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Yuichiro Saito

Publications and source records attributed to Yuichiro Saito.

18 recordsLinked to original sources
PubMed2006

Azelnidipine down-regulates renal angiotensin-converting enzyme and mineralocorticoid receptor mRNA in diabetic hypertensive rats.

Effects of a new lipophilic L-type calcium channel blocker, azelnidipine, on the expression of molecular components of the renin-angiotensin-aldosterone system (RAAS) were assessed. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of diabetes with hypertension, and their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats, were treated with azelnidipine for 2 weeks. The renal cortical mineralocorticoid receptor mRNA in OLETF was higher than in LETO, but was suppressed (P<0.05) by azelnidipine. Renal cortical angiotensin-converting enzyme mRNA of OLETF was lower than that of LETO rats, and it was further suppressed by azelnidipine (P<0.05). Azelnidipine can down-regulate the gene expression of molecular components of RAAS.

Animals↗
PubMed2006

Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice.

BACKGROUND: Homozygous Klotho mutant mice (KL(-/-) mice) exhibit multiple phenotypes resembling human ageing. Increases in the ratio of urinary calcium to urinary creatinine (uCa/uCr) and in serum Ca concentration and decreases in urinary Cr excretion and serum parathyroid hormone (PTH) concentration were reported; however, precise information about renal Ca handling was not reported in these animals. METHODS: We evaluated the PTH-induced increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in cells of isolated perfused connecting tubules (CNTs) of KL(-/-) mice. We also determined fractional excretion of Ca from the urine and serum samples of the same animals (n = 7), and compared them with KL(+/+) mice and hemi-nephrectomized KL(-+/+) mice (n = 10 in each) as controls. RESULTS: FECa was significantly higher in KL(-/-) mice than in controls (0.67 +/- 0.13 vs 0.20 +/- 0.04%). The PTH (10 nM)-induced increase in [Ca(2+)]i was diminished in KL(-/-) mice (58 +/- 5 vs 231 +/- 15 nM). Addition of 10 nM of 8-(4-chlorophenylthio)-cyclic adenosine 3',5'-monophosphate had a similar effect. The PTH-induced increase had completely disappeared by the removal of Ca from lumen and bath in both groups of animals. Removal of sodium (Na) from the solution increased [Ca(2+)]i to a similar extent in both groups. Conclusion. We conclude that renal Ca excretion estimated by determining FECa was defective in the KL(-/-) mice. Impairment of Ca absorption from the lumen by stimulation of PTH in CNTs is one of the mechanisms of this defect. Activity of the basolateral Na/Ca exchanger was preserved in this strain. Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene.

Absorption↗
PubMed2006

[Klotho gene and endothelial function].

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g. arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, skin atrophy). We have demonstrated that mice deficient for the klotho gene show endothelial dysfunction as manifested by an attenuated response of aortic relaxation in response to acetylcholine stimulation. Systemic nitric oxide production was also significantly reduced in klotho deficient mice. Oxidative stress was increased in klotho deficient mice. The klotho gene delivery improves multiple aging phenotypes. Our findings establish the basis for the therapeutic potential of klotho gene delivery in age-related diseases.

Aging↗
PubMed2006

[Klotho gene].

Explore the source record for details and available documents.

Animals↗
PubMed2005

Effect of transdermal hormone replacement therapy on the monocyte chemoattractant protein-1 concentrations and other vascular inflammatory markers and on endothelial function in postmenopausal women.

Monocyte chemoattractant protein-1 (MCP-1) is related to the progression of atherosclerosis. However, little is known about the effects of transdermal hormone replacement therapy (HRT) on circulating MCP-1, vascular inflammatory marker concentrations, and endothelial function in postmenopausal women. The effects of transdermal HRT on circulating MCP-1, vascular inflammatory marker concentrations, and endothelium-dependent vasodilation were investigated in postmenopausal women. Thirty-three women received transdermal HRT (continuous 17-beta estradiol patch 36 microg/day plus cyclic oral medroxyprogesterone acetate 2.5 mg/day for 12 days/month) for 12 months, and 27 control patients did not. Brachial artery flow-mediated vasodilation (FMD), assessed by ultrasound, and circulating MCP-1 and vascular inflammatory marker (C-reactive protein, intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and E-selectin) concentrations were measured before and after 12 months of treatment. In the HRT group, MCP-1 concentrations decreased significantly (p <0.001), and ICAM-1, VCAM-1, and E-selectin concentrations decreased significantly (p <0.01 for all), but C-reactive protein concentrations did not change. MCP-1 and other marker concentrations did not change in the control group. FMD increased significantly in the HRT group (p <0.001) but did not change in the control group. Nitroglycerin-induced vasodilation did not change in either group. In conclusion, transdermal HRT decreased MCP-1 and cell adhesion molecule concentrations and improved endothelial function in postmenopausal women. Transdermal HRT may exert an antiatherosclerotic effect by improving MCP-1 and cell adhesion molecule expression and endothelial function.

Administration, Cutaneous↗
PubMed2005

Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction: the antioxidative properties of fluvastatin.

BACKGROUND: Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia. METHODS AND RESULTS: In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction. CONCLUSIONS: Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.

Animals↗
PubMed2005

Selective angiotensin receptor antagonism with valsartan decreases arterial stiffness independently of blood pressure lowering in hypertensive patients.

Angiotensin II plays a key role in the development of vascular disease. We examined the long-term effects of selective angiotensin II receptor (ATR) blockade with valsartan on arterial wall stiffness. Brachial to ankle pulse wave velocity (baPWV) was measured in 28 women and 25 men with hypertension (mean age: 62+/-2 years). The measurements were repeated after 24 weeks of treatment with valsartan, 40 to 160 mg/day, with (n=10) or without (n=36) concomitant statin therapy. By multiple regression analysis, baseline baPWV was correlated with age (p<0.001), systolic blood pressure (SBP, p<0.0001), body mass index (p=0.018), and pulse pressure (p=0.005), but not with total cholesterol (p=0.446). Valsartan lowered mean SBP and diastolic blood pressure (DBP) from 155+/-3 to 140+/-3 mmHg and from 90+/-2 to 82+/-2 mmHg, respectively, and mean baPWV from 1,853+/-49 to 1,682+/-52 cm/s. Lowering of baPWV was not influenced by statin therapy. An overlap analysis was performed to separate the effect of angiotensin II receptor blockade from that of blood pressure (BP) lowering. The decrease in the baPWV value of 1,794+/-46 cm/s before valsartan (n=39) vs. 1,663+/-45 cm/s during valsartan (p=0.048, n=31) at a similar mean SBP level (149+/-2 vs. 146+/-3 mmHg, p=0.304) confirmed that ATR blockade had a beneficial effect independent of BP lowering. SBP strongly influences baPWV. However, the decrease in baPWV with valsartan was independent of BP lowering. Statins had no synergistic effect on baPWV. Lowering of baPWV may account for the therapeutic benefit conferred by valsartan independent of its BP-lowering effect.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Effect of cerivastatin on endothelial dysfunction and aortic CD36 expression in diabetic hyperlipidemic rats.

A mutation of the CD36 gene that encodes a fatty acid transporter has been reported to play a role in insulin resistance in spontaneously hypertensive rat (SHR). Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study was to determine the role of CD36 and the significance of statin therapy in insulin-resistance syndromes. We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARgamma. The CD36 genotype and microsatellite markers on chromosome 4 were also determined. The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF rats but restored by a low dose of cerivastatin without significant changes in serum cholesterol. These relaxations were also restored by a high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased the aortic expression of CD36 and PPARgamma mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF rats, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats. In conclusion, insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have pronounced beneficial effects in insulin-resistance syndromes.

Animals↗
PubMed2004

[klotho gene].

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes(e.g. arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, short lifespan). We have shown that mice deficient for the klotho gene show endothelial dysfunction as manifested by an attenuated response of aortic relaxation in response to acetylcholine stimulation. Nitric oxide production was also significantly reduced in klotho deficient mice. A decrease in klotho gene expression in animals under sustained circulatory and metabolic stress(e.g. atherosclerosis). The klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function(e.g. hypertension, vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease.

Animals↗
PubMed2002

Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression.

OBJECTIVE: Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). METHODS AND RESULTS: Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively; P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N(omega)-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%, respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. CONCLUSIONS: Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.

Adipose Tissue↗
PubMed2002

Regulation of angiogenesis by the aging suppressor gene klotho.

Advanced age is a major risk factor of peripheral artery disease. We examined the effects of the aging-suppressor gene klotho on angiogenesis in response to ischemia by introducing ischemic hindlimb model in mice heterozygously deficient for the klotho gene and in wild type mice. Blood flow recovery as assessed by laser doppler perfusion imaging and angiogenesis as assessed by density of PECAM-1/CD31-positive positive capillaries were markedly impaired in mice heterozygously deficient for the klotho gene (both <0.05). Our findings show that the aging-suppressor gene klotho affects angiogenesis and the possibility that age-related impairment of angiogenesis might be regulated by the klotho gene. Our results present a new possibility of therapeutic angiogenesis for patients of advanced age.

Aging↗
PubMed2002

Diet-induced mild hyperhomocysteinemia and increased salt intake diminish vascular endothelial function in a synergistic manner.

OBJECTIVES: We investigated the influence of hyperhomocysteinemia and high salt intake on sodium handling, oxidative state, vascular endothelial function and blood pressure in a rat model. METHODS: Eight-week-old male Sprague-Dawley rats were divided into subgroups and maintained for 4 weeks prior to experimentation on either control chow containing 0.36% methionine and 0.5% NaCl; or one of the following modified diets containing either 0.7% methionine, 8% NaCl or 0.7% methionine + 8% NaCl. Sodium handling, homocysteine metabolism, lipid profile, NO synthesis, oxidative state, blood pressure and relaxation to acetylcholine of carotid rings were evaluated and compared. RESULTS: Diet-induced mild hyperhomocysteinemia (plasma homocysteine levels 1.4-fold higher than control), by itself, had no significant influence on sodium excretion, vascular endothelial function and blood pressure. Increased salt intake had no influence on homocysteine metabolism, vascular endothelial function and blood pressure. The coexistence of mild hyperhomocysteinemia and high salt intake significantly diminished vascular endothelial function (rmax to acetylcholine; control chow 83.2 +/- 6.2%, 0.7% methionine diet 74.7 +/- 3.9%, 8% NaCl diet 85.1 +/- 4.6%, 0.7% methionine + 8% NaCl diet 57.9 +/- 6.6%) but manifested no rise in blood pressure. No significant difference in oxidative state was observed in this analysis. CONCLUSIONS: Diet-induced mild hyperhomocysteinemia, the extent of which is comparable with the levels that are associated with a predisposition to common atherosclerotic diseases, was found to induce vascular endothelial dysfunction only when accompanied by high salt intake.

Acetylcholine↗
PubMed2002

Reciprocal expression of vascular endothelial growth factor and nitric oxide synthase by coronary arterial wall cells during chronic inhibition of nitric oxide synthesis in rats.

Chronic inhibition of nitric oxide (NO) synthesis by oral administration of N(G)-nitro-L-arginine methyl ester (L-NAME) causes hypertension and produces arteriosclerosis in rats. Balloon injury induces upregulation of vascular endothelial growth factor (VEGF) in medial smooth muscle cells of the rat arterial wall, and NO secreted by a restored endothelium acts as the negative feedback mechanism that downregulates VEGF expression to basal levels. In this study, we tested the hypothesis that a reciprocal relation between VEGF and NO would be established in a rat model of chronic NO blockade. Male Wister rats received plain drinking water (n = 10) or L-NAME (0.5 mg/ml) in the drinking water (n = 11) for 6 weeks. After 6 weeks, the wall-to-lumen ratios and perivascular fibrosis in the coronary arteries were greater in the L-NAME group than in the control group. NO synthase-positive cells in the intima were abundantly observed in the control group, whereas no such cells were seen in the L-NAME group. In contrast, the number of VEGF-positive smooth muscle cells in the media was greater in the L-NAME group than in the control group. These findings strongly suggest a reciprocal relation between VEGF and NO even in a rat model of chronic NO blockade.

Animals↗
PubMed2002

Production of nitric oxide, but not prostacyclin, is reduced in klotho mice.

A novel murine model of aging (kl/kl mice) has been developed by in vivo mutagenesis. We analyzed endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from 6- to 9-week old wild-type (+/+) and heterozygous (kl/+) klotho mice. The aortas of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) compared to +/+ mice. The response to sodium nitroprusside was unaltered in kl/+ mice. The contraction in response to norepinephrine was augmented by treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) to a greater extent in +/+ mice than in kl/+ mice. Treatment with L-NAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD. NO metabolites (NO2- and NO3-) and cGMP concentrations in the urine were significantly reduced in kl/+ mice compared to +/+ mice. However, the urinary excretion of 6-keto-prostaglandin F1alpha was unaltered. There was little immunostaining for NO synthase and vascular endothelial growth factor (VEGF) in the aorta of kl/+ mice. No immunostaining for NO synthase was noted in the aorta of kl/kl mice. The expression of the klotho gene product may have a role in the regulation of VEGF expression and is tightly linked to endothelial release of NO.

Animals↗
PubMedDate not supplied

Steep elevation of blood interleukin-6 (IL-6) associated only with late stages of cachexia in cancer patients.

Changes in blood cytokines of 28, consenting, terminally ill cancer patients were studied to determine a relationship between cachexia and changes in cytokine levels. Levels of PTHrP and five types of cytokines considered to be associated with cachexia, TNFalpha, IL-1beta, IL-6, IFNgamma and LIF, were measured during routine blood examination and were compared with clinical findings. With the exception of TNF-alpha, which was detected in one patient, only IL-6 was detected in all 28 patients recruited in this study. Ten patients showed a sharp elevation of IL-6 just before death, following a 40-day period in which IL-6 was continually detected in the blood. In six out of these ten patients, levels of 100 pg/mL or more of IL-6 were detected in the week prior to death. The average period between detection of these levels of IL-6 and death was 2.0 days. Progression of carcinoma is believed to induce a variety of cytokines, which cause loss of appetite, weight loss, tissue wasting, and finally patients may become cachectic. Of the six cytokines studied during this test, only the level of IL-6 was significantly elevated, and this sharp rise occurred approximately one week before patients died. We conclude that IL-6 increases only gradually during the early stages of cachexia but then shows a sudden and steep rise just before death.

Adult↗