Hypertension Research
Online ISSN : 1348-4214
Print ISSN : 0916-9636
ISSN-L : 0916-9636
Volume 27, Issue 5
May
Displaying 1-10 of 10 articles from this issue
Review
  • Atsuhisa SATO, Takao SARUTA
    2004 Volume 27 Issue 5 Pages 303-310
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    In recent years, it has been clarified that aldosterone can directly damage various organs, such as the heart, blood vessel, and kidneys, via non-epithelial mineralocorticoid receptors, independent of changes in blood pressure. Anti-aldosterone drugs have been clinically reported to be useful for their organ-protecting effects. The fact that these effects have been considered important for almost 10 years seems to indicate that aldosterone-induced organ damage can develop as a consequence of plasma aldosterone levels being in disproportion to salt status. In a previous study, cardiac fibrosis could not be induced in an experimental model of hyperaldosteronism with a low-salt diet. It is, therefore, extremely important to understand the relationship between plasma aldosterone level and inappropriate salt balance when considering diseases or states for which an anti-aldosterone drug is called for. In this paper we review the fundamental and clinical studies reported to date, mainly to investigate the pathology of organ damage induced by aldosterone and excess salt. Aldosterone-induced direct organ damage mediated through vasculitis essentially requires salt, which is inappropriate for plasma aldosterone level, and studies performed from this standpoint may provide a clue to the clarification of the involvement of salt in the actions of aldosterone via non-epithelial mineralocorticoid receptors. In humans, it is also strongly suggested that organ damage may occur, even at a plasma aldosterone level within a normal range, if salt intake is imbalanced to the aldosterone level. This means that the new aldosterone blocker eplerenone may also have significance as a drug inhibiting inflammation, possibly serving as a trigger of organ damage. (Hypertens Res 2004; 27: 303-310)
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Original Articles
Clinical studies
  • Tatsuya TAGAWA, Yoshitoshi URABE, Yoshikuni KIMURA, Satoshi SUZUKI, Hi ...
    2004 Volume 27 Issue 5 Pages 311-318
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Recent studies have shown that endothelial function is impaired in patients with coronary artery disease (CAD). Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and may improve endothelial function. The aim of this study was to evaluate the effects of probucol on endothelial function in patients with CAD. We evaluated endothelial function, based on flow-mediated vasodilation during reactive hyperemia (FMD), and the intima-media thickness (IMT) of the common carotid artery using high resolution ultrasonography in patients either with (CAD group, n =26) or without CAD (Control group, n =12). We measured the serum cholesterol concentration, including the low-density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA). Measurements of FMD and serum cholesterol were repeated after 3 months of probucol (500 mg/day, n =9) or placebo (n =9) treatment in patients with CAD. The IMT was significantly greater (p <0.001) and FMD was significantly lower (p <0.001) in the CAD group than in the Control group. While the serum cholesterol concentration and plasma ADMA were similar in the two groups, the plasma homocyst(e)ine concentrations were higher in the CAD group than in the Control group (p <0.01). After probucol therapy, FMD was significantly improved in the CAD group (p <0.05). The serum LDL-cholesterol concentration did not significantly decrease after probucol treatment. Placebo treatment did not alter FMD or the serum cholesterol concentration. Our findings suggest that long-term treatment with probucol improves endothelial function in patients with CAD, an outcome independent of the LDL-cholesterol-lowering effects of probucol, and that homocyst(e)ine may be a better predictor of atherosclerosis than ADMA. (Hypertens Res 2004; 27: 311-318)
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  • Hidekatsu NAKASHIMA, Ryoji OZONO, Chizuko SUYAMA, Taijiro SUEDA, Masay ...
    2004 Volume 27 Issue 5 Pages 319-325
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Aging is a major risk factor for cardiovascular disease. Chronological aging does not always parallel biological aging, but there is no reliable biomarker for the latter. In the present study, we tested the hypothesis that telomere attrition in white blood cells is related to endothelial dysfunction and the extent of atherosclerosis, and thus may serve as a useful marker for biological aging. We evaluated telomere lengths in white blood cells by measuring the mean telomere restriction fragment length (mTRFL), as well as endothelial function by flow mediated dilatation (FMD) in the brachial artery, in patients with various degrees of cardiovascular damage and in normal subjects. Cardiovascular damage was assessed by a cardiovascular damage (CVD) score, with 1 point being given for the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and diabetes) and for each event (angina, myocardial infarction, cerebrovascular event and peripheral vascular disease). Subset analysis of CVD score groups revealed that mTRFL and FMD decreased in the rank order of CVD score. Although mTRFL was inversely correlated with age, telomere index, defined as the ratio of TRFL to TRFL predicted by age, also decreased with increase in CVD score. These results indicate that telomere attrition in white blood cells is more closely associated with endothelial damage and atherosclerosis than is chronological aging, supporting the hypothesis that mTRFL in white blood cells is a useful marker for biological aging of the cardiovascular system. (Hypertens Res 2004; 27: 319-325)
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  • Naomi TAGO, Yoshihiro KOKUBO, Nozomu INAMOTO, Hiroaki NARABA, Hitonobu ...
    2004 Volume 27 Issue 5 Pages 327-331
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Although Gitelman’s syndrome (GS) is considered a rare disorder, it is an autosomal recessive phenotype and the frequency of heterozygote subjects might be higher than suspected. The purpose of this study was to assess the prevalence of GS in Japanese and the effects of heterozygous GS mutations on blood pressure levels. We used the TaqMan system to detect 9 Gitelman’s syndrome mutations in SLC12A3 that have been reported in Japanese. We then conducted association studies between these mutations and blood pressure in 1,852 subjects recruited from the Suita study, representing the general population in Japan. Among these 1,852 subjects, we detected the T180K, A569V, L623P, R642C, and L849H heterozygote genotypes in 56, 14, 1, 1, and 47 subjects, respectively. The overall frequency of GS mutations was (56+14+1+1+47) / (1,852×2)=0.0321, which was much higher than suspected. This means we should expect to find one subject with a heterozygous GS mutation among 15.6 Japanese or that we should find 10.3 GS subjects among 10,000 Japanese. Although the blood pressure levels of subjects heterozygous for the T180K, A569V, or L849H genotype were not significantly different from those of wild-type subjects, urine pH in subjects with GS mutations was significantly higher than that in subjects without mutations. In conclusion, GS could be one of the major causes of low blood pressure in Japanese. (Hypertens Res 2004; 27: 327-331)
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  • Kei KAMIDE, Chihiro TANAKA, Shin TAKIUCHI, Yoshikazu MIWA, Masayoshi Y ...
    2004 Volume 27 Issue 5 Pages 333-338
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Liddle’s syndrome is an autosomal dominant disease characterized by sodium-sensitive early hypertension and mutations in either the β- or γ-subunit of the amiloride-sensitive epithelial sodium channel encoded by SCNN1B and SCNN1G. We sequenced the 381 bp-coding regions in exon 13 of SCNN1B and the 381 bp-coding regions in exon 12 of SCNN1G in 948 and 953 Japanese patients with hypertension, respectively. In the SCNN1B gene, we identified three missense mutations, P592S (n =3), T594M (n =2), and E632K (n =1) in a heterozygous state in addition to four synonymous ones, Ile515 (n =1), Ser520 (n =19), Ser533 (n =1), and Thr594 (n =11). In the SCNN1G gene, we identified three missense mutations, A578V (n =1), P603S (n =1), and L609F (n =1) in a heterozygous state in addition to two synonymous ones, Ile550 (n =1) and Leu649 (n =91, heterozygous; n =2, homozygous). We did not identify the same mutations previously reported in Liddle’s syndrome kindreds. Two of the six hypertensive patients with missense mutation in the SCNN1B gene showed atypical renin and aldosterone levels, though one of them was diagnosed with renovascular hypertension. One patient with T594M in the SCNN1B gene was resistant to hypertension. The roles of these missense mutations in the SCNN1B or SCNN1G gene identified in hypertensive patients are not clear in the pathogenesis of hypertension and the regulation of electrolytes. Thus, further investigation of these mutations, including functional analyses, will be needed. (Hypertens Res 2004; 27: 333-338)
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  • Jin Gang YANG, Dayi HU, Tianchang LI, Jianjun PENG, Hong YU, Wenyue PA ...
    2004 Volume 27 Issue 5 Pages 339-344
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    The efficacy of angiotensin converting enzyme (ACE) inhibitors in treatment of renovascular disease has been controversial. It has been reported that patients with incidental atherosclerotic renal artery stenosis (ARAS) are sometimes treated with ACE inhibitors before being considered for renal revascularization. This study was designed to describe the frequency and the characteristics of patients with incidental ARAS, and to examine the frequency of ACE inhibitor usage in such patients. We studied a cohort of consecutive patients undergoing abdominal aortography at the time of cardiac catheterization. Patients were stratified and compared based on the presence and severity of ARAS. ARAS (≥50%) was present in 146 (17.0%) of 859 evaluable patients. Factors independently related to the presence of ARAS were age (odds ratio (OR)=1.07, p <0.001), severity of coronary artery disease (OR=2.13, p <0.001) and peripheral vascular disease (OR=1.79, p =0.021). Among all patients with ARAS, the percentage of ACE inhibitor usage was 74.7% (109/146). Among patients with severe ARAS, moderate ARAS, mild ARAS, insignificant ARAS and normal renal arteries, the percentage of ACE inhibitor usage was 85.7% (95% confidence interval (CI): 69-100%), 82.9% (95% CI: 71-95%), 68.5% (95% CI: 59-78%), 68.6% (95% CI: 55-82%) and 53.9% (95% CI: 50-58%), respectively (contingency coefficient=0.17, p <0.001). In patients with severe ARAS, ACE inhibitor use, calcium channel blocker use and diuretic use were shown to correlate significantly with serum creatinine levels after controlling for potential confounding factors. In this study, ACE inhibitors were used commonly in patients with incidental ARAS; the frequency of ACE inhibitor use correlated with the severity of ARAS. (Hypertens Res 2004; 27: 339-344)
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  • Noriko KISHIMOTO, Yasukiyo MORI, Takashi NISHIUE, Atsuko NOSE, Yasuaki ...
    2004 Volume 27 Issue 5 Pages 345-349
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    An increase in renal blood flow with a concomitant decrease in filtration fraction at the onset of angiotensin II receptor blocker treatment has been shown to predict a long-term renoprotective effect. However, no studies are available regarding angiotensin receptor blocker-induced changes in renal cortical perfusion observed in the clinical setting. We have recently developed a convenient method of evaluating human renal cortical blood flow with contrast-enhanced harmonic ultrasonography. The goal of this study was to use this method to examine the effect of valsartan, an angiotensin II receptor blocker, on renal cortical perfusion. We performed intermittent second harmonic imaging with venous infusion of a microbubble contrast agent in 7 healthy volunteers. Contrast-enhanced harmonic ultrasonography performed after oral administration of valsartan (80 mg) showed a significant increase in microbubble velocity, which correlated well with the increase in total renal blood flow determined by p-aminohippurate clearance (r =0.950, p <0.001). Although fractional vascular volume was not significantly increased, alterations in renal cortical blood flow calculated by the product of microbubble velocity and fractional volume were also correlated with the change in total renal blood flow (r =0.756, p <0.05). These results indicate that valsartan increases the renal cortical blood flow in normal kidneys, mainly by increasing blood flow velocity. Contrast-enhanced harmonic ultrasonography is a promising technique for evaluating the precise effect on renal cortical perfusion and optimal dose of valsartan in diseased kidneys. (Hypertens Res 2004; 27: 345-349)
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  • Shinichiro UEDA, Atsushi WADA, Satoshi UMEMURA
    2004 Volume 27 Issue 5 Pages 351-357
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    NG-methyl-L-arginine (L-NMMA) has been widely used for nitric oxide (NO) research, particularly for the assessment of NO-dependent vasodilatation evoked by agonists. However, such experiments may not be straightforward because L-NMMA causes vasoconstriction, which itself must non-specifically affect responses to any vasoactive agents. Therefore, in order to more accurately estimate the roles of NO in human vessels in vivo, we developed an NO clamp technique that uses co-infusion of an NO donor with L-NMMA. To assess the validity and feasibility of this technique, we compared the effects of intra-arterial infusion of L-NMMA on the forearm blood flow responses to vasodilators with and without the NO clamp technique in healthy males. All drugs were intra-arterially infused and changes in forearm blood flow (FBF) were measured by strain-gauge plethysmography. Vasodilatation evoked by atrial natriuretic peptide was significantly attenuated by L-NMMA alone (p =0.001) but not by the NO clamp technique. L-NMMA significantly attenuated the responses to acetylcholine either with or without the NO clamp technique. However, the ratio of the area under the curve (AUC) of acetylcholine with L-NMMA to that without L-NMMA was significantly higher when the NO clamp technique was not used (AUC ratio: 0.62±0.13 vs. 0.48±0.14, respectively; p =0.031). The contribution of NO to the FBF responses to vasodilators may be more properly assessed by the co-infusion of L-NMMA with the NO clamp technique than by L-NMMA alone. Our NO clamp technique thus appears to be valid and feasible for human NO research. (Hypertens Res 2004; 27: 351-357)
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Experimental studies
  • Hironori NAKAGAMI, Ryuichi MORISHITA, Tomoyuki NISHIKAWA, Hideo SHIMIZ ...
    2004 Volume 27 Issue 5 Pages 359-365
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Bag-1 is a novel multifunctional protein. It was identified based on its ability to bind the anti-apoptotic protein, bcl-2, and also reported to interact with the heat shock protein 70 kDa (Hsp70). Thus, bag-1 may modulate apoptosis and the chaperone activity. More interestingly, bag-1 can bind to several growth factor receptors or steroid hormone receptors and regulate their function and signaling. The receptor of hepatocyte growth factor (HGF), c-met, associated with bag-1 in a study measuring immunoprecipitation in endothelial cells, we decided to investigate the contribution of bag-1 to the anti-apoptotic action of HGF. Endogenous expression of bag-1 in endothelial cells was confirmed mainly in the cytosol fraction. The treatment of human recombinant HGF (rHGF) increased tyrosine kinase and ERK phosphorylation, whereas over-expression of bag-1 had no effect on this phosphorylation. In DNA synthesis as assessed by thymidine incorporation, over-expression of bag-1 also did not induce any additional increase. In contrast, in an assay of cell death as assessed by caspase activity and lactate dehydrogenase release, over-expression of bag-1 alone attenuated serum-free and tumor necrosis factor-α-induced cell death in endothelial cells. No synergistic effect was observed between bag-1 and rHGF. To further study the association of HGF and bag-1, we examined the effect of a deletion mutant of the bag-1 C-terminal region (CTR), because bag-1 CTR is necessary to bind to c-met. Unexpectedly, over-expression of bag-1 CTR also attenuated the endothelial cell death, similar to rHGF. Taken together, these results indicate that over-expression of bag-1 has an anti-apoptotic effect on endothelial cells independent of HGF signaling. (Hypertens Res 2004; 27: 359-365)
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  • Chihiro TANAKA, Kei KAMIDE, Shin TAKIUCHI, Yuhei KAWANO, Toshiyuki MIY ...
    2004 Volume 27 Issue 5 Pages 367-371
    Published: 2004
    Released on J-STAGE: August 01, 2005
    JOURNAL FREE ACCESS
    Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134 delA) located in the 5′-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo. (Hypertens Res 2004; 27: 367-371)
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