Hypertension Research

Original Articles

Clinical studies

Role of Insulin Resistance in Nondipper Essential Hypertensive Patients

Futoshi ANAN, Naohiko TAKAHASHI, Tatsuhiko OOIE, Kunio YUFU, Tetsunori ...

2003 年 26 巻 9 号 p. 669-676
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.669

ジャーナルフリー

抄録を表示する抄録を非表示にする

In hypertensive patients, diminished nocturnal blood pressure (BP) fall is associated with poor prognosis for cardiovascular events. However, the relation of insulin resistance with the etiology of nondipper essential hypertension remains unclear. The aim of the present study was to assess the role of insulin resistance in diminished nocturnal BP fall, left ventricular hypertrophy (LVH), and increased plasma atrial (ANP) and brain natriuretic peptides (BNP) in essential hypertensive patients. One hundred and three patients with essential hypertension were divided into dippers (n =57; age: 57±5 years, mean±SD) or age-matched nondippers (n =46; 57±4 years), based on ambulatory BP (ABP) monitoring. Although the systolic and diastolic ABP values were similar during the day, those at night were higher in nondippers than in dippers (p <0.0001 for each). Echocardiographic findings revealed that the left ventricular mass index (LVMI) was higher in nondippers (p <0.0001). Plasma ANP and BNP were also higher in nondippers (p <0.0001 for each). Fasting plasma concentrations of glucose and insulin (p <0.0001 for each) and the homeostasis model assessment (HOMA) index (p <0.0001) were also higher in nondippers. Multivariate analysis revealed that systolic ABP at night was a significant factor for LVMI, ANP and BNP. In addition, the HOMA index was a significant factor for LVMI and BNP. These observations suggest that diminished nocturnal BP fall is closely related to the development of LVH with concomitant increase in BNP in essential hypertensive patients, and that insulin resistance may play a key role in these processes. (Hypertens Res 2003; 26: 669-676)

抄録全体を表示

PDF形式でダウンロード (58K)
Polymorphism of the Monocyte Chemoattractant Protein (MCP-1) Gene Is Associated with the Plasma Level of MCP-1 But Not with Carotid Intima-Media Thickness

Yasuharu TABARA, Katsuhiko KOHARA, Yoshikuni YAMAMOTO, Michiya IGASE, ...

2003 年 26 巻 9 号 p. 677-683
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.677

ジャーナルフリー

抄録を表示する抄録を非表示にする

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in atherosclerosis. Recently, single nucleotide polymorphisms (SNPs) in the MCP-1 regulatory region have been identified, and an in vitro study demonstrated that the SNP at position -2518 of the MCP-1 gene affected transcription of the gene. The purpose of this study was to clarify the association of the plasma level of MCP-1 and the SNP of the MCP-1 gene with carotid atherosclerosis in community-based subjects. The study subjects consisted of 325 community residents, aged 50 years or older (mean age, 70.5±9.4 years) and free from any cardiovascular complications. Carotid intima-media thickness (IMT) was measured in the right common carotid artery using ultrasonography. The plasma level of MCP-1 was measured by enzyme-linked immunosorbent assay (ELISA). The SNP of the MCP-1 gene was determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique. The plasma level of MCP-1 was significantly associated with IMT (r =0.12, p <0.05) and carotid arterial dimension (r =0.13, p <0.05). There was a significant difference in plasma MCP-1 level between the genotypes (AA, 166±36 ng/ml; GG+AG, 184±56 ng/ml; p =0.036). Analysis restricted to the subjects not receiving antihypertensive drugs or other medication further increased the statistical significance. However, carotid IMT and carotid arterial diameter were not significantly different among the MCP-1 genotypes. Stepwise regression analysis for plasma MCP-1 revealed that the MCP-1 genotype was an independent determinant of plasma MCP-1 level. These findings indicate that plasma MCP-1 is associated with carotid atherosclerosis. Although -2518 SNP is associated with the plasma level of MCP-1, it was not directly associated with carotid atherosclerosis. (Hypertens Res 2003; 26: 677-683)

抄録全体を表示

PDF形式でダウンロード (78K)
Epidemiological Evidence of an Association between SLC6A2 Gene Polymorphism and Hypertension

Koh ONO, Yoshitaka IWANAGA, Toshifumi MANNAMI, Yoshihiro KOKUBO, Hiton ...

2003 年 26 巻 9 号 p. 685-689
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.685

ジャーナルフリー

抄録を表示する抄録を非表示にする

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A>G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p =0.0223), age (p <0.0001), body mass index (p <0.0001), alcohol consumption (p =0.0002), and the Promoter 3 genotype (AA=1, AG+GG=2) (p =0.0090) were predictive of hypertensive status. The odds ratio of the AG+GG genotypes for hypertension was 1.35 (95% confidence interval: 1.08-1.69) over the AA genotype. SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure. (Hypertens Res 2003; 26: 685-689)

抄録全体を表示

PDF形式でダウンロード (33K)
Candesartan Reduces Oxidative Stress and Inflammation in Patients with Essential Hypertension

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

2003 年 26 巻 9 号 p. 691-697
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.691

ジャーナルフリー

抄録を表示する抄録を非表示にする

The present study was designed to test the hypothesis that blockade of angiotensin II type-1 receptors reduces oxidative stress and inflammation in patients with essential hypertension. The study population comprised 132 hypertensive patients, some receiving and others not receiving medical treatment. At enrollment their systolic and/or diastolic blood pressures were ≥140 and/or ≥90 mmHg, respectively. The serum concentration of C-reactive protein, and the urine concentrations of 8-epi-prostaglandin F_2α and 8-hydroxydeoxyguanosine were measured at baseline and after 12 weeks of treatment either with an angiotensin II type-1 receptor blocker, candesartan (8 mg daily) (age 64±12 years; male/female 28/39; n =67), or other antihypertensive agents that do not block the renin-angiotensin system (age 65±10 years, male/female 25/40, n =65). Candesartan reduced the levels of C-reactive protein (from 0.07±0.04 [median value ± median absolute deviation] to 0.06±0.03 mg/dl, p <0.0001), 8-epi-prostaglandin F_2α (from 210±92 to 148±59 pg/mg creatinine, p <0.0001), and 8-hydroxydeoxyguanosine (from 5.7±1.9 to 4.0±1.3 ng/mg creatinine, p <0.0001), while the levels of these markers were not altered after the treatment with other antihypertensive agents. Blood pressure decreased by a similar amount in both groups, and the reductions in the levels of the markers did not correlate with that of blood pressure. These results suggest that candesartan reduces oxidative stress and inflammation in hypertensive patients independently of its effects on blood pressure. This may provide useful information for determining therapeutic strategies to minimize tissue injury by inflammation and oxidative stress in hypertensive patients. (Hypertens Res 2003; 26: 691-697)

抄録全体を表示

PDF形式でダウンロード (86K)
Current Status of Lipid Management of Hypertensive Patients

Koichi MATSUBARA, Yasutaka YAMAMOTO, Kazuhiko SONOYAMA, Go IGAWA, Masa ...

2003 年 26 巻 9 号 p. 699-704
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.699

ジャーナルフリー

抄録を表示する抄録を非表示にする

Hypertensives, in addition to requiring strict blood pressure control, need lipid management to prevent cardiovascular disease. To assess the current status of lipid management of hypertensives, we reviewed the profiles of 830 hypertensives. The quality of lipid management was assessed using the Japan Atherosclerosis Society (JAS) Guideline for Diagnosis and Treatment of Hyperlipidemia in Japanese Adults announced in 1997. Hyperlipidemia was diagnosed in 45.2% of hypertensives and in 56.6% of patients in category C (a group of patients with coronary heart disease). Lipid-lowering drugs were used in 63.5% of all hypercholesterolemic patients and in 78.1% of category C patients. Statins were administered to more than 80% of hypercholesterolemic patients. Only 39.4% of hypertensives achieved the target total cholesterol level and only a very small percentage (17.1%) of patients in category C reached the target levels. The elderly hypertensives were the single largest group (42.2% of all hypertensives) in this study population, and the target cholesterol level for this group has been elevated from 200 mg/dl to 220 mg/dl in the JAS Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases announced in 2002 (new guidelines). In conclusion, in hypertensives requiring lipid management, the lipid-lowering approach appeared insufficient, as the target achievement rate was relatively low despite a high treatment rate. This was most marked for patients in category C. (Hypertens Res 2003; 26: 699-704)

抄録全体を表示

PDF形式でダウンロード (49K)
Role of Adiponectin in Insulin-Resistant Hypertension and Atherosclerosis

Hideyuki MURAKAMI, Nobuyuki URA, Masato FURUHASHI, Katsuhiro HIGASHIUR ...

2003 年 26 巻 9 号 p. 705-710
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.705

ジャーナルフリー

抄録を表示する抄録を非表示にする

Insulin resistance is one of the major risk factors associated with development of hypertension and atherosclerosis. Recent studies have shown that adiponectin, an adipocyte-derived hormone, may be involved in insulin resistance and development of atherosclerosis in diabetes patients. The aim of this study was to examine adiponectin levels in patients with essential hypertension to determine the relationships between adiponectin levels and insulin sensitivity and to examine the relationship of adiponectin with pulse wave velocity (PWV) in a general population based on the results of an epidemiological survey in Japan. In a clinical study, 20 normotensives (NT) and 30 non-treated essential hypertensives (EHT) were hospitalized, and euglycemic hyperinsulinemic glucose clamp (GC) was performed to evaluate insulin sensitivity defined as M value. EHT were divided into insulin-resistant EHT (EHT-R) and insulin-nonresistant EHT (EHT-N) according to the mean -1 SD of the M value of NT as a cut-off point. Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and adiponectin concentrations were measured. There were no significant differences in body mass index (BMI) or FPG among the NT, EHT-N, and EHT-R groups. The M value and adiponectin concentration in EHT-R were significantly lower than those in the NT or EHT-N. The IRI level in the EHT-R was significantly higher than those in the other groups. A positive correlation between adiponectin concentration and M value was found in all subjects, and adiponectin concentration and M value were found to be significant determinants of each other in multiple regression analysis. In an epidemiological study, we studied 391 male inhabitants of rural communities in Hokkaido, Japan. Systolic blood pressure (SBP), BMI, FPG, IRI, and adiponectin were measured in all subjects early in the morning. Homeostasis model assessment (HOMA) values were calculated as an index of insulin sensitivity, and PWV was used as an index of atherosclerosis. A negative correlation between HOMA values and adiponectin concentration was found in all of the subjects. Multiple regression analysis revealed that adiponectin was a significant determinant for PWV in subjects less than 70 years of age. The results of the clinical study indicate that EHT-R had not only hyperinsulinemia but also a low concentration of adiponectin. The results of multiple regression analysis for determinants of degree of PWV using data obtained in the epidemiological study suggest that adiponectin plays a role in anti-atherosclerosis, partly through improvement of insulin resistance. (Hypertens Res 2003; 26: 705-710)

抄録全体を表示

PDF形式でダウンロード (56K)
Relation between Blood Pressure Control, Body Mass Index, and Intensity of Medical Treatment

Ikuo SAITO, Kazuko MURATA, Hiroshi HIROSE, Minako TSUJIOKA, Hiroshi KA ...

2003 年 26 巻 9 号 p. 711-715
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.711

ジャーナルフリー

抄録を表示する抄録を非表示にする

A cross-sectional study was performed to assess the rates of blood pressure (BP) control to a systolic goal (<140 mmHg), to a diastolic goal (<90 mmHg), and to both in a sample of 226 treated hypertensive patients. We also examined the association between obesity, BP control, intensity of treatment defined as dose score (summed ranks of doses of all antihypertensive drugs taken), and number of drugs. Of the 226 treated patients (mean age, 60 years; 20.4% women), 67.7% were controlled to the systolic goal, 72.1% were controlled to the diastolic goal, and 53.5% were controlled to both. Patients were divided into four groups according to body mass index (BMI): less than 23, A; 23-24.9, B; 25-26.9, C; and 27 or more, D. There were no differences in the rates of BP control to the systolic goal, to the diastolic goal, or to both among the four groups; however, the dose score and number of drugs administered were higher in patients of group D than in those of the other groups. There was a tendency toward a higher intensity of drug treatment in obese patients with either controlled or uncontrolled BP. The dose score and number of drugs correlated positively with BMI. In representative subgroups (n =62), serum insulin and the homeostasis model assessment value of insulin resistance were higher in the patients in group D than in the other groups. These findings indicate that hypertensive patients managed in a hypertension clinic had satisfactory BP control in 53.5% of cases. A higher intensity of medical treatment is needed to achieve BP control in obese hypertensive patients characterized by insulin resistance. (Hypertens Res 2003; 26: 711-715)

抄録全体を表示

PDF形式でダウンロード (39K)
Trends in Blood Pressure Control in Hypertensive Patients with Diabetes Mellitus in Japan

Hiroshi HIROSE, Ikuo SAITO

2003 年 26 巻 9 号 p. 717-722
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.717

ジャーナルフリー

抄録を表示する抄録を非表示にする

Hypertension is often accompanied by type 2 diabetes mellitus. Recently, the American Diabetes Association (ADA) published guidelines on the treatment of hypertension in adult patients with diabetes mellitus. However, the views of general physicians on how to control blood pressure (BP) in diabetic patients and the impact of the ADA guidelines in Japan are still not known. We conducted an internet survey in May 2002: Questionnaires were e-mailed to a total of 3,616 medical doctors, of whom 441 (12.2%) properly responded. About half of the respondents (48.3%) had already read the ADA guidelines. Before being given an outline of the guidelines, the respondents’ average BP level for starting medication was 152/94 mmHg, and the BP goal 133/83 mmHg; after reading the outline, these values were 149/92 and 132/82 mmHg, respectively. The goal BP decreased more after reading the guidelines in doctors who had not previously read the ADA guidelines than in those who had already read. After being given an outline of the ADA guidelines, 40.3% of respondents reported that they would select, as a first-line agent, an angiotensin II receptor antagonist (ARB), 35.6% an angiotensin-converting enzyme inhibitor (ACEI), and 18.6% a calcium channel blocker (CCB); as a second-line medication, 39.7% of the respondents would select a CCB. Seventy percent of doctors reported having at least one patient receiving CCB monotherapy; after reading the guidelines, 41.5% of these doctors said they would continue CCB monotherapy, 36.6% said they would add an ACEI or ARB, and 29.7% planned to change to an ACEI or ARB. In conclusion, our data suggest the impact of the ADA guidelines on the target BP and the first choice of antihypertensive medication in diabetic patients. ARBs and ACEIs became first-line medications, and CCBs became second-line medications to achieve the BP goal and prevent organ damage. (Hypertens Res 2003; 26: 717-722)

抄録全体を表示

PDF形式でダウンロード (34K)

Experimental studies

Increased Expression of Plasminogen Activator Inhibitor-1 by Mediators of the Acute Phase Response: a Potential Progenitor of Vasculopathy in Hypertensives

Jie DONG, Satoshi FUJII, Daisuke GOTO, Tomoo FURUMOTO, Takeaki KANEKO, ...

2003 年 26 巻 9 号 p. 723-729
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.723

ジャーナルフリー

抄録を表示する抄録を非表示にする

Hypertension is an important risk factor for coronary atherosclerosis, which is accelerated by inflammation and diminished fibrinolysis. We have previously shown that levels of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis, are increased with atherogenic metabolic derangement. Because the liver is one of the major sources of circulating PAI-1, we here examined the effects of two proinflammatory cytokines, interleukin (IL)-1β and IL-6, on PAI-1 production in a human hepatoma cell line, HepG2. IL-1β (1 ng/ml) and IL-6 (1 ng/ml) increased the accumulation of PAI-1 in the conditioned media over 24 h (IL-1β: 2.1±0.2 (mean±SD) fold over the control; IL-6:1.4±0.2 fold; Western blot, p <0.05). The increase in PAI-1 protein accumulation correlated with the increased expression of PAI-1 mRNA (Northern blot). An HMG-CoA reductase inhibitor (mevastatin, 10μmol/l) attenuated the PAI-1 production induced by IL-1β and IL-6. The plasma PAI-1 activity level was higher in hypertensives than in normotensives (10.0±9.8 AU/ml vs. 6.2±4.5 AU/ml, p <0.05). The plasma PAI-1 antigen level was also higher in hypertensives than in normotensives (30.9±22.4 ng/ml vs. 24.4±13.3 ng/ml, p <0.05). Thus, 1) IL-1β and IL-6 can increase PAI-1 production in hepatic cells and 2) mevastatin may exert anti-thrombotic effects by decreasing the PAI-1 protein production induced by these proinflammatory cytokines. These results provide further insights into how inflammation is involved in the atherothrombotic complications observed in hypertensives, which may be ameliorated by HMG-CoA reductase inhibitors. (Hypertens Res 2003; 26: 723-729)

抄録全体を表示

PDF形式でダウンロード (95K)
Accelerated Cardiac Hypertrophy and Renal Damage Induced by Angiotensin II in Adrenomedullin Knockout Mice

Pei NIU, Takayuki SHINDO, Hiroshi IWATA, Aya EBIHARA, Yoshihiro SUEMAT ...

2003 年 26 巻 9 号 p. 731-736
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.731

ジャーナルフリー

抄録を表示する抄録を非表示にする

Adrenomedullin (AM) is a potent vasodilating and natriuretic peptide that is thought to play important roles in cardiovascular function. Whether or not AM is involved in the development of cardiac hypertrophy and renal damage remains controversial. In the present study, using heterozygote knockout mice of the AM gene (AM+/-), we analyzed the physiological and pathological roles of the endogenous AM gene. There were no differences in body size or heart and kidney weight compared with wild-type (AM+/+) mice. However, angiotensin II (Ang II) infusion resulted in more severe cardiac hypertrophy in AM+/- mice. The increases in the heart weight-to-body weight ratio and wall thickness of the left ventricle were more prominent in the AM+/- mice. Renal dysfunction characterized by decreased creatinine clearance (C_cr) was more severe in AM+/- after Ang II infusion. These results suggest that AM plays critical roles in the defense mechanism against cardiac hypertrophy and renal dysfunction. An improved understanding of these roles may pave the way to a novel pharmacological approach for the prevention of cardiovascular diseases. (Hypertens Res 2003; 26: 731-736)

抄録全体を表示

PDF形式でダウンロード (119K)
A Newly Developed Angiotensin II Type 1 Receptor Antagonist, CS866, Promotes Regression of Cardiac Hypertrophy by Reducing Integrin β₁ Expression

Nan JIA, Hiroshi OKAMOTO, Toshihiro SHIMIZU, Satoru CHIBA, Yutaka MATS ...

2003 年 26 巻 9 号 p. 737-742
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.737

ジャーナルフリー

抄録を表示する抄録を非表示にする

Previous studies have demonstrated that integrins link the extracellular matrix to the hypertrophic response pathway of cardiac myocytes in vitro. To examine the direct relation between integrin β₁ and cardiac hypertrophy in vivo, we studied the effects of a newly developed angiotensin II type 1 (AT₁) blocker, CS866 (ARB; 10 mg/kg/day), an angiotensin-converting enzyme inhibitor, temocapril (ACEI, 10 mg/kg/day), or both on modulation of integrin β₁ in the hypertrophied hearts of stroke-prone spontaneously hypertensive rats (SHRSP) 6 to 12 weeks of age. Treatments with ARB, ACEI, and combination therapy significantly reduced systolic blood pressure. However, the reduction in cardiac hypertrophy was greater in SHRSP treated with ARB or combination therapy than in those treated with ACEI. Multiplex reverse transcription-polymerase chain reaction revealed significantly higher mRNA expression of atrial natriuretic factor, AT₁ receptor, and integrin β₁ in untreated SHRSP than in normotensive Wistar-Kyoto rats (WKY). The mRNA levels of ANP, AT₁ receptor, and integrin β₁ in SHRSP were significantly decreased by treatment with ARB, ACEI, or combination therapy. Decreased mRNA expression of ANP, AT₁ receptor, and integrin β₁ in the treated SHRSP was associated with reductions in blood pressure; ARB and combination therapy produced greater decreases in expression than did ACEI. These observations suggest that CS866 has a beneficial effect on myocyte hypertrophy and that down-regulation of AT₁ receptor and suppression of integrin β₁ participate in the regression of pressure-induced cardiac hypertrophy in vivo. The correlation between the expression of integrin β₁ and AT₁ receptor was significant. Our results also suggest that integrin expression by myocytes might be modulated by angiotensin II via AT₁ receptor. (Hypertens Res 2003; 26: 737-742)

抄録全体を表示

PDF形式でダウンロード (116K)
Neuronal Ca²⁺ Channel Blocking Action of an Antihypertensive Drug, Cilnidipine, in IMR-32 Human Neuroblastoma Cells

Akira TAKAHARA, Shin-ichi FUJITA, Keiko MOKI, Yukitsugu ONO, Hajime KO ...

2003 年 26 巻 9 号 p. 743-747
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.743

ジャーナルフリー

抄録を表示する抄録を非表示にする

Although the anti-sympathetic mechanisms of the antihypertensive drug cilnidipine have been analyzed in neuronal cells derived from rodents, there is little information regarding the effects of cilnidipine in human neuronal cells. We investigated the effects of cilnidipine on N-type Ca²⁺ channels in IMR-32 human neuroblastoma cells using fura-2-based microfluorimetry. The ratio of the intensities of the emitted fluorescence at an excitation wavelength of 340 nm to that at 380 nm was calibrated to estimate the intracellular concentration of Ca²⁺. Stimulation of IMR-32 cells by 40 mmol/l KCl immediately increased the intensities ratio. In the presence of 10 μmol/l of nifedipine to block L-type Ca²⁺ channels, ω-conotoxin GVIA, a selective N-type Ca²⁺ channel blocker, in a concentration of 1 μmol/l suppressed the elevation of the intensities ratio induced by 40 mmol/l KCl. Similarly, cilnidipine in a concentration of 10 μmol/l suppressed the elevation of the ratio induced by 40 mmol/l KCl, and this suppression was effectively inhibited after the treatment with ω-conotoxin GVIA. These results suggest that cilnidipine potentially inhibits N-type Ca²⁺ channels in human neuronal cells and might be applied as a prospective therapeutic tool to provide neuronal protection as well as its antihypertensive effects and anti-sympathetic actions. (Hypertens Res 2003; 26: 743-747)

抄録全体を表示

PDF形式でダウンロード (53K)
Effects of Angiotensin II on Nitric Oxide Generation in Proliferating and Quiescent Rat Coronary Microvascular Endothelial Cells

Ulvi BAYRAKTUTAN, Sibel ÜLKER

2003 年 26 巻 9 号 p. 749-757
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.749

ジャーナルフリー

抄録を表示する抄録を非表示にする

Nitric oxide (NO) and the mitogenic peptide angiotensin II (Ang II) have been implicated in endothelial cell growth. However, the putative relationship between these two opposing agents with respect to endothelial cell growth remains unknown. In this study, proliferating and confluent rat coronary microvascular endothelial cells (CMEC) were treated with different doses of Ang II, Ca²⁺ ionophore A23187, or valsartan (an Ang II type 1 (AT₁) receptor inhibitor) alone or in combination for 24 h before measuring the nitrite levels as an index of NO generation. NO production and endothelial NO synthase (eNOS) mRNA/protein expression were found to be 3-fold greater in proliferating vs. quiescent CMEC. Treatments of CMEC with Ang II or Ca²⁺ ionophore A23187 equally increased NO production without altering the fold-difference in the basal release of NO from proliferating vs. confluent CMEC. Valsartan abolished NO production in CMEC treated with Ang II but not Ca²⁺ ionophore A23187. Treatments of endothelium-intact vascular rings with Ang II (1 nmol/l to 10 μmol/l) plus valsartan or PD-123319, an Ang II type 2 (AT₂) receptor inhibitor, attenuated vascular responses to acetylcholine in an Ang II dose-dependent manner. In these rings, phenylephrine produced significant increases in contractile responses only at nmol/l concentrations of Ang II. In contrast, pharmacological and mechanical inactivation of endothelium enhanced contractile responses to phenylephrine at μmol/l concentrations of Ang II. These data demonstrate that Ang II stimulates NO production in CMEC in both an AT₁- and an AT₂ receptor-regulated manner, and that this stimulation of NO may be beneficial in counterbalancing the direct vasoconstrictor effect of Ang II on underlying smooth muscle cells. (Hypertens Res 2003; 26: 749-757)

抄録全体を表示

PDF形式でダウンロード (140K)
Human Chymase Expression in a Mice Induces Mild Hypertension with Left Ventricular Hypertrophy

Takafumi KOGA, Hidenori URATA, Yukiko INOUE, Takafumi HOSHINO, Takehir ...

2003 年 26 巻 9 号 p. 759-768
発行日: 2003年
公開日: 2004/05/21

DOIhttps://doi.org/10.1291/hypres.26.759

ジャーナルフリー

抄録を表示する抄録を非表示にする

A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken βactin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT₁) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT₁ receptor-dependent) with left ventricular hypertrophy (partially AT₁ receptor-dependent), and also chronic inflammatory changes (AT₁ receptor-independent). (Hypertens Res 2003; 26: 759-768)

抄録全体を表示

PDF形式でダウンロード (269K)

J-STAGEへの登録はこちら（無料）