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Kazuo EGUCHI, Kazuomi KARIO, Kazuyuki SHIMADA
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
329-333
Published: 2002
Released on J-STAGE: December 24, 2002
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We studied differences in the effects of a long-acting angiotensin-converting enzyme (ACE) inhibitor (temocapril) and a long-acting calcium channel blocker (amlodipine) on ventricular ectopic beats (VEB) in relation to sympathetic nerve activity in 46 patients with essential hypertension. We performed 24-h Holter electrocardiography and ambulatory blood pressure (BP) monitoring simultaneously, and examined blood samples during the baseline, temocapril and amlodipine treatment periods. The ambulatory BP was lower in the amlodipine period than in the temocapril period. However, the number of VEB was significantly increased in the amlodipine period compared to that in the baseline period (11.9 vs. 7.4⁄day, p <0.05). In the temocapril period, the number of VEB was not significantly increased compared to that in the baseline period (8.6 vs. 7.4⁄day, p =0.30). Ambulatory heart rate (HR) was significantly increased in the amlodipine period compared to that in the baseline period (24-h HR: 70 vs. 66 bpm, p <0.001; daytime HR: 75 vs. 71 bpm, p <0.001; nocturnal HR: 60 vs. 58 bpm, p <0.05). Plasma norepinephrine (NE) also was significantly increased in the amlodipine period compared to that in the baseline period (457 vs. 369 pg⁄ml, p <0.001). However, when patients receiving amlodipine were divided into a high dose group (8.6±1.2 mg⁄day) and a low dose group (4.6±1.2 mg⁄day), increases in HR and plasma NE levels were found only in the high dose group. These results indicate that amlodipine is effective at lowering BP in older hypertensives, although it may increase VEB, especially when given at a high dose. (Hypertens Res 2002; 25: 329-333)
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Takako MIYAGI, Hiromi MURATANI, Yorio KIMURA, Koshiro FUKIYAMA, Yuhei ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
335-341
Published: 2002
Released on J-STAGE: December 24, 2002
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Higher pulse pressure is associated with higher cardiovascular risk. We investigated the relationship between pulse pressure and known metabolic risk factors in hypertensive patients who had not experienced stroke or myocardial infarction. In a multicenter cross-sectional survey made in 1995, we registered 939 hypertensive patients aged ≥50 years. Of these, 734 had never experienced stroke or myocardial infarction. We divided these 734 patients into two groups based on the value of their pulse pressures: 396 patients with a pulse pressure ≥60 mmHg, and 338 patients with a pulse pressure<60 mmHg. The average pulse pressure value was 72±12 mmHg in the former group, and 49±8 mmHg in the latter group. The former group exhibited advanced age, a higher women-to-men ratio, lower high-density lipoprotein (HDL) cholesterol, and higher systolic and lower diastolic blood pressure. Diabetes mellitus (DM) and left ventricular hypertrophy were more frequently noticed in the former group than in the latter group. The prevalence of hyperlipidemia, however, was similar in the two groups. The association of pulse pressure with DM and low HDL cholesterol was statistically significant by multiple logistic analysis adjusted for age, sex, and other known cardiovascular risk factors. In conclusion, pulse pressure increases with advancing age. DM made a substantially larger contribution to the increase in pulse pressure than hyperlipidemia. (Hypertens Res 2002; 25: 335-341)
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Masanori MUNAKATA, Yuki SAITO, Tohru NUNOKAWA, Nobuhiko ITO, Shin FUKU ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
343-349
Published: 2002
Released on J-STAGE: December 24, 2002
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The clinical significance of the pressor response triggered by blood pressure measurement, the so-called “white-coat effect, ” was studied in relation to left ventricular structure and function in patients with essential hypertension. We studied 75 consecutive, never-before treated patients with essential hypertension (54±2 (SE) years; 31 men). Beat-to-beat blood pressure (Finapres) was monitored at rest, during conventional blood pressure measurement by a doctor, and during a mental stress test. The left ventricular mass index and diastolic function (E⁄A ratio) were determined by echocardiography. The systolic blood pressure response triggered by the doctor’s visit (ΔSBP) correlated positively with the left ventricular mass index (r =0.326, p<0.03) and negatively with the E⁄A ratio (r =-0.325, p<0.02). A positive relationship between the ΔSBP and left ventricular mass index was observed in men (r =0.556, p<0.01) but not in women. The greater ΔSBP also was associated with lower E⁄A ratio in women (r =-0.434, p<0.02). The ΔSBP correlated with the mental stress-induced increase in systolic blood pressure in men (r =0.586, p<0.005) but not in women (r =0.148, n.s.). Blood pressures outside the clinic were higher in men than in women (p<0.05 for systolic and p<0.005 for diastolic) despite the similar level of clinic blood pressures between the sexes. Stepwise multiple linear regression analysis showed that the ΔSBP was an independent predictor of the left ventricular mass index in men (β=0.783, p =0.0009) and of the E⁄A ratio in women (β=-0.003, p =0.05). These data suggest that the pressor response triggered by a doctor’s visit has clinical significance in never-before treated hypertensive patients, possibly because it mirrors real-life stress reactivity in men. (Hypertens Res 2002; 25: 343-349)
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Tadahiro KUBO, Masaaki MIYATA, Shinichi MINAGOE, Shiro SETOYAMA, Ikuro ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
351-358
Published: 2002
Released on J-STAGE: December 24, 2002
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Recently, oscillometric devices have been developed that can measure blood pressure in the extremities and analyze pulse volume record. On the basis of the extremity pulse volume record, these devices can automatically determine three types of simply measured pulse wave velocity (PWV) (brachial PWV: heart to right upper arm; R-PWV: right upper arm-right ankle; and L-PWV: right upper arm-left ankle). The percent mean pulse volume record (%MPVR=the height that bisects the area of the pulse volume record⁄pulse pressure ×100), a quantitative index of right brachial pulse volume record, can also be determined. To evaluate the usefulness of these new indices, we studied 1, 067 consecutive subjects undergoing health checkups (648 men, 419 women; mean age, 50±9 years). In both sexes, age correlated positively with simply measured PWVs (men, brachial PWV: r =0.46, p<0.0001; R-PWV: r =0.46, p<0.0001; L-PWV: r =0.47, p<0.0001; women, brachial PWV: r =0.37, p<0.0001; R-PWV: r =0.47, p<0.0001; L-PWV: r =0.48, p<0.0001) and correlated negatively with %MPVR (men: r =-0.40, p<0.0001; women: r =-0.45, p<0.0001). Simply measured PWVs and %MPVR were significantly correlated with mean blood pressure. In a separate group of 60 patients, simply measured PWVs correlated positively with carotid PWV (heart to carotid) derived from an elastic vessel (brachial PWV: r =0.76, p<0.0001; R-PWV: r =0.43, p<0.01; L-PWV: r =0.43, p<0.01). %MPVR correlated negatively with carotid PWV (r =-0.35, p<0.01). In conclusion, simply measured PWVs and %MPVR are easier to determine than conventional PWV and may be useful as new indices of age-related changes in arterial distensibility. (Hypertens Res 2002; 25: 351-358)
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Akira YAMASHINA, Hirofumi TOMIYAMA, Kazuhiro TAKEDA, Hideichi TSUDA, T ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
359-364
Published: 2002
Released on J-STAGE: December 24, 2002
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The present study was conducted to evaluate the validity and reproducibility of noninvasive brachial-ankle pulse wave velocity (baPWV) measurements and to examine the alteration of baPWV in patients with coronary artery disease (CAD). Simultaneous recordings of baPWV by a simple, noninvasive method and aortic pulse wave velosity (PWV) using a catheter tip with pressure manometer were performed in 41 patients with CAD, vasospastic angina, or cardiomyopathy. In 32 subjects (15 controls and 17 patients with CAD), baPWV was recorded independently by two observers in a random manner. In 55 subjects (14 controls and 41 patients with CAD), baPWV was recorded twice by a single observer on different days. baPWV were compared among 172 patients with CAD (aged 62±8 years); 655 age-matched patients without CAD but with hypertension, diabetes mellitus, or dyslipidemia; and 595 age-matched healthy subjects without these risk factors. baPWV correlated well with aortic PWV (r =0.87, p<0.01). Pearson’s correlation coefficients of interobserver and intraobserver reproducibility were r =0.98 and r =0.87, respectively. The corresponding coefficients of variation were 8.4% and 10.0%. baPWV were significantly higher in CAD patients than in non-CAD patients with risk factors, for both genders (p<0.01). In addition, baPWV were higher in non-CAD patients with risk factors than in healthy subjects without risk factors. Thus, the validity and reproducibility of baPWV measurements are considerably high, and this method seems to be an acceptable marker reflecting vascular damages. baPWV measured by this simple, noninvasive method is suitable for screening vascular damages in a large population. (Hypertens Res 2002; 25: 359-364)
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Young-Keun ON, Cheol-Ho KIM, Byung-Hee OH, Myoung-Mook LEE, Young-Bae ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
365-371
Published: 2002
Released on J-STAGE: December 24, 2002
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The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(NG-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity. (Hypertens Res 2002; 25: 365-371)
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Rie SASAKI, Shigeru YAMANO, Yuta YAMAMOTO, Shigetoshi MINAMI, Junko YA ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
373-379
Published: 2002
Released on J-STAGE: December 24, 2002
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We examined whether hypertrophy of the carotid artery in patients with untreated essential hypertension is associated with compensatory carotid artery enlargement as these patients age. Carotid ultrasonography was evaluated in 163 patients with untreated essential hypertension (74 males and 89 females) and in 76 normotensive subjects. Intima-media end-diastolic thickness (IMT) and outer vessel diameter (VD) were measured, and relative wall thickness (IMT⁄R, R =VD⁄2) and vascular mass (VM) were calculated. Determinants of vascular hypertrophy in patients with untreated essential hypertension were also investigated. VD, VM, and IMT were significantly correlated with age in both the normotensive and hypertensive groups. Additionally, IMT was significantly correlated with VD in both groups. There was no correlation between increasing age and IMT⁄R in either group. IMT, VD and VM were significantly higher in the hypertensive group >50 years than in age-matched normotensive controls. However, IMT⁄R was significantly higher in the 50-59 years hypertensive group than in normotensive controls of the same age group. In addition to age, VM was related to systolic blood pressure, pulse pressure, fasting blood sugar, IMT, VD, and IMT⁄R in the hypertensive group. Multivariate regression analysis in the hypertensive group indicated that IMT⁄R was the strongest predictor of carotid vascular mass. Age and pulse pressure were also independently related to vascular mass. These results indicate that, as patients with untreated hypertension age, carotid arteries undergo remodeling. This should add further impetus to the implementation of appropriate hypertension treatment for such patients. (Hypertens Res 2002; 25: 373-379)
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Naoyuki HASEBE, Shinsuke KIDO, Akira IDO, Kenjiro KIKUCHI
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
381-387
Published: 2002
Released on J-STAGE: December 24, 2002
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The existence of the J-curve in hypertension treatment remains controversial. The major question is whether the increase in mortality from coronary disease is induced by the lowering of blood pressure (BP) or by the severity of underlying coronary artery disease. We recruited patients with a history of hypertension (systolic BP (SBP) >160 mmHg and⁄or diastolic BP (DBP) >90 mmHg) and a diagnosis of angina pectoris with angiographically confirmed coronary artery lesion. The relationship among the treated levels of SBP and DBP, the severity of coronary artery lesion, and the clinical consequences were investigated. Among the 234 enrolled patients, 115 experienced further events, 19 of which were serious. There were no significant differences in the average BP of patients with and those without events, but the coronary severity indices (CSI) were significantly greater in patients with events. As a function of DBP from ≤74 to 105≤mmHg, there was a positive association with the incidence of serious events, and a reversed J-curve in CSI with a nadir at 95-104 mmHg. A similar relationship was observed in SBP, but a potentially unfavorable outcome was suggested in the lowest SBP range of ≤124 mmHg. In conclusion, there was no J-curve for DBP in hypertensive patients with angina pectoris; rather, the lower the DBP, the better was the prognosis. Interestingly, the severity of coronary lesion is in a reversed J-curve relation with DBP, suggesting that high BP plays a critical role in serious events in hypertensive patients with moderate coronary artery lesions. (Hypertens Res 2002; 25: 381-387)
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Hyun-Young PARK, Toru NABIKA, Yangsoo JANG, Hyuck Moon KWON, Seung Yun ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
389-394
Published: 2002
Released on J-STAGE: December 24, 2002
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Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G-33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G-33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were divided into 3 groups according to the number of coronary arteries in which stenosis was found angiographically (1-vessel disease (1VD) to 3-vessel disease (3VD)). The criterion of coronary stenosis was 50% or more stenosis on angiography. In addition, 102 controls (CONT) who had no significant stenosis were employed. The number of AA⁄GA genotypes of G-33A was found to be significantly greater in the 1VD than in the CONT (p =0.004 by Χ2-test) while no significant difference was found between the multivessel disease (2-3VD) and the CONT. Multiple logistic analysis showed that G-33A was an independent risk factor for the 1VD with an odds ratio of 4.63 (95% confidence interval; 1.62-13.3). C1418T and C1922T were both in linkage disequilibrium with G-33A; however, they were not independent risks for either the 1VD or the 2-3VD. A reporter gene assay showed that G-33A had a significant effect on the TM promoter activity. These results indicated that G-33A polymorphism in TM might be a genetic risk factor for myocardial infarction. (Hypertens Res 2002; 25: 389-394)
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Tomohiro NAKAYAMA, Masayoshi SOMA, Yoshihiro MIZUTANI, Xu XINJUAN, Jun ...
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
395-401
Published: 2002
Released on J-STAGE: December 24, 2002
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The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We recently characterized the exon⁄intron organization of the human type A NP receptor (hNPRA) gene. The aim of this study was to isolate the genetic markers according to the organization of this gene, and to study the association between this gene and essential hypertension. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we identified a novel missense mutation, M341I, consisting of a methionine (ATG) to isoleucine (ATC) substitution at nucleotide 1023 in exon 3. Computer-aided three-dimensional structural analysis suggested that M341 exists in the loop between two α-helices, and that the mutation may influence receptor activities by altering the conformation of the α-helices. We performed an association study of the mutation in 210 essential hypertension (EH) patients and 210 normotensive controls. The overall distribution of alleles was not significantly different between the control and EH groups. However, the C⁄C homozygous genotype was found only in the EH group. The ratio of plasma brain natriuretic peptide (BNP)⁄mean blood pressure of the C⁄C genotype was significantly higher than that of the G⁄G genotype or the G⁄C genotype. We conclude that the significance of homozygous M341I mutation in exon 3 is worth investigating for its possible association with EH. (Hypertens Res 2002; 25: 395-401)
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Junko MIYAZATO, Takeshi HORIO, Shuichi TAKISHITA, Yuhei KAWANO
Article type: Original Article
Subject area: Clinical studies
2002 Volume 25 Issue 3 Pages
403-409
Published: 2002
Released on J-STAGE: December 24, 2002
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Left ventricular (LV) hypertrophy and LV diastolic dysfunction are common cardiac changes in hypertensive patients, and these changes are modified by various factors other than blood pressure. The present study was conducted to investigate the influence of mild abnormalities in glucose metabolism on LV structure and function in essential hypertension. In 193 nondiabetic patients with treated essential hypertension, two-dimensional and Doppler echocardiographic examinations were performed, and relative wall thickness (RWT), LV mass index (LVMI), fractional shortening, and the ratio of the peak velocity of atrial filling to early diastolic filling (A⁄E) were calculated. Fasting plasma glucose (FPG) and HbA1c levels were positively correlated with the A⁄E ratio and the deceleration time of the E wave. However, these plasma levels had no correlation with RWT, LVMI, or fractional shortening. Peak A wave velocity and the A⁄E ratio were significantly higher in patients who had FPG of ≥100 mg⁄dl (and <126 mg⁄dl) than those who had FPG of <100 mg⁄dl, although age, blood pressure, RWT, LVMI, and fractional shortening did not differ between the two groups. In a multiple regression analysis of all subjects, only FPG and age were independent determinants of the A/E ratio. These observations suggest that FPG is a sensitive predictor for LV diastolic dysfunction in nondiabetic patients with treated hypertension. Since a slight increase in plasma glucose levels is associated with abnormalities in diastolic function independent of LV hypertrophy, an early stage of impaired glucose metabolism in hypertensive patients may specifically deteriorate cardiac diastolic function. (Hypertens Res 2002; 25: 403-409)
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Sachiyo IWATA, Takeshi TSUJINO, Yoshihiro IKEDA, Tatsuro ISHIDA, Tomom ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
411-418
Published: 2002
Released on J-STAGE: December 24, 2002
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Arginase catalyzes the hydrolysis of arginine to urea and ornithine. Urea is not only an important solute for concentrating urine but also inhibits Na-K-2Cl cotransport. To elucidate the roles of arginase in the development of salt-sensitive hypertension, we examined arginase activity and expression in the kidney and other organs of Dahl⁄Rapp salt-sensitive (SS) and salt-resistant (SR) rats before and after 4 weeks’ administration of a 4% NaCl or control diet. At 4 weeks of age, arginase activity in the kidney was lower in SS rats than in SR rats. Kidney arginase activity was lower in SS rats than in SR rats at 8 weeks of age, and salt loading did not alter arginase activity. Arginase II (the dominant isoform in the kidney) mRNA and protein in the kidney of salt-loaded SS rats were also lower than those of salt-loaded SR rats. Arginase activities in the liver and cerebellum did not differ between SS and SR rats. To examine the effect of urea, the product of arginase reaction, on the development of hypertension, SS rats were given a 4% NaCl diet containing 5% kaolin or 5% urea. Six-week urea supplementation attenuated the development of hypertension in SS rats. These findings suggest that decreased arginase expression in the kidney may be at least partially responsible for the salt-sensitive hypertension in SS rats. (Hypertens Res 2002; 25: 411-418)
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Kenichi YASUNARI, Kensaku MAEDA, Munehiro NAKAMURA, Junichi YOSHIKAWA
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
419-425
Published: 2002
Released on J-STAGE: December 24, 2002
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The cellular mechanisms by which hypertension enhances atherosclerosis are still not known in detail. Recently, evidence has been obtained that oxidative stress plays a role in the pathogenesis of pressure-induced atherosclerosis. We examined the effects of pressure on oxidative stress in cultured human coronary smooth muscle cells (SMCs). Application of increased pressure (+100 mmHg) with He gas for 48 h increased oxidative stress of measured by flow cytometry by 71% and F2-isopretane by 77%. Increased pressure also increased the activities of phospholipase D (PLD), and particulate protein kinase C (PKC). The PLD inhibitor suramin 100 μmol⁄l, 1-butanol 40 mmol⁄l, and the PKC inhibitors chelerythrine 1 μmol⁄l and calphostin C 100 nmol⁄l and completely blocked the increase in oxidative stress induced by pressure. Carvedilol 1 μmol⁄l but not propranolol 1 μmol⁄l blocked pressure-induced increases in oxidative stress in cultured SMCs. These findings suggest that pressure increases oxidative stress and that carvedilol significantly inhibits pressure-induced increase in oxidative stress in cultured human coronary smooth muscle cells. (Hypertens Res 2002; 25: 419-425)
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Ken YAMAKAWA, Kenichiro KITAMURA, Hiroshi NONOGUCHI, Nobuyuki TAKASU, ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
427-432
Published: 2002
Released on J-STAGE: December 24, 2002
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The endothelin B receptor (ETBR) has been shown to mediate autoinduction of endothelin-1 (ET-1). We previously reported that the ETBR interacts with Gα13, a member of the heterotrimeric GTP-binding protein family. In the present study, we examined whether Gα13 induces preproET-1 (ppET-1) gene transcription, which could result in ET-1 autoinduction in a renal epithelial cell line. We generated a reporter gene construct under control of the ppET-1 promoter region. The construct was transiently expressed in COS-7 cells. Transient expression of ETBR increased the promoter activity of ppET-1 following treatment with 100 nmol⁄l of ET-1. Expression of Gα13Q226L or GαqQ209L, constitutively active forms of Gα13 and Gαq, also activated the ppET-1 promoter. ETBR-stimulated ppET-1 promoter activity was partially diminished by the expression of dominant negative forms of c-Jun N-terminal kinase (JNK1APF) or MAPK⁄ERK kinase (MEKK97M). Expression of JNK1APF also inhibited Gα13Q226L-induced ppET-1 promoter activation. These findings indicate that Gα13 can induce ppET-1 gene expression through a JNK-mediated pathway. Our results also suggest that this Gα13-coupled signaling pathway may play an important role in a sustained ET-1 autoinduction loop in various pathophysiological conditions. (Hypertens Res 2002; 25: 427-432)
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Hideki INADA, Hidehiko ONO, Junichi MINAMI, Toshihiko ISHIMITSU, Hiroa ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
433-440
Published: 2002
Released on J-STAGE: December 24, 2002
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The proliferative cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase δand appears to be required for both DNA synthesis and repair. Previously, we showed that prolonged NO synthase (NOS) inhibition produced severe nephrosclerosis with an increase of glomerular cell DNA fragmentation (apoptosis), glomerular ischemia and hypertension in spontaneously hypertensive rats (SHR). The objective of the present study was to investigate the effects of the vasodilating, nonselective, NO-releasing β-adrenoceptor blocker nipradilol on DNA fragmentation and synthesis⁄repair of glomerular cells in this prolonged NOS blockaded SHR. Twenty-week-old SHR were administered an NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 80 mg/l in drinking water) or co-treated with the same dose of L-NAME and nipradilol (20 mg/kg/day) for 3 weeks. After this treatment, expression of apoptosis was histologically examined using caspase-3, an apoptosis inducer, in addition PCNA (DNA synthesis/repair), and examination of glomerular morphometric changes, including cell number and tuft area. Nipradilol reduced blood pressure and preserved creatinine clearance reduction in L-NAME/SHR. These effects were associated with normalization of the glomerular cell apoptosis index and caspase-3 score, an increase in PCNA index, and increases in glomerular cell numbers and glomerular tuft area, resulting in a decreased glomerular injury score. Thus, in SHR administered an NOS inhibitor, nipradilol improved nephrosclerosis in association with a decrease in apoptosis and an increase in DNA synthesis/repair of glomerular cells. These findings may provide important insights into DNA repair/repair and apoptosis in nephrosclerosis. (Hypertens Res 2002; 25: 433-440)
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Junsuke KAWAI, Katsuyuki ANDO, Tatsuo SHIMOSAWA, Kiyonori HARII, Toshi ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
441-446
Published: 2002
Released on J-STAGE: December 24, 2002
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Because both vasodilation induced by adrenomedullin (AM) and that induced by calcitonin gene-related peptide (CGRP) may occur via the same receptor, the two peptides might play similar roles in circulation. To examine this possibility, we used the colored microsphere technique and an ultrasonic flowmeter to investigate the systemic and regional effects of an equivalent dose (650 pmol⁄l) of AM and CGRP in conscious Wistar rats. AM significantly decreased mean arterial pressure and peripheral resistance but increased heart rate and cardiac index (CI). On the other hand, hypotension induced by CGRP was not accompanied by an increment in CI. Both AM and CGRP increased the femoral arterial blood flow measured by the flowmeter, with the increase by AM being significantly larger. The regional hemodynamic effects were quite different between the two peptides. AM increased the blood flow in the heart, lungs, kidneys, adrenal glands, and spleen, whereas CGRP increased blood flow only in the heart. On the other hand, CGRP increased the cutaneous and gastric blood flows, which were not affected by AM. These differences in the regional vasodilatory effects of AM and CGRP suggest that the two peptides do not play similar roles in circulatory regulation. (Hypertens Res 2002; 25: 441-446)
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Masayuki KANAZAWA, Masahiro KOHZUKI, Kazunori YOSHIDA, Hajime KUROSAWA ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
447-453
Published: 2002
Released on J-STAGE: December 24, 2002
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To assess the renal benefits of combined angiotensin-converting enzyme inhibition and calcium antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone or in combination with azelnidipine (AZN) in a spontaneously hypertensive rat (SHR) remnant kidney model of chronic renal failure. Male 5⁄6-nephrectomized SHR⁄Izumo rats were randomly assigned to receive vehicle (control group), TMP (TMP group; 10 mg•kg-1•day-1), AZN (AZN group; 3 mg•kg-1•day-1), or both (TMP+AZN group) orally for 12 weeks. Systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) were measured every 2 weeks. At the end of the experiment, serum creatinine (Scr), heart weight (HW), and blood urea nitrogen (BUN) levels were measured and the remnant kidneys were examined to determine the index of glomerular sclerosis (IGS). SBP and UalbV in the control group increased progressively throughout the experimental period. TMP, AZN, and TMP+AZN blocked the development of hypertension. TMP+AZN did not enhance the antihypertensive effects of either TMP or AZN used singly. TMP, AZN, and TMP+AZN all significantly decreased the UalbV, Scr, BUN, and HW⁄body weight (BW) ratio. The level of UalbV and the HW⁄BW ratio in the TMP+AZN group were significantly lower than those in the TMP and AZN groups, and the level of Scr in the TMP+AZN group was significantly lower than that in the TMP group. TMP, AZN, and TMP+AZN all significantly protected against an increase in the IGS. The IGS in the TMP+AZN group was significantly lower than that in the TMP and AZN groups. These results indicate that both TMP and AZN have antihypertensive and renoprotective effects in this model. They also suggest that simultaneous administration of TMP and AZN provides greater renoprotective effects than TMP alone. (Hypertens Res 2002; 25: 447-453)
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Tsuguru HATTA, Tetsuo NAKATA, Sanae HARADA, Masahiro KIYAMA, Jiro MORI ...
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
455-460
Published: 2002
Released on J-STAGE: December 24, 2002
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To investigate the effects of angiotensin converting enzyme inhibitor (ACE-I) and other antihypertensive agents on the nitric oxide (NO) release during hypertension, seven- and fourteen-week-old SHR and deoxycorticosterone acetate (DOCA)-salt rats were treated with hydralazine, manidipine (Ca antagonist) or quinapril (ACE-I) for 3 weeks to lower blood pressure. Systolic blood pressure (SBP) was measured by the tail cuff method once each week. Endothelial cells (ECs) derived from the descending aorta of the treated rats were cultured and NOx levels in culture media were measured with an NO analyzer based on the Griess reaction. In both SHR and DOCA-salt rats, antihypertensive therapy lowered SBP to levels similar to those of control rats. The only exception was quinapril treatment of DOCA-salt rats. Although NOx release by ECs derived from hypertensive rats was improved by antihypertensive therapy, the effect was most pronounced in SHR treated with quinapril. In addition, restoration of NOx release was much more remarkable in younger SHR. NOx release was significantly higher in DOCA-salt rats treated with quinapril than in control rats without reduction of SBP. These results suggest that lowering blood pressure improves release of NO by ECs during hypertension and that the time at which antihypertensive therapy is started is also important to preserve endothelial function. Furthermore, ACE-I is suggested to protect endothelial function by increasing NO production in addition to lowering blood pressure. (Hypertens Res 2002; 25: 455-460)
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Masashi NAMBA, Shokei KIM, Yumei ZHAN, Takafumi NAKAO, Hiroshi IWAO
Article type: Original Article
Subject area: Experimental studies
2002 Volume 25 Issue 3 Pages
461-466
Published: 2002
Released on J-STAGE: December 24, 2002
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The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg⁄kg), an angiotensin receptor blocker (candesartan, 3 mg⁄kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg⁄kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg⁄kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg⁄kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure. (Hypertens Res 2002; 25: 461-466)
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