Hypertension Research

Original Articles

Clinical studies

Renal Vascular Resistance and Renin-Angiotensin System in the Pathogenesis of Early Hypertension in Autosomal Dominant Polycystic Kidney Disease

Alfonso RAMUNNI, Angelo SARACINO, Tommaso ESPOSITO, Maria Teresa SALIA ...

2004 Volume 27 Issue 4 Pages 221-225
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.221

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Activation of the renin-angiotensin system (RAS) has been proposed to increase renal vascular resistance (RVR) and to play a role in the development of hypertension in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to investigate the relationship among RVR, RAS and blood pressure (BP) profile in patients without renal impairment. Thirty-four ADPKD patients underwent ambulatory blood pressure monitoring (ABPM) over a 24-h period and were divided into two groups: 17 hypertensive (group A, day-systolic BP ≥135 mmHg and/or day-diastolic BP ≥85 mmHg) and 17 normotensive (group B, day-BP<135/85 mmHg) patients. The two groups were comparable with respect to age, sex, and renal function. None of the patients assumed therapy. In all subjects the plasma renin activity (PRA) was measured, and the RVR was assessed by measuring resistivity indices (RI). RI was significantly higher in the hypertensive than in normotensive patients (0.67±0.05 vs. 0.62±0.03), while PRA was normal in all subjects, and showed no statistical difference between the two groups. Taking all the patients together (group A+group B), a significant positive correlation between RI and 24-h mean arterial pressure (MAP) was discovered, but no correlation was found between RI and PRA or between MAP and PRA. We conclude that in ADPKD patients without renal impairment the MAP values are strictly correlated with the RVR, but not with PRA. Thus factors other than RAS probably contribute to the increase of the RVR and to the early development of hypertension. (Hypertens Res 2004; 27: 221-225)

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Hyperuricemia and Cardiovascular Risk Factor Clustering in a Screened Cohort in Okinawa, Japan

Kazufumi NAGAHAMA, Kunitoshi ISEKI, Taku INOUE, Takashi TOUMA, Yosihar ...

2004 Volume 27 Issue 4 Pages 227-233
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.227

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The relation between serum uric acid level and cardiovascular risk factors is complex and has been investigated mainly in men. We examined the correlation between serum uric acid level and obesity, hypertension, dyslipidemia, and diabetes mellitus (DM) in both men and women of a screened cohort in Okinawa, Japan. A total of 9,914 individuals (6,163 men and 3,751 women ranging in age from 18 to 89 years) who were screened at Okinawa General Health Maintenance Association were subjects in this study. Hyperuricemia was defined as a serum uric acid level ≥7.0 mg/dl in men and ≥6.0 mg/dl in women. The odds ratios (95% confidence intervals) for the presence of hyperuricemia in men were 1.75 (1.56-1.97) for obesity, 1.42 (1.25-1.62) for hypertension, 1.16 (1.02-1.30) for hypercholesterolemia, 1.80 (1.60-2.03) for hypertriglyceridemia, 1.19 (1.02-1.40) for hypo-high density lipoprotein (HDL) cholesterolemia, and 0.61 (0.49-0.75) for DM; in women, they were 2.02 (1.62-2.53) for obesity, 1.64 (1.29-2.10) for hypertension, 1.31 (1.04-1.65) for hypercholesterolemia, 1.95 (1.51-2.51) for hypertriglyceridemia, 1.53 (0.96-2.44) for hypo-HDL cholesterolemia, and 1.20 (0.76-1.90) for DM. Hyperuricemic subjects had higher rates of coexistence of two or more of these cardiovascular risk factors than non-hyperuricemic subjects (63.8% vs. 43.2% in men; 58.9% vs. 27.6% in women). The present study revealed that hyperuricemia is positively associated with obesity, hypertension, and dyslipidemia in both men and women, and that hyperuricemic subjects tend to have a clustering of these cardiovascular risk factors. (Hypertens Res 2004; 27: 227-233)

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Greater Change of Orthostatic Blood Pressure Is Related to Silent Cerebral Infarct and Cardiac Overload in Hypertensive Subjects

Kazuo EGUCHI, Kazuomi KARIO, Satoshi HOSHIDE, Yoko HOSHIDE, Joji ISHIK ...

2004 Volume 27 Issue 4 Pages 235-241
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.235

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Greater change of postural blood pressure (BP) is often seen in elderly hypertensives and is recognized as a risk factor for cognitive decline and poorer cerebrovascular outcome, but its clinical significance still remains to be clarified. We performed a head-up tilting test, ambulatory BP monitoring, and brain MRI in 59 hypertensives and 27 normotensive subjects. We measured plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels at rest to assess cardiac burden. The 59 hypertensive patients were classified into 3 groups: an orthostatic hypertension (OHT) group with orthostatic increase in systolic BP (SBP) ≥10 mmHg (n =16); an orthostatic hypotension (OHYPO) group with orthostatic SBP decrease ≤-10 mmHg (n =18); and an orthostatic normotension (ONT) group with neither of these two patterns (n =25). A group of 27 normotensive subjects (NT) was also included as a control. Plasma BNP (72±92 vs. 29±24 pg/ml, p <0.05) and BNP/ANP ratio (4.6±3.3 vs. 2.4±1.5, p <0.05) were significantly higher in the OHYPO than in the NT group. The BNP/ANP ratio was also higher in the OHT than in the NT group (5.1±3.9 vs. 2.4±1.5, p <0.01). The number of silent cerebral infarct (SCI), prevalence of SCI and number of multiple SCIs was the highest in the OHT group, followed in order by the OHYPO, ONT and NT groups. Blood pressure and left ventricular mass index were not significantly different among the 3 hypertensive groups. In conclusion, hypertensive patients with greater change of postural BP (OHT and OHYPO) were shown to have increased risk of advanced silent brain lesions and greater cardiac burden. (Hypertens Res 2004; 27: 235-241)

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Relationship between the Awareness of Salt Restriction and the Actual Salt Intake in Hypertensive Patients

Yuko OHTA, Takuya TSUCHIHASHI, Michio UENO, Tomoko KAJIOKA, Uran ONAKA ...

2004 Volume 27 Issue 4 Pages 243-246
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.243

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A 24-h home urine collection was conducted to estimate accurate salt intake in hypertensive outpatients. Using 24-h urinary creatinine excretion as a criterion for success, urine samples were obtained from 534 hypertensive patients. The urinary salt excretion of hypertensive outpatients ranged widely from 1.5 to 23.4 g/day (mean value 9.7±3.9 g/day). Urinary salt excretion was higher in males than in females (10.6±4.0 vs. 9.2±3.7 g/day, p <0.01). Based on the questionnaires, the patients were divided into salt-conscious patients, or those who were careful to reduce their daily salt intake, and non-salt-conscious patients. It was found that urinary salt excretion was lower in the salt-conscious group than in the non-salt-conscious group (9.4±3.8 vs. 10.6±4.0 g/day, p <0.01), but that urinary salt excretion adjusted for body weight was not significantly different between the two groups (0.16±0.06 vs. 0.17±0.07 g/kg/day). Our results suggest that there was no obvious reduction in the actual salt intake in salt-conscious patients, suggesting the importance of monitoring salt intake by 24-h home urine collection and informing patients of their actual salt intake as a means of encouraging the achievement of salt restriction. (Hypertens Res 2004; 27: 243-246)

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Association between Hepatocyte Growth Factor Gene Polymorphism and Essential Hypertension

Masaharu MOTONE, Tomohiro KATSUYA, Kazuhiko ISHIKAWA, Yoshio IWASHIMA, ...

2004 Volume 27 Issue 4 Pages 247-251
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.247

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Hepatocyte growth factor (HGF) is a growth factor which contributes to protection and/or repair of vascular endothelial cells. Serum HGF level is elevated in response to hypertensive organ damage, which suggests that blood pressure regulation may be affected by HGF gene polymorphisms via serum HGF. To examine the interaction between a HGF gene polymorphism and hypertension, we carried out a case-control study. The present study was conducted in outpatients of Osaka University Hospital. Subjects (n =654) who gave informed consent to the study protocol and genetic analysis were recruited. A C to A nucleotide substitution in intron 13 of the HGF gene was determined by the TaqMan polymerase chain reaction (PCR) method using an MGB (Minor Groove Binder) probe. The genotype distribution of the C/A polymorphism of the HGF gene in total subjects was as follows: CC, 83%; CA, 16%; and AA 1%. This distribution was not significantly different from the predicted by Hardy-Weinberg’s equilibrium. The prevalence of hypertension was significantly higher in subjects with the CC genotype than in those with an A allele, and the positive association remained after adjustment for confounding factors, with the estimated odds ratio for hypertension (CC vs. CA+AA) being 1.71 (95% confidence interval: 1.02-2.93). A significant association with hypertension was observed in lean or female subjects but not in obese or male subjects. In conclusion, our data suggested that C/A polymorphism in intron 13 of the HGF gene is associated with susceptibility to essential hypertension in lean or female subjects. (Hypertens Res 2004; 27: 247-251)

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Experimental studies

Erectile Dysfunction in Hypertensive Rats Results from Impairment of the Relaxation Evoked by Neurogenic Carbon Monoxide and Nitric Oxide

Masayuki USHIYAMA, Toshisuke MORITA, Tomoya KURAMOCHI, Shinji YAGI, Sh ...

2004 Volume 27 Issue 4 Pages 253-261
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.253

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Erectile dysfunction (ED) with aging and diabetes mellitus is caused by impairment of the relaxation evoked by nitric oxide (NO) of penile cavernous smooth muscles and arterioles. However, the mechanism of ED in hypertension is unknown. Carbon monoxide (CO), which is produced by heme oxygenase (HO)-2 in the neuronal system is a neurotransmitter and a vasodilator. We examined the neurogenic role of CO in penile erection and the neurogenic mechanisms of ED in hypertension, using spontaneously hypertensive rats (SHR) or Wistar-Kyoto rats (WKY). The isometric tension of corpus cavernosum tissues from both strains was recorded after guanethidine and atropine treatment. Relaxation in response to electrical field stimulation (EFS) in WKY was suppressed dose-dependently by HO inhibitors both in the absence and presence of an NO synthase (NOS) inhibitor. Reverse transcription-polymerase chain reaction (RT-PCR) showed that the HO-2 gene was expressed in the corpus cavernosum. CO-saturated solution induced a concentration-dependent relaxation in WKY. The neurogenic relaxation to EFS in SHR was impaired as compared with that in WKY after the age of 5 weeks, when blood pressure began to be elevated, due to the attenuated relaxation in response to neurogenic NO and CO. In the corpus cavernosum of SHR, expression of the HO-2 and nNOS genes was similar, and NO_x levels after EFS were similar to those of WKY. cGMP levels after EFS and the relaxation evoked by the NO donor was lower in SHR than WKY. Thiobarbituric acid-reacting substance (TBARS) levels were increased, and superoxide dismutase (SOD) activity was suppressed in SHR, as compared with those in WKY, suggesting that the increasing oxidative stress partially causes the impairment of NO-dependent relaxation. These findings suggest that CO regulates the relaxation evoked by EFS in the rat corpus cavernosum, and that ED in hypertension in rats results from an impairment of the relaxation induced by neurogenic CO and NO. (Hypertens Res 2004; 27: 253-261)

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RhoA Activation in Vascular Smooth Muscle Cells from Stroke-Prone Spontaneously Hypertensive Rats

Nobuyuki MORIKI, Masaaki ITO, Tetsuya SEKO, Yasuko KUREISHI, Ryuji OKA ...

2004 Volume 27 Issue 4 Pages 263-270
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.263

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RhoA is commonly activated in the aorta in various hypertensive models, indicating that RhoA seems to be a molecular switch in hypertension. The molecular mechanisms for RhoA activation in stroke-prone spontaneously hypertensive rats (SHRSP) were here investigated using cultured aortic smooth muscle cells (VSMC). The level of the active form of RhoA was higher in VSMC from SHRSP than in those from Wistar-Kyoto rats (WKY). The phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) at the inhibitory site was also significantly higher in SHRSP, and the phosphorylation levels in both VSMCs were strongly inhibited to a similar extent by treatment with Y-27632, a Rho-kinase inhibitor. The expression levels of RhoA/Rho-kinase related molecules, namely RhoA, Rho-kinase, MYPT1, CPI-17 (inhibitory phosphoprotein for myosin phosphatase) and myosin light chain kinase, were not different between SHRSP and WKY. Valsartan, an angiotensin II (Ang II)- type 1 receptor antagonist, selectively and significantly reduced the RhoA activation in VSMC from SHRSP. The expression levels of the Rho GDP-dissociation inhibitor (RhoGDI) and leukemia- associated Rho-specific guanine nucleotide exchange factor (RhoGEF) did not differ between SHRSP and WKY. In cyclic nucleotide signaling, cyclic GMP (cGMP)-dependent protein kinase Iα(cGKIα) was significantly downregulated in SHRSP cells, although there were no changes in the expression levels of guanylate cyclase β and cyclic AMP (cAMP)-dependent protein kinase or the intracellular contents of cGMP and cAMP between the two rat models. These results suggest that the possible mechanisms underlying RhoA activation in VSMC from SHRSP are autocrine/paracrine regulation by Ang II and/or cGKIα downregulation. (Hypertens Res 2004; 27: 263-270)

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Amlodipine and Carvedilol Prevent Cytotoxicity in Cortical Neurons Isolated from Stroke-Prone Spontaneously Hypertensive Rats

Kazuo YAMAGATA, Shizuko ICHINOSE, Motoki TAGAMI

2004 Volume 27 Issue 4 Pages 271-282
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.271

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We previously reported that vitamin E prevents apoptosis in neurons during cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats (SHRSP). In this paper, we analyzed the effects of antihypertensives as well as vitamin E, which were added to neuron cultures after reoxygenation (20% O₂) following hypoxia (1% O₂). When added after hypoxia before reoxygenation, vitamin E conferred significant protection to neuronal cells. It was also shown that vitamin E conferred complete protection from neural cell death when added hypoxia and again before reoxygenation. At higher concentrations of vitamin E, strong neuroprotection was observed. Moreover, we verified that pretreatment with either amlodipine, carvedilol or dipyridamole consistently prevented cell death during hypoxia and reoxygenation (H/R). On the other hand, nilvadipine, a dihydropyridine-type calcium entry blocker, had no apparent effect on neuroprotection during H/R. The order of neuroprotective potency was vitamin E>dipyridamole>carvedilol≥amlodipine>nilvadipine. In parallel experiments, we examined whether these antihypertensive agents were more effective when combined with vitamin E and dipyridamole. The results suggested that in our in vitro model system, antioxidants were the most important agents for the reduction of oxygen-free radical damage in cortical neurons. These findings suggest that amlodipine and carvedilol, with their antioxidant properties and antihypertensive activity, would be useful to inhibit neuronal cell death in the treatment of cerebrovascular stroke and neurodegenerative diseases in hypertensive patients. (Hypertens Res 2004; 27: 271-282)

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Cyclin-Dependent Kinase Inhibitor, p21Waf1, Regulates Vascular Smooth Muscle Cell Hypertrophy

Kenichi OKAMOTO, Seiya KATO, Nobuyuki ARIMA, Teruhiko FUJII, Minoru MO ...

2004 Volume 27 Issue 4 Pages 283-291
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.283

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In the process of vascular diseases, smooth muscle cells (SMC) undergo not only hyperplasia but also hypertrophy, resulting in vascular remodeling. A cyclin-dependent kinase inhibitor (CDKI), p21Waf1, has been shown to play an important role in SMC hyperplasia. Here we investigated a potential role of p21Waf1 in SMC hypertrophy. An exposure of cultured rat SMC to serum drove the cell cycle progression with up-regulation of various cell cycle markers and increased activities of cyclin-dependent kinases, but did not cause SMC hypertrophy. In contrast, incubation of SMC for 48 h with angiotensin II (AII, 100 nmol/l) resulted in a significant increase in the cell size measured by flowcytometric forward-angle light scatter assay, in association with an increase in the ratio of [³H]leucine/[³H]thymidine uptake, indicating SMC hypertrophy. At 48 h, p21Waf1 expression was up-regulated in SMC exposed to AII but not in those exposed to serum. These results suggest that p21Waf1 may be involved in hypertrophy. To further investigate this issue, two manipulations of the p21Waf1 gene were performed. Adenovirus-mediated over-expression of p21Waf1 not only reduced S-phasic cells but also caused hypertrophy, despite the exposure to serum. Antisense oligodeoxynucleotide for p21Waf1 inhibited the hypertrophy of SMC exposed to AII. Our data suggest that p21Waf1 may play a role in SMC hypertrophy as well. (Hypertens Res 2004; 27: 283-291)

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Olmesartan Medoxomil, an Angiotensin II Receptor Blocker Ameliorates Insulin Resistance and Decreases Triglyceride Production in Fructose-Fed Rats

Kenta OKADA, Tsutomu HIRANO, Jianmin RAN, Mitsuru ADACHI

2004 Volume 27 Issue 4 Pages 293-299
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.293

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Although angiotensin II receptor blockers (ARBs) have been recommended as a first line of anti-hypertensive agents in patients with diabetes, it remains unclear whether ARBs have a favorable effect on insulin action and triglyceride (TG) metabolism, both of which are impaired in type 2 diabetes. In this study we addressed this issue by investigating how a newly developed ARB, olmesartan medoxomil, influenced insulin sensitivity and TG metabolism in fructose-fed rats, a representative animal model of insulin resistance. Olmesartan was administrated as a 0.01% drinking solution ad libitum to rats either fed normal chow or fructose-enriched chow (60%) for 21 days. Olmesartan treatment markedly decreased both systolic and diastolic blood pressure in both chow-fed and fructose-fed animals. The area under the curve of insulin (AUCI) was substantially greater in fructose-fed rats in the intravenous glucose tolerance test, and olmesartan treatment significantly reduced the AUCI. Olmesartan significantly improved the insulin sensitivity index in fructose-fed rats assessed by Bergman’s minimal model without affecting insulin-independent glucose disposal. Olmesartan significantly decreased plasma TG and non-esterified fatty acid levels in fructose-fed rats without affecting lipoprotein lipase mass. The TG secretion rate determined by the triton WR1339 technique was two-fold higher in fructose-fed rats, but olmesartan restored the TG secretion to a normal rate. Olmesartan did not affect plasma parameters, insulin sensitivity or TG metabolism in chow-fed rats. Olmesartan ameliorates insulin resistance and overproduction of TG in fructose-fed rats, and these effects appear to be independent of its hypotensive action. (Hypertens Res 2004; 27: 293-299)

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