiple linear regression analysis showed that PAC was one of the independent determinants of E⁄A in the overall subject group. These observations indicate that PAC is associated with the eccentric change in LV geometry in patients with treated essential hypertension and also suggest that the increase in PAC participates in the impairment of LV diastolic function apart from the concentric change in LV geometry, although concentric hypertrophy clearly impairs LV diastolic function. (Hypertens Res 2002; 25: 49-56)
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Atsushi HOZAWA, Takayoshi OHKUBO, Masahiro KIKUYA, Junko YAMAGUCHI, Ka ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
57-63
Published: 2002
Released on J-STAGE: July 09, 2002
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To assess blood pressure control in the Japanese population, we analyzed previously obtained measurements of conventional, home and ambulatory blood pressures in 1, 174 subjects aged ≥40 in a Japanese community. On the basis of conventional blood pressure values and the use of antihypertensive medication, participants were classified as normotensive, untreated hypertensive and treated hypertensive subjects. When 140⁄90, 135⁄85 and 135⁄85 mmHg were used as the hypertension criteria for conventional, home and ambulatory blood pressure measurements, respectively, all three blood pressure values were higher in untreated and treated hypertensive subjects than in normotensive subjects. Among the treated hypertensive subjects, approximately half were classified as hypertensive not only by conventional blood pressure, but also by home or ambulatory measurements. Approximately 10% of the subjects defined as normotensive by conventional blood pressure measurement were classified as hypertensive by home or ambulatory measurements, whereas 60% of the untreated hypertensive subjects as defined by conventional blood pressure measurement had normal home or ambulatory blood pressure values. Therefore, we concluded that 1) the poor blood pressure control in treated hypertensive subjects was attributable not only to the white coat effect but also to inadequate control of blood pressure; and 2) a certain percentage of subjects were misclassified as hypertensive or normotensive by conventional blood pressure measurement. (Hypertens Res 2002; 25: 57-63)
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Tomohiro NAKAYAMA, Masayoshi SOMA, Dolkun RAHMUTULA, Hideko TOBE, Mika ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
65-68
Published: 2002
Released on J-STAGE: July 09, 2002
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The purpose of this study was to investigate whether an association exists between the promoter region of the prostacyclin synthase gene and essential hypertension (EH). Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a novel single nucleotide polymorphism (SNP), T-192G, in the 5′-flanking region. We performed an association study using the SNP in 200 patients and 200 controls. The allele frequency distribution in the two groups was not significantly different. Thus, this SNP in the PGIS gene is not associated with EH. (Hypertens Res 2002; 25: 65-68)
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Toshio OGIHARA, Shigeto MORIMOTO, Kohya OKAISHI, Kunio HIWADA, Hiroaki ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
69-75
Published: 2002
Released on J-STAGE: July 09, 2002
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A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines. (Hypertens Res 2002; 25: 69-75)
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Yoko HOSOTANI, Norihiro TAKAHASHI, Hideyasu KIYOMOTO, Koji OHMORI, Hir ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
77-83
Published: 2002
Released on J-STAGE: July 09, 2002
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The recent development of contrast echography has made renal enhancement possible through an intravenous injection of microbubble-based contrast. In animal models, tissue perfusion can be quantified using contrast echography by measurement of the rate at which microbubbles replenish tissue after their ultrasound-induced destruction. Our purpose in this study was to evaluate renal blood flow with contrast echography in humans. To increase the sensitivity for microbubbles, we used a combination of power Doppler harmonic and intermittent imaging. The pulsing interval (PI) was changed from 10 cardiac cycles to 1 cardiac cycle during an intravenous infusion of the contrast agent, and alterations in the intensity of the renal cortex were represented as a decline ratio (DR). In 24 patients with various renal diseases, we were able to observe all 48 kidneys with adequate enhancement of the renal cortex. At PI of 10 cardiac cycles, the enhancement was homogeneous and strong, while, obviously, changing PI from 10 to 1 cardiac cycles caused a decline of enhancement. An excellent correlation was found between DR using contrast echography and renal plasma flow determined by clearance and radionuclide measurements. An excellent correlation was found between the DR values determined by contrast echography and the renal plasma flow values determined using clearance and radionuclide measurements. These results suggest that DR may be useful for evaluation of both total and split renal blood flow. Thus the contrast echographic method presented here could succeed in assessing renal cortical blood flow less invasively than conventional methods in humans. (Hypertens Res 2002; 25: 77-83)
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Tatsuyuki ONODERA, Fumiko OKAZAKI, Hidekazu MIYAZAKI, Shunrou MINAMI, ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
85-90
Published: 2002
Released on J-STAGE: July 09, 2002
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Studies have shown that the renin-angiotensin system (RAS) plays an important role in cardiac remodeling induced by hypertension. However, the role of this system on myocyte remodeling remains unclear. In the present study, we have assessed the effect of perindopril, an angiotensin converting enzyme (ACE) inhibitor, in spontaneously hypertensive rats (SHRs) as a means to evaluate the role of RAS in myocyte remodeling. We also investigated the effect of β blockade on myocyte remodeling. We used female SHRs at 12 weeks of age. They were divided into four experimental groups: a control group, group C; low dose perindopril group (0.3 mg⁄kg⁄day, p.o.), group PL; high dose perindopril group (3 mg⁄kg⁄day, p.o.), group PH; and bisoprolol group (60 mg⁄kg⁄day, p.o.), group B. We isolated myocytes from these rats after 4 weeks. LV myocyte volume and cross-sectional area decreased in groups PL and PH compared to group C. LV myocyte length decreased in group PH compared to group C. However, there was no morphological change in LV myocytes in group B compared to group C. In summary, ACE inhibitors reversed cardiac hypertrophy mainly by a reduction in LV myocyte volume; however, β blockade did not reverse myocyte remodeling. These results suggest that RAS plays an important role in myocyte remodeling in the hypertensive heart. (Hypertens Res 2002; 25: 85-90)
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Kaori SHINOMIYA, Megumu FUKUNAGA, Hideyasu KIYOMOTO, Katsufumi MIZUSHI ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
91-98
Published: 2002
Released on J-STAGE: July 09, 2002
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Diabetes mellitus (DM) is a well-established risk factor of cardiovascular diseases. We investigated the mechanism of the progression of arteriosclerosis in DM, focusing on the role of oxidative stress and insulin resistance in vivo. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 DM, were assigned to 3 groups, based on supplementation with vitamin E (VE) or troglitazone (TR), a VE-derived agent which improves insulin-resistance. At 36 weeks, plasma and aortic tissue 8-iso-PGF2α contents, a vascular proliferating eicosanoid produced in vivo by oxidative stress, were measured by EIA. TGF-β1 and TGF-β1 receptor II were immunohistochemically analyzed. Histopathologically, medial area and the nuclear number of smooth muscle cells of the aorta were measured. The tissue 8-iso-PGF2α content (pg⁄g tissue) was significantly decreased by either VE or TR in the aorta (untreated-OLETF, 15,332±3,254 vs. TR-treated-OLETF, 7,092±1,992 or VE-treated-OLETF, 5,394±836, both p<0.01), but that in plasma decreased by only VE. VE and TR improved the increased the level of the actual medial area and the number of smooth muscle cells. The expression of TGF-β1 was reduced, but TGF-β1 receptor II was not. 8-iso-PGF2α may play an important role in the progression of arteriosclerosis. Antioxidant treatment may promise significant clinical benefits in the early diabetic stage. (Hypertens Res 2002; 25: 91-98)
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Atsushi SUZUKI, Daiji KAGAWA, Ryuji OCHIAI, Ichiro TOKIMITSU, Ikuo SAI ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
99-107
Published: 2002
Released on J-STAGE: July 09, 2002
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The effects of a water-soluble green coffee bean extract (GCE) on blood pressure were investigated using spontaneously hypertensive rats (SHR). There was a dose-dependent reduction in blood pressure after a single ingestion (180 to 720 mg⁄kg, p.o.) or long-term ingestion (0.25 to 1% diet for 6 weeks) of GCE. A single oral ingestion (50 to 200 mg⁄kg) of 5-caffeoylquinic acid (5-CQA), the major component of GCE, dose-dependently decreased blood pressure, suggesting that 5-CQA is involved in the hypotensive effect of GCE in SHR. Because significant increases in caffeic acid (CA) or ferulic acid (FA) were detected in plasma after oral ingestion of 5-CQA in SHR, these acids (2.5, 5, 10 μmol⁄kg) were intravenously injected into SHR under anesthesia and the carotid arterial pressure was measured. Of the two components, FA had a stronger depressor effect than CA. The depressor effect of FA (50 mg⁄kg, p.o.) was attenuated by the concurrent injection of atropine sulfate (5 mg⁄kg, s.c.), suggesting that the hypotensive effect of FA in SHR might be mediated via the muscarinic acetylcholine receptors. These findings indicate that oral ingestion of GCE or 5-CQA decreases blood pressure in SHR, and that FA, which is a metabolite of 5-CQA, is a candidate hypotensive component. (Hypertens Res 2002; 25: 99-107)
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Yi-Mu LAI, Noboru FUKUDA, Jin-Zi SU, Ryo SUZUKI, Yukihiro IKEDA, Hirot ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
109-115
Published: 2002
Released on J-STAGE: July 09, 2002
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The calcium channel blocker amlodipine continues to be of interest due to its potential proven ability to hinder the progression of atherosclerosis and reduce the number of clinical ischemic events. Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) are useful in the study of atherosclerosis because they show exaggerated growth with production of angiotensin II (Ang II) by conversion to the synthetic phenotype. To clarify mechanisms of the antiproliferative effects of amlodipine, we evaluated effects of the expression of growth factors, the changes in phenotype, and the proliferation of VSMC from SHR. Amlodipine significantly inhibited basal DNA synthesis and proliferation of VSMC from SHR. Amlodipine also inhibited expression of platelet-derived growth factor (PDGF) A-chain, transforming growth factor β1 (TGF-β1) and basic fibroblast growth factor (bFGF) mRNAs in VSMC from SHR. Decreases in levels of PDGF A-chain and bFGF mRNAs in VSMC from SHR were greater with amlodipine than with nifedipine. Amlodipine significantly inhibited expression of the synthetic phenotype markers osteopontin and matrix Gla mRNAs, indicating that it inhibited the exaggerated growth of VSMC from SHR and suppressed the change from the contractile phenotype to the synthetic phenotype. Thus, amlodipine may be a beneficial therapeutic agent for patients with hypertensive vascular diseases. (Hypertens Res 2002; 25: 109-115)
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Yunzeng ZOU, Tsutomu YAMAZAKI, Keiichi NAKAGAWA, Haruyasu YAMADA, Nori ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
117-124
Published: 2002
Released on J-STAGE: July 09, 2002
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We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg⁄kg⁄day) from 12 to 24 weeks of age. Systolic blood pressure (BP) and heart rate were measured every week after the treatment using the tail-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BP, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity. (Hypertens Res 2002; 25: 117-124)
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Masahisa GOTO, Masashi MUKOYAMA, Akira SUGAWARA, Takayoshi SUGANAMI, M ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
125-133
Published: 2002
Released on J-STAGE: July 09, 2002
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Angiotensin II type 2 (AT2) receptor is developmentally regulated and exerts antiproliferative and proapoptotic actions. Genetic ablation of this receptor in mice affects regulation of blood pressure, but the involvement of the AT2 receptor in the pathogenesis of hypertension remains unknown. In the present study, we examined developmental changes of angiotensin receptor subtypes in the kidney of stroke-prone spontaneously hypertensive rats (SHRSP), and compared them with those in normotensive Wistar-Kyoto rats (WKY). We also investigated the regulation and functional role of the AT2 receptor in cultured mesangial cells. Receptor binding and Northern blot analyses revealed that AT2 receptor expression is significantly lower in the SHRSP kidney than in the WKY kidney during the perinatal period, while AT1 receptor expression is not different between them. In WKY mesangial cells, AT2 receptor stimulation exerted a potent antiproliferative effect; this effect was not observed in SHRSP cells lacking the AT2 receptor expression. The expression of interferon regulatory factor (IRF)-1 paralleled the growth-dependent induction of AT2 receptor in WKY mesangial cells, and transfection of IRF-1 antisense oligonucleotide significantly suppressed AT2 receptor expression, indicating IRF-1-dependent regulation of AT2 receptor expression in mesangial cells. However, this induction was inefficient in SHRSP cells. Thus, we found impaired AT2 receptor expression in the SHRSP kidney in vivo and in mesangial cells in vitro. The unbalanced expression of renal angiotensin receptor subtypes with exaggerated AT1 receptor signaling during early life in SHRSP may play a role in the programming for hypertension and related renal injury. (Hypertens Res 2002; 25: 125-133)
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Ken-ichi MIZUTANI, Ken SUGIMOTO, Tomohiko OKUDA, Tomohiro KATSUYA, Tos ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 1 Pages
135-140
Published: 2002
Released on J-STAGE: July 09, 2002
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The rostral ventrolateral medulla (RVLM) plays a critical role in the tonic and reflexive regulation of arterial blood pressure. Recent studies have demonstrated that injection of kynurenic acid (KYN) into the RVLM of spontaneously hypertensive rats (SHR) decreases arterial blood pressure. We hypothesized that a relative increase in the excitatory amino acid-mediated drive of RVLM vasomotor neurons in SHR may be due to derangement of one of the enzymes that affect the KYN level in the brain. We selected kynureninase, kynureninase hydroxylase, kynurenine aminotransferase type I, and kynurenine aminotransferase type II as candidates that may affect the KYN level in the brainstem. We conducted association studies between polymorphisms of these genes and blood pressure in an F2 population derived from SHR and Wistar-Kyoto rats (WKY). The cosegregation analysis indicated that only the kynureninase gene (KYNU) polymorphism influenced systolic blood pressure (SBP) and residuals of systolic blood pressure after adjusting for heart rate and body weight (RSBP). KYNU was found to be located on rat chromosome 3, and quantitative trait loci analysis at this locus indicated that the logarithms of the odds scores for KYNU in terms of SBP and RSBP were 2.0 and 3.3, respectively. This association with blood pressure decreased in proportion to the distance from KYNU. The expression level of KYNU mRNA in the brainstem was about 3.1 and 2.9 times higher in 10-week-old and 16-week-old SHR than in age-matched WKY, respectively. The increased expression of KYNU in SHR is thought to decrease the KYN level. KYNU seems to be one of the genes that contributes to hypertension in SHR. (Hypertens Res 2002; 25: 135-140)
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