Hypertension Research

Original Articles

Clinical studies

High Brachial-Ankle Pulse Wave Velocity Is an Independent Predictor of the Presence of Coronary Artery Disease in Men

Ryo IMANISHI, Shinji SETO, Genji TODA, Masanori YOSHIDA, Akira OHTSURU ...

2004 Volume 27 Issue 2 Pages 71-78
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.71

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Pulse wave velocity (PWV) is an index of arterial stiffness, and a simple device for measuring brachial-ankle PWV (baPWV) has recently been developed. However, the clinical application of baPWV in patients with coronary artery disease (CAD) remains to be fully evaluated. This cross-sectional study was conducted to evaluate whether a higher baPWV predicts the presence of CAD. The baPWV was measured in 123 patients (77 males, 46 females; 63.5±11.8 years) who were undergoing coronary angiography. CAD was defined as >50% diameter stenosis. Hemodynamic data and cardiovascular risk factors were examined according to the presence or absence of CAD. Patients with CAD were significantly older across both sexes. The presence of hypertension and chest pain, but not baPWV, was correlated with CAD in females. The baPWV, and the presence of diabetes, hyperlipidemia, and chest pain were related to the presence of CAD in males. Multivariate logistic regression analysis in male patients showed that baPWV, diabetes, hyperlipidemia, and chest pain were independent risk factors for the presence of CAD. Furthermore, high baPWV in males with or without chest pain had a positive predictive value of 81.8% and 71.7% for the presence of CAD, respectively. In conclusion, high baPWV was shown to be a good independent predictor for the presence of CAD in men. (Hypertens Res 2004; 27: 71-78)

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Blood Pressure Response to Erythropoietin Injection in Hemodialysis and Predialysis Patients

Kazuhisa MIYASHITA, Akihiro TOJO, Kenjiro KIMURA, Atsuo GOTO, Masao OM ...

2004 Volume 27 Issue 2 Pages 79-84
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.79

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Recombinant human erythropoietin (rHuEPO) has been reported to induce hypertension. We investigated the effect of a single injection of rHuEPO on blood pressure in patients receiving hemodialysis (HD) and in patients with predialysis chronic renal failure (CRF). Forty-one patients receiving HD and 36 patients with predialysis CRF received an intravenous injection of rHuEPO, and blood pressure and plasma endothelin-1 were measured before and 30 min after the injection. Mean blood pressure was increased significantly in HD patients, but not in CRF patients (HD: 103±5 to 105±6 mmHg, p <0.05; CRF: 103±4 to 103±6, NS). The percentage of patients with increased mean blood pressure of more than 10 mmHg after rHuEPO injection was significantly larger in the HD than in the CRF group (27.0% vs. 5.5%, p <0.01). A positive correlation was found between changes in endothelin-1 level and mean blood pressure in the HD (r =0.43, p <0.01) but not in predialysis chronic renal failure. In conclusion, a single injection of rHuEPO increased blood pressure with a positive correlation with endothelin-1 release in hemodialysis patients, but not in predialysis chronic renal failure patients. (Hypertens Res 2004; 27: 79-84)

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Increase in Peripheral Blood Flow by Intravenous Administration of Prostaglandin E1 in Patients with Peripheral Arterial Disease, Accompanied by Up-Regulation of Hepatocyte Growth Factor

Hirofumi MAKINO, Motokuni AOKI, Naotaka HASHIYA, Keita YAMASAKI, Kazuy ...

2004 Volume 27 Issue 2 Pages 85-91
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.85

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Since endothelial damage is a trigger for the progression of atherosclerosis, we evaluated the clinical utility of prostaglandin E1 (PGE1) in relation to peripheral blood flow and regulation of hepatocyte growth factor (HGF), an angiogenic growth factor, in patients with peripheral arterial disease (PAD). Fourteen male patients with PAD who showed the characteristic symptoms of arteriosclerosis obliterans (Fontaine I: n =2; Fontaine II: n =4; Fontaine III: n =2; Fontaine IV: n =6), confirmed by angiography, were enrolled in this study. Patients were administrated synthetic PGE1 at a dose of 120μg per day for 14 consecutive days. Measurement of peripheral blood flow and serum HGF concentration was performed before PGE1 treatment and after 14 days of administration. Interestingly, intravenous administration of PGE1 for 2 weeks significantly increased the blood flow as assessed by a laser Doppler imager (p <0.01). In patients with Fontaine III and IV, serum HGF concentration was significantly higher than that in patients with Fontaine I or II and normal subjects. Of importance, administration of PGE1 further increased serum HGF concentration as compared to that before treatment (p <0.01). The increase in circulating HGF might work as a compensatory mechanism to decrease local HGF expression in patients with PAD, since HGF acts as an angiogenic growth factor with anti-apoptotic actions on endothelial cells. Moreover, to confirm the stimulatory effect of PGE1 on HGF in vessels, we employed an in vitro culture system. PGE1 increased HGF production and the growth of human cultured vascular endothelial cells. The stimulatory effect of PGE1 on HGF production might be due to an increase in cAMP, since forskolin and 8-bromo-cAMP induced HGF production. In conclusion, we demonstrated that administration of PGE1 stimulated peripheral blood flow, accompanied by an increase in systemic HGF concentration. Also, our in vitro data suggested that PGE1 augmented not only the systemic HGF level, but also local HGF production, probably through cAMP accumulation, resulting in improvement of endothelial function and blood flow. (Hypertens Res 2004; 27: 85-91)

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Experimental studies

Laminar Shear Stress Up-Regulates Inducible Nitric Oxide Synthase in the Endothelium

Naoko OZAWA, Masayoshi SHICHIRI, Masatora IWASHINA, Nozomi FUKAI, Taka ...

2004 Volume 27 Issue 2 Pages 93-99
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.93

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Shear stress caused by blood flow is a potent physiological stimulus for the generation of nitric oxide (NO) in endothelial cells, which is believed to derive from the up-regulation and post-transcriptional activation of endothelial constitutive NO synthase (ecNOS). However, it has yet to be demonstrated that inducible NO synthase (iNOS) plays a significant role in shear stress-induced NO production from endothelial cells. We used parallel plate-type flow chambers that detect fluid shear stress to determine that shear stress, as quantified by a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), increased iNOS gene transcripts in cultured endothelial cells, which resulted in increased NO production. Shear stress-induced iNOS expression was inhibited by pyrrolidine dithiocarbamate (PDTC), an antioxidant and nuclear factor κB (NF-κB) blocker, and by MG132, an aldehyde peptide proteasome inhibitor that antagonizes IκB-kinase. Laminar shear stress increased the transcriptional activity of NF-κB, whereas over-expression of an IκB-α mutant that inhibits the activation of NF-κB in a dominant-negative fashion was found to attenuate the induction of endothelial iNOS by shear stress. The present results demonstrate that shear stress induces iNOS in the endothelium, mainly via the activation of NF-κB. (Hypertens Res 2004; 27: 93-99)

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Angiotensin II Potentiates Vascular Endothelial Growth Factor-Induced Proliferation and Network Formation of Endothelial Progenitor Cells

Toshio IMANISHI, Takuzo HANO, Ichiro NISHIO

2004 Volume 27 Issue 2 Pages 101-108
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.101

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Bone marrow-derived endothelial progenitor cells (EPCs) in the peripheral blood of adult animals and adult humans have been shown to play a role in neovascularization into neovascular structures. On the other hand, angiotensin II (Ang II) plays a role in the development of many vascular diseases. To investigate whether Ang II affects human vascular endothelial growth factor (VEGF)-induced EPCs proliferation and network formation. Reverse transcription-polymelase chain reaction analysis demonstrated that Ang II induced a significant increase of VEGF receptor kinase domain-containing receptor (KDR) mRNA in a dose- and time-dependent manner; the maximal increase, which was 3-fold the control value, occurred after a 4-h stimulation. In addition, flow cytometric analysis revealed that Ang II up-regulated KDR protein expression in human EPCs. Both the angiotensin type 1 (AT₁) receptor antagonist (valsartan: 200 nmol/l) and the PKC inhibitor, bisindolylmaleimide (GFX: 10 μmol/l) reduced Ang II-induced KDR mRNA expression to almost the control level. The culture assay showed that Ang II dose-dependently enhanced VEGF-induced EPC proliferation by activating AT₁ receptors, which was also confirmed by the colorimetric MTS assay with the electron coupling reagent mathosulfate. Finally, in a Matrigel assay, EPCs treated with both Ang II and VEGF were shown to be more likely to integrate into the network formation than those treated with VEGF alone. In conclusion, our data indicate that Ang II potentiates VEGF-induced human EPCs proliferation and network formation through the up-regulation of KDR. (Hypertens Res 2004; 27: 101-108)

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Relationship between the Contents of Adrenomedullin and Distributions of Neutral Endopeptidase in Blood and Tissues of Spontaneously Hypertensive Rats

Wei JIANG, Hong-Feng JIANG, Chun-Shui PAN, Da-Yong CAI, Yong-Feng QI, ...

2004 Volume 27 Issue 2 Pages 109-117
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.109

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Adrenomedullin (ADM) is a multifunctional peptide with important roles in the cardiovascular system, especially in the adjustment of cardiovascular and renal homeostasis. ADM is present in plasma, organs and tissues, and its activity increases during hypertension. It remains unknown whether the clearance of this peptide is altered during hypertension. Neutral endopeptidase (NEP) is the major enzyme in ADM’s degradation. We observed the activity and distribution of NEP and the expression of its mRNA in the plasma, cardiac ventricle, aorta, jejunum and kidney of spontaneously hypertensive rats (SHRs) in order to study the possible role of NEP in elevating tissue ADM concentrations during hypertension. ADM and NEP were diffuse in all tissues studied. The level of tissue ADM was generally higher in SHR tissues than in control tissues, except in the renal medulla, and its mRNA expression was higher in all tissues. Plasma NEP activity, general NEP activity and the expression of NEP mRNA in the left ventricle, aorta and jejunum in SHRs was lower than that of controls, and the level of ADM was inversely correlated with NEP activity. NEP activity and mRNA and protein expression in SHR kidneys were higher than in control kidneys; moreover, the ADM content was positively correlated with NEP activity in the renal cortex. NEP activity in the lung of SHRs did not differ from that of controls. Thus, in SHRs, the local concentration and action of ADM in the tissues may be differentially regulated by NEP. (Hypertens Res 2004; 27: 109-117)

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Development of Angiogenic Cell and Gene Therapy by Transplantation of Umbilical Cord Blood with Vascular Endothelial Growth Factor Gene

Yukihiro IKEDA, Noboru FUKUDA, Mika WADA, Taro MATSUMOTO, Aya SATOMI, ...

2004 Volume 27 Issue 2 Pages 119-128
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.119

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Endothelial progenitor cells (EPCs) are present in the mononuclear cells (MNCs) of umbilical cord blood and peripheral blood. To establish the efficiency of angiogenic cell and gene therapies, we transfected the human vascular endothelial growth factor (hVEGF) gene into cord blood MNCs to enhance endothelialization. MNCs from cord blood and peripheral blood were isolated and transfected with pCR3 expressing hVEGF165 or GFP by the Hemagglutinating Virus of Japan (HVJ)-envelope and the cells were cultured in endothelium basal medium-2. The number of attached cells from cord blood was higher than that from peripheral blood. Attached cells expressed Flk-1, VE-cadherin, PECAM-1, CD34, and Tie-2. The increase in the number of attached cells was transient with the transfection of vascular endothelial growth factor (VEGF) gene early in the experimental period. Flt-1 mRNA was not expressed early in the culture period, but was expressed at 2 weeks after separation. VEGF gene transfer into MNCs at 12 days after separation, i.e., when Flt-1 mRNA was expressed continuously, increased the number of attached cells. We evaluated the effects of the transplantation of cord blood MNCs expressing the hVEGF gene on regional blood flow in an ischemic area in a rat model of chronic hindlimb ischemia. Blood flow was significantly improved in nude rats that received transplanted control MNCs. Transplantation of cord blood MNCs transfected with the hVEGF gene yielded greater improvements in blood flow. These results indicate that the hVEGF gene enhances endothelialization of EPCs, and that the transplantation of cord blood MNCs transfected with the VEGF gene may be feasible for the treatment of ischemic diseases as a type of angiogenic cell and gene therapy. (Hypertens Res 2004; 27: 119-128)

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Combined Treatment with an AT₁ Receptor Blocker and Angiotensin Converting Enzyme Inhibitor Has an Additive Effect on Inhibiting Neointima Formation via Improvement of Nitric Oxide Production and Suppression of Oxidative Stress

Shinji YAGI, Toshisuke MORITA, Shigehiro KATAYAMA

2004 Volume 27 Issue 2 Pages 129-135
Published: 2004
Released on J-STAGE: October 19, 2004

DOIhttps://doi.org/10.1291/hypres.27.129

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Accumulating evidence shows that inhibition of the vascular renin-angiotensin system results in suppression of injury-elicited neointima formation. We attempted to determine whether or not combined treatment with an angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) has an additive inhibitory effect on balloon-injury-elicited neointima formation in the carotid artery. Male Sprague-Dawley rats were treated with an ARB (valsartan: 3 mg/kg/day) and/or an ACEI (benazepril: 0.3 mg/kg/day) from 1 week before until 2 weeks after balloon injury. Experiments were also conducted with one-third of the dose combination used in the original experiments. Both ARB and ACEI inhibited neointima formation without any blood pressure changes. The full-dose combination lowered blood pressure and suppressed neointima formation significantly compared with the levels in the groups treated with either ACEI or ARB alone. The low-dose combination without blood pressure reduction also inhibited neointima formation to a similar extent as the full-dose combination. We measured 8-iso-prostaglandin F_2α (8-iso-PGF_2α), a marker of oxidative stress, and nitrite and nitrate (NO_x), an index of nitric monoxide production, in media conditioned by the injured artery. NO_x production was lower and 8-iso-PGF_2α was higher in the media of the injured artery, compared with those in the normal artery. ACEI restored NO_x production more dramatically than ARB, and ARB suppressed 8-iso-PGF_2α markedly compared with ACEI. These results suggest that the combination of an ARB and an ACEI exerts an additive inhibitory effect, presumably through an increase in production and bioavailability of NO from the endothelium. (Hypertens Res 2004; 27: 129-135)

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