Hypertension Research

Review

Molecular Analysis of the Structure and Function of the Angiotensin II Type 1 Receptor

Shin-ichiro MIURA, Keijiro SAKU, Sadashiva S KARNIK

2003 年 26 巻 12 号 p. 937-943
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.937

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The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of hypertension, cardiac hypertrophy, congestive heart failure, and coronary heart disease. Two distinct subtypes of Ang II receptor, type 1 (AT1) and type 2 (AT2), have been identified, and both have been shown to belong to the G-protein-coupled receptor superfamily (GPCRs). The recent Human Genome Project has revealed more than 1,000 transmembrane (TM) receptors that belong to this superfamily, and it has been estimated that 50% of all clinically used medicines modulate GPCRs activity. Recently, there have been many new insights regarding Ang II receptors and other GPCRs, such as on homo- and hetero-oligomerization, constitutive activation, movement of TM helices, internalization, desensitization and phosphorylation, trafficking, nuclear localization, intracellular protein-induced receptor activation, and receptor-associated proteins. Although AT1 receptor antagonists which prevent Ang II-induced signaling are already clinically available, we here summarize new findings regarding their structure and function, and the possibility of new therapeutic strategies for targeting Ang II receptors through molecular biological techniques. (Hypertens Res 2003; 26: 937-943)

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Original Articles

Clinical studies

Carotid Intima-Media Thickness Is Correlated with Impairment of Coronary Flow Reserve in Hypertensive Patients without Coronary Artery Disease

Shin TAKIUCHI, Hiromi RAKUGI, Hideki FUJII, Kei KAMIDE, Takeshi HORIO, ...

2003 年 26 巻 12 号 p. 945-951
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.945

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Hypertensive individuals occasionally experience angina-like chest pain despite having angiographically normal coronary arteries, and the etiology of this phenomenon has been suggested to be associated with depressed coronary flow reserve (CFR). Carotid intima-media thickness (IMT) assessed by ultrasound is correlated with not only cerebrovascular disease but also coronary artery disease and left ventricular hypertrophy (LVH). The aim of our study was to investigate the association between CFR and carotid IMT in patients with essential hypertension. We performed transthoracic Doppler recording of diastolic coronary flow velocity in the left anterior descending coronary artery at baseline and after maximal vasodilation by adenosine triphosphate infusion in 24 normotensive subjects and 125 hypertensive patients. CFR was defined as the ratio of hyperemic to basal averaged peak coronary flow velocity. Common cardiovascular risk factors, left ventricular mass index (LVMI), relative wall thickness (RWT), and carotid IMT were evaluated. The CFR of hypertensive patients (2.55±0.52) was significantly decreased compared with that of normotensive subjects (3.15±0.45). CFR showed a significant correlation with age, systolic blood pressure, RWT, and carotid IMT. Stepwise regression analysis revealed that, among carotid IMT, LVMI and RWT, only carotid IMT was a strong and independent parameter for predicting CFR in hypertensive patients. In conclusion, B-mode ultrasound scanning of the carotid artery seemed to be of clinical value in the screening of patients with LVH and impaired microcoronary circulation. These associations may explain the links between cardiac and cerebrovascular involvements in patients with hypertension. (Hypertens Res 2003; 26: 945-951)

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Vitamin C Improves Attenuated Angiotensin II-Induced Endothelium-Dependent Vasodilation in Human Forearm Vessels

Yoshitaka HIROOKA, Kenichi ESHIMA, Soko SETOGUCHI, Takuya KISHI, Kensu ...

2003 年 26 巻 12 号 p. 953-959
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.953

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Endothelial dysfunction might be related to an increase in superoxide anion production in patients with hypertension, hypercholesterolemia, diabetes mellitus, and heart failure. Studies in animal models indicate that angiotensin II increases superoxide anion production by vascular tissues. We examined whether angiotensin II attenuates endothelium-dependent vasodilation via an increase in superoxide anion production in human forearm vessels in vivo. Forearm blood flow was measured in 23 healthy young men. We examined forearm vasodilator responses to an intra-arterial infusion of acetylcholine (4, 8, and 16 μg/min) and sodium nitroprusside (0.8, 1.6, and 3.2μg/min) before and during an intra-arterial infusion of angiotensin II (n =8), angiotensin II plus vitamin C (n =8), and vitamin C alone (n =4). Angiotensin II attenuated the forearm vasodilatory response to acetylcholine (p <0.05), and this attenuated response was abolished by vitamin C. Angiotensin II did not alter the forearm vasodilatory response to sodium nitroprusside, and vitamin C infusion did not affect the forearm vasodilatory response to either acetylcholine or sodium nitroprusside. The forearm vasodilator response to acetylcholine did not change during infusion of norepinephrine (n =3), which reduced forearm blood flow to a degree similar to that by angiotensin II infusion. These results suggest that angiotensin II attenuates endothelium-dependent forearm vasodilation, and vitamin C improves this impairment. Thus, angiotensin II likely attenuates endothelium-dependent vasodilation via an increase of superoxide anion production in the human forearm in vivo. (Hypertens Res 2003; 26: 953-959)

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Relation between Blood Pressure and Rhinitis in a Japanese Adolescent Population

Ikuo SAITO, Masaaki MORI, Hirotaka SHIBATA, Hiroshi HIROSE, Minako TSU ...

2003 年 26 巻 12 号 p. 961-963
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.961

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Recent studies have reported an association between systolic blood pressure (BP) and rhinitis. The prevalence of allergic rhinitis is 20% to 30% in Japan. The present cross-sectional study was performed to assess the relation between BP and allergic rhinitis in a sample of 2,292 male adolescent high school students who attended the annual school health examination. Of the 2,292 students (mean age, 16 years), 26.6% were considered to have allergic rhinitis based on their responses to a questionnaire, 25.1% were diagnosed with allergic rhinitis by an otolaryngologist, and 12.6% were consistently diagnosed with allergic rhinitis by both questionnaire and an otolaryngologist. There was no difference in systolic BP between subjects with and without allergic rhinitis. Diastolic BP, however, was higher in subjects without allergic rhinitis than in those with allergic rhinitis as diagnosed by questionnaire alone or by both questionnaire and an otolaryngologist. When the subjects were divided into three BP categories (normal, high normal, and hypertension) according to the criteria in the JSH 2000, the rates of allergic rhinitis were similar in the three BP categories. These findings do not confirm a relation between allergic rhinitis and systolic BP. (Hypertens Res 2003; 26: 961-963)

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Effects of Radiation on Fatty Liver and Metabolic Coronary Risk Factors among Atomic Bomb Survivors in Nagasaki

Masazumi AKAHOSHI, Yasuko AMASAKI, Midori SODA, Ayumi HIDA, Misa IMAIZ ...

2003 年 26 巻 12 号 p. 965-970
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.965

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In order to clarify the basic mechanism(s) linking radiation exposure and coronary heart disease (CHD), we here collected ultrasonographic data on fatty liver and measured levels of metabolic CHD risk factors from November 1990 through October 1992 in 1,517 Nagasaki atomic bomb survivors (575 men and 942 women). Using a cross-sectional study design, we examined the effects of radiation dose on fatty liver and CHD risk factors by means of a multiple logistic regression model. Fatty liver was related to the metabolic CHD risk factors associated with insulin resistance syndrome: obesity, hypertension, hypercholesterolemia, low high density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, and abnormal glucose metabolism. Radiation dose was positively related to fatty liver, low HDL-cholesterol, and hypertriglyceridemia, whereas it had no effects on obesity, hypertension, hypercholesterolemia, or abnormal glucose metabolism. The present results suggested that radiation dose was related to 1) fatty liver, which clustered the metabolic CHD risk factors associated with insulin resistance syndrome and 2) atherogenic lipid profiles. It is suggested that these associations are involved in the basic mechanism(s) linking radiation exposure and CHD. (Hypertens Res 2003; 26: 965-970)

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Association between Left Ventricular Diastolic Dysfunction and Renal Hemodynamic Change in Patients with Treated Essential Hypertension

Chinami OGATA, Takeshi HORIO, Kei KAMIDE, Shin TAKIUCHI, Yuhei KAWANO

2003 年 26 巻 12 号 p. 971-978
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.971

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The heart and kidneys are important target organs in hypertension. Early signs of hypertensive target organ damage can be detected by evaluating left ventricular (LV) diastolic function and intrarenal hemodynamics using Doppler ultrasonography. However, it has not been sufficiently clarified whether cardiac damage and renal impairment progress in parallel, especially from the early stage. In the present study, Doppler echocardiography and renal Doppler ultrasonography were performed in 99 patients with treated essential hypertension, and LV diastolic filling parameters, i.e., the velocity ratio of atrial filling to early diastolic filling (A/E), and the deceleration time of the E wave (DcT) and renal Doppler parameters, i.e., the diastolic to systolic ratio (D/S) and resistance index (RI), were determined. D/S was negatively correlated and RI was positively correlated with A/E and DcT. These cardiac and renal Doppler parameters were also associated with age, diastolic blood pressure, creatinine clearance, and/or glucose levels. By multiple regression analysis, D/S was found to have a significant association with DcT, independent of other clinical parameters, including age. In subgroup analysis in which patients were divided by their glucose tolerance, a significant correlation between renal Doppler parameters and LV diastolic function was observed in subjects with normal glucose tolerance, but this correlation disappeared in those with impaired glucose tolerance and diabetes mellitus. The present findings show that there is a significant relation between LV diastolic function and renal Doppler parameters in treated hypertensive patients, and suggest that cardiac damage progresses in parallel with renal involvement in these patients from the early stage. (Hypertens Res 2003; 26: 971-978)

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Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial of Cardiovascular Events in High-Risk Hypertensive Patients: Rationale, Design, and Methods

Tsuguya FUKUI, Mahbubur RAHMAN, Koichi HAYASHI, Kazuo TAKEDA, Jitsuo H ...

2003 年 26 巻 12 号 p. 979-990
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.979

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Hypertension continues to be a major public health issue in the world. To combat this problem, many antihypertensive drugs have been developed and proven effective at controlling blood pressure in the last half century. In recent decades, antihypertensive drugs have been shown to have cardiovascular benefits beyond the reduction of blood pressure, and the focus has shifted to clarification of these effects. Angiotensin II receptor antagonists and calcium channel blockers are the most widely used antihypertensive drugs in Japan. However, these two classes of drugs have not yet been compared with respect to their efficacy for treating cardiovascular events. The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial described herein is a prospective, multicenter, randomized, open-label, active-controlled, 2-arm parallel group comparison with a response-dependent dose titration and blinded assessment of endpoints in high-risk hypertensive patients treated with either an angiotensin II receptor antagonist (candesartan cilexetil) or a third-generation calcium channel blocker (amlodipine besilate). The eligibility criteria in this study were 1) age between 20 and 85 years; 2) systolic blood pressure (SBP) ≥140 mmHg in those below 70 years of age or ≥160 mmHg in those above 70 years of age or diastolic blood pressure (DBP) ≥90 mmHg on two consecutive measurements at clinic; and 3) at least one of the following high risk factors for cardiovascular events: a) SBP ≥180 mmHg or DBP ≥110 mmHg on two consecutive visits, b) type 2 diabetes mellitus (fasting blood glucose ≥126 mg/dl, casual blood glucose ≥200 mg/dl, HbA1c ≥6.5%, 2 h blood glucose on 75 g oral glucose tolerance test (OGTT) ≥200 mg/dl, or current treatment with hypoglycemic therapy), c) history of cerebral hemorrhage, cerebral infarction, or transient ischemic attack until 6 months prior to the screening, d) left ventricular hypertrophy on either echocardiography or ECG, angina pectoris, or history of myocardial infarction until 6 months prior to screening, e) proteinuria or serum creatinine ≥1.3 mg/dl, and f) symptoms of arteriosclerotic artery obstruction. The therapeutic goals of blood pressure control were set as follows: SBP<130 mmHg and DBP<85 mmHg for patients below 60 years of age, SBP<140 mmHg and DBP<90 mmHg for those in their 60 s, SBP<150 mmHg and DBP<90 mmHg for those in their 70 s, and SBP<160 mmHg and DBP<90 mmHg for those in their 80 s. A total of 3,200 patients, equally allocated to each of the two treatment arms, were required based on a two-sided α level 0.05 and 90% power. The CASE-J is also the first study to employ the newly developed Automatic Bar Code Data-Capturing/Allocation, Booking & Trial Coding, Data Management^TM (ABCD^TM) system for data collection and management. Enrollment of patients started in September 2001 and ended in December 2002. Follow-up data will be collected every 6 months until December 2005. The CASE-J trial will provide important evidence on the comparative effectiveness of candesartan cilexetil and amlodipine besilate on cardiovascular morbidity and mortality among Japanese. In addition, the use of the ABCD^TM system is expected to contribute to the development of more efficient data management systems for large-scale clinical trials. (Hypertens Res 2003; 26: 979-990)

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Experimental studies

Reduced Endothelial Vasomotor Function and Enhanced Neointimal Formation after Vascular Injury in a Rat Model of Blood Pressure Lability

Masato ETO, Kenji TOBA, Masahiro AKISHITA, Koichi KOZAKI, Tokumitsu WA ...

2003 年 26 巻 12 号 p. 991-998
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.991

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Increased short-term blood pressure variability is known to be associated with hypertensive target organ damage. Sinoaortic denervation (SAD) induces a marked increase in blood pressure lability without affecting the average blood pressure level. The aim of this study was to investigate the effects of blood pressure lability on endothelial vasomotor function and neointimal formation after balloon injury in SAD rats. Direct long-term measurement of mean arterial pressure showed no significant difference in the average of mean arterial pressure between the SAD group and sham-operated control group. In contrast, the standard deviation of mean arterial pressure, as an index of blood pressure lability, was 3-fold greater in SAD rats. To study endothelial function, isometric tension of aortic rings was measured 4 weeks after SAD or sham operation. Endothelium-dependent vasorelaxation induced by acetylcholine was significantly reduced in the SAD group (20% reduction at maximum relaxation). Endothelium-independent vasorelaxation induced by sodium nitroprusside was similar in each group. Acetylcholine-induced NO release from aortic rings was significantly reduced in the SAD group. Next, we examined neointimal formation in carotid arteries in SAD and sham-operated rats at 2 weeks after balloon injury. The neointimal-to-medial area ratio in the SAD group was 50% higher than that in the sham-operated group. The percentage of proliferating cell nuclear antigen-positive cells in the intima was significantly higher in the SAD group. These findings suggest that increased blood pressure lability, independently of average blood pressure level, impairs endothelial function by inhibiting NO production, enhances neointimal formation after balloon injury, and may thereby contribute to atherogenesis. (Hypertens Res 2003; 26: 991-998)

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Activation of Protein Kinase C and Nicotinamide Adenine Dinucleotide Phosphate Oxidase in Leukocytes of Spontaneously Hypertensive Rats

Kensaku MAEDA, Kenichi YASUNARI, Eisuke F SATO, Junichi YOSHIKAWA, Mas ...

2003 年 26 巻 12 号 p. 999-1006
発行日: 2003年
公開日: 2004/07/07

DOIhttps://doi.org/10.1291/hypres.26.999

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The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase Cα(PKCα), but not PKCβI or βII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCα and p47phox. (Hypertens Res 2003; 26: 999-1006)

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