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Biomedical subjects

Takeshi Horio

Publications and source records attributed to Takeshi Horio.

At least 37 records · Page 2Linked to original sources
PubMed2005

Upregulation of intracardiac adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy.

Specific adrenomedullin receptors have been identified as calcitonin receptor-like receptor (CRLR)/receptor activity-modifying proteins (RAMP2 and RAMP3) complexes. Although we have demonstrated that adrenomedullin is increased in volume overload-induced cardiac hypertrophy, it remains unknown whether the adrenomedullin receptor is altered or not. This study sought to investigate the significance of intracardiac adrenomedullin and its receptor system in volume overload-induced cardiac hypertrophy. Left ventricular adrenomedullin levels were higher in aortocaval shunt (ACS) rats than in controls (+58%). The left ventricular gene expressions of adrenomedullin, CRLR, RAMP2 and RAMP3 were increased (+27%, +76%, +108% and +131%, respectively) and the left ventricular collagen gene expressions were also increased (type I: +138%, type III: +87%). The left ventricular adrenomedullin level correlated with the gene expression of type III collagen (R=0.42). These results suggest that intracardiac adrenomedullin and its receptor system are upregulated and may participate in the regulation of cardiac remodeling in volume overload-induced cardiac hypertrophy.

Adrenomedullin↗
PubMed2005

C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction.

OBJECTIVES: We assessed the hypothesis that in vivo administration of C-type natriuretic peptide (CNP) might attenuate cardiac remodeling after myocardial infarction (MI) through its antifibrotic and antihypertrophic action. BACKGROUND: Recently, we have shown that CNP has more potent antifibrotic and antihypertrophic effects than atrial natriuretic peptide (ANP) in cultured cardiac fibroblasts and cardiomyocytes. METHODS: Experimental MI was induced by coronary ligation in male Sprague-Dawley rats; CNP at 0.1 mug/kg/min (n = 34) or vehicle (n = 35) was intravenously infused by osmotic mini-pump starting four days after MI. Sham-operated rats (n = 34) served as controls. After two weeks of infusion, the effects of CNP on cardiac remodeling were evaluated by echocardiograpic, hemodynamic, histopathologic, and gene analysis. RESULTS: C-type natriuretic peptide markedly attenuated the left ventricular (LV) enlargement caused by MI (LV end-diastolic dimension, sham: 6.7 +/- 0.1 mm; MI+vehicle; 8.3 +/- 0.1 mm; MI+CNP: 7.7 +/- 0.1 mm, p < 0.01) without affecting arterial pressure. Moreover, there was a substantial decrease in LV end-diastolic pressure, and increases in dP/dt(max), dP/dt(min), and cardiac output in CNP-treated MI rats compared with vehicle-treated MI rats. Importantly, CNP infusion markedly attenuated an increase in morphometrical collagen volume fraction in the noninfarct region (sham: 3.1 +/- 0.2%; MI+vehicle: 5.7 +/- 0.5%; MI+CNP: 3.9 +/- 0.3%, p < 0.01). In addition, CNP significantly reduced an increase in cross-sectional area of the cardiomyocytes. These effects of CNP were accompanied by suppression of MI-induced increases in collagen I, collagen III, ANP, and beta-myosin heavy chain messenger ribonucleic acid levels in the noninfarct region. CONCLUSIONS: These data suggest that CNP may be useful as a novel antiremodeling agent.

Animals↗
PubMed2005

Response of adrenomedullin system to cytokine in cardiac fibroblasts-role of adrenomedullin as an antifibrotic factor.

OBJECTIVE: The adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function. However, several aspects of the local action of adrenomedullin remain unclear. We studied the effects of interleukin 1-beta (IL-1beta) on the adrenomedullin system in cardiac fibroblasts and also examined the pathophysiological significance of such effects. METHODS: We cultured rat neonatal cardiac fibroblasts with or without IL-1beta and measured (1) two molecular forms of adrenomedullin in culture medium by specific immunoradiometric assay; (2) gene expression of adrenomedullin, calcitonin receptor like receptor (CRLR), receptor activity modifying protein2 (RAMP2), and RAMP3, components of the adrenomedullin receptor, by Northern blot analysis or RT-PCR analysis; (3) intracellular cAMP levels in response to exogenously administered adrenomedullin; and (4) (3)H-proline incorporation with and without a specific adrenomedullin antisense oligodeoxynucleotide. RESULTS: (1) IL-1beta time-dependently increased the levels of two molecular forms of adrenomedullin, adrenomedullin-mature and adrenomedullin-glycine (P<0.01). In contrast to known levels in plasma (about 10%), adrenomedullin-mature was a major molecular form in the culture medium of cardiac fibroblasts and myocytes (65-80%). (2) IL-1beta significantly increased gene expression of adrenomedullin and its receptor components (adrenomedullin: +46%, CRLR: +460%, RAMP2: +32%, RAMP3: +350%, all P<0.01). (3) Preincubated IL-1beta elevated the intracellular cAMP response to exogenous adrenomedullin administered at a concentration of 10(-7) M (+26%, P<0.05). (4) Adrenomedullin antisense oligodeoxynucleotide treatment significantly lowered adrenomedullin-mature levels in culture medium (-50%). Adrenomedullin nonsense oligodeoxynucleotide treatment did not change (3)H-proline incorporation or mRNA levels of collagen I and III, whereas adrenomedullin antisense oligodeoxynucleotide treatment significantly increased (3)H-proline incorporation and mRNA levels of collagen I and III in IL-1beta-treated cardiac fibroblasts. CONCLUSION: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels. This may beneficially modulate the pathophysiology of certain cardiac diseases.

Adrenomedullin↗
PubMed2005

Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts.

Insulin-like growth factor (IGF)-1 appears to play an important role in cardiac hypertrophy or remodeling. However, the role of endogenous IGF-1 in the growth of cardiac myocytes and fibroblasts remains unclear. This study investigated the major site of the production of cardiac IGF-1 and the local effects of endogenous IGF-1 secreted from cardiac cells. A significant expression of IGF-1 mRNA was found in cultured neonatal and adult rat cardiac fibroblasts, but not in myocytes. In addition, an in vivo examination by in situ hybridization histochemical analyses demonstrated the IGF-1 transcripts in the interstitial fibrotic tissue of the ventricle. Time-dependent secretion of IGF-1 protein was also observed in cultured cardiac fibroblasts. An antibody against IGF-1 decreased collagen synthesis in cardiac fibroblasts under basal conditions. Fibroblast-conditioned medium, as well as exogenous IGF-1, increased protein synthesis in cardiac myocytes, and this increase was inhibited by antibodies against IGF-1 and IGF-1 receptor, IGF binding protein-3, and IGF-1 receptor antagonist. These observations suggest that IGF-1 is produced and released mainly from cardiac fibroblasts and that endogenous IGF-1 promotes collagen synthesis by cardiac fibroblasts and hypertrophy of myocytes as an autocrine and a paracrine factor. Cardiac IGF-1 may function as an endogenous modulator of cardiac hypertrophy or remodeling.

Animals↗
PubMed2005

Asymptomatic renal infarction, due to fibromuscular dysplasia, in a young woman with 11 years of follow-up.

We report a 27-year-old woman with renovascular hypertension, renal infarction, and hepatic artery aneurysm due to fibromuscular dysplasia. The patient was first noted to have renal artery aneurysm and hepatic artery aneurysm at the age of 17. The renal infarction was asymptomatic and was incidentally detected by magnetic resonance imaging (MRI) examination. Because of the rather peripheral location of the aneurysms, percutaneous transluminal renal artery angioplasty was considered inappropriate. This case suggests the need for long-term and periodical follow-up of patients with fibromuscular dysplasia.

Adult↗
PubMed2005

Pioglitazone improves left ventricular diastolic function in patients with essential hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy and diastolic dysfunction, which are common cardiac consequences of hypertension, are modified by insulin resistance. The present study assessed the hypothesis that primary treatment of insulin resistance may reverse such cardiac changes in hypertensive patients. METHODS: A total of 30 patients with essential hypertension were enrolled in this study. In echocardiographic examinations, LV mass index, the peak velocity ratio of early diastolic to atrial filling (E/A), and the E-wave deceleration time (DcT) were determined. Insulin sensitivity test with steady-state plasma glucose (SSPG) method, oral glucose tolerance test, and blood samplings for measurement of adiponectin and matrix metalloproteinase (MMP)-2 were also performed. Six months after treatment with pioglitazone (30 mg/day), an insulin sensitizer, these examinations were repeated. RESULTS: Pioglitazone significantly increased E/A and decreased DcT, without a change in LV mass index. These improvements in diastolic properties were much greater in subjects with a marked (>or==3.3 mmol/L) decrease in SSPG (n=11) than the others (n=19), although the decrease in glucose levels did not differ between the two groups. In addition, the changes in E/A and DcT were closely correlated with the decrease in SSPG. Pioglitazone treatment significantly elevated plasma adiponectin and MMP-2 levels, and the increase in MMP-2 was positively correlated with the increase in adiponectin. CONCLUSIONS: The present findings demonstrate that pioglitazone improves LV diastolic function without LV mass regression in hypertensive patients in proportion to the amelioration of insulin resistance. These findings suggest that increased adiponectin and MMP may be involved in the beneficial effect of pioglitazone on diastolic function.

Adiponectin↗
PubMed2005

Pioglitazone-induced insulin sensitization improves vascular endothelial function in nondiabetic patients with essential hypertension.

BACKGROUND: It has been suggested that insulin resistance is involved in the impaired vascular endothelial function not only in diabetic patients but also in hypertensive patients. The present study assessed the hypothesis that primary treatment of insulin resistance may reverse endothelial dysfunction in hypertensive subjects. METHODS: Fifteen nondiabetic patients with essential hypertension were enrolled in this study. An oral glucose tolerance test (OGTT) and insulin sensitivity test were performed. Insulin sensitivity was determined with the steady-state plasma glucose (SSPG) method. Only subjects with insulin resistance (SSPG > or =8.3 mmol/L) were included. Endothelium-dependent vasodilation during reactive hyperemia (flow-mediated dilation) was evaluated using ultrasonography. Six months after treatment with the insulin-sensitizing agent pioglitazone (30 mg/day), these examinations were repeated in all subjects. RESULTS: Pioglitazone did not decrease fasting plasma glucose and hemoglobin A1c (HbA1c) in the nondiabetic subjects, although the area under the curve for glucose and insulin on OGTT significantly decreased. A marked decrease in SSPG was observed after pioglitazone treatment (10.7 +/- 1.4 to 7.9 +/- 2.1 mmol/L, P < .001). Endothelium-dependent vasodilation evaluated by flow-mediated dilation was also improved by pioglitazone (5.0% +/- 2.2% to 6.3% +/- 2.4%, P = .023). Furthermore, the increase in flow-mediated dilation was closely correlated with the decrease in SSPG (r = 0.72, P = .002) but not with the decrease in area under the curve for glucose or insulin on OGTT. Endothelium-independent dilation induced by glyceryl trinitrate was not altered by pioglitazone. CONCLUSIONS: The present findings demonstrate that pioglitazone improves endothelial function in nondiabetic hypertensive individuals with insulin resistance, and that the improvement is associated with the amelioration of insulin resistance itself rather than that of hyperglycemia or hyperinsulinemia.

Aged↗
PubMed2005

Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population.

OBJECTIVES: Mice deficient in the regulator of G-protein signaling 2 (RGS2) exhibit a strong hypertensive phenotype. We studied whether genetic variations in RGS2 are implicated in hypertension or other phenotypes in Japanese hypertensive individuals and the general population. METHODS: We sequenced all exons of RGS2 and the promoter region in 953 and 48 hypertensive individuals, respectively. Genotyping by the TaqMan polymerase chain reaction method was performed for six missense or frameshift mutations and common single nucleotide polymorphisms in the general population, with a sample size of 1872 individuals (862 men and 1011 women). RESULTS: We identified five novel missense mutations (Q2L; n = 2, Q2R; n = 1, M5V; n = 1, R44H; n = 2, Q78H; n = 1) and one novel frameshift mutation (1925-1926insT; n = 2) in a heterozygous state, in addition to 33 variations including five common single nucleotide polymorphisms. Six missense/frameshift mutations and three common single nucleotide polymorphisms (-638A > G, 1026T > A, 1891-1892delTC) were successfully genotyped in the general population. Mutations Q2L (n = 2), M5V (n = 1), and 1925-1926insT (n = 2) were only identified in hypertensive subjects. Six out of seven individuals with the R44H mutation, which occurs in the amphipathic alpha-helical domain of RGS2, had hypertension. The results showed a significant association of two common single nucleotide polymorphisms, 1026T > A [TT versus TA + AA: odds ratio (OR) 1.33; 95% confidence interval (CI) 1.02-1.74; P = 0.035] and 1891-1892delTC (I: insertion allele, D: deletion allele, II versus ID + DD: OR 1.47; 95% CI 1.09-1.97; P = 0.012), with hypertension in women by multivariate logistic regression analysis. CONCLUSION: Our results suggest that genetic variations in RGS2 contribute partly to the hypertensive phenotype.

Aged↗
PubMed2005

Ultraviolet radiation-induced impairment of tumor rejection is enhanced in xeroderma pigmentosum a gene-deficient mice.

Xeroderma pigmentosum (XP)A gene-deficient mice display dermatologic abnormalities similar to human XP, such as enhanced ultraviolet (UV)-induced acute inflammation and high incidence of UVB-induced skin cancer. We have previously reported that UVB-induced immunosuppression of contact hypersensitivity was greatly enhanced in XPA mice. In the present study, we examined the effects of UVB radiation on tumor rejection in XPA mice. Tumor cells established from UVB-induced squamous cell carcinoma in XPA mice were injected subcutaneously. No difference in the development of tumors was observed between the non-irradiated XPA and wild-type mice. Tumors developed, grew in size, and reached the maximum at 7-10 d after the inoculation. Thereafter, all tumors decreased in size and were completely rejected by 4 wk in both strains of mice. When tumor cells were inoculated into the skin that had been irradiated with 50-150 mJ per cm2 of UVB, tumor grew in 60% (12 of 20) of the XPA mice, but only in 4% (one of 23) of wild-type mice. Phenotyping of tumor-infiltrating cells revealed that the migration of natural killer cells and CD8+ T cells was inhibited in UVB-irradiated XPA mice. These data suggest that enhanced UVB-induced impairment of tumor rejection could be partially involved in the cancer development of XP patients.

Animals↗
PubMed2005

Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma.

It is well established that exposure to sunlight or ultraviolet radiation (UVR) is the major environmental risk factor for the development of skin neoplasms. To date, however, there have been few appropriate mouse models available for studying the role of UVR in melanoma carcinogenesis, mainly because of the murine lack of the epidermal melanocyte, which is a major source of origin of human melanoma. In this study, we established xeroderma pigmentosum group A gene-deficient, stem cell factor-transgenic mice, which are defective in the repair of damaged DNA and do have epidermal melanocytes. The mice were exposed to UVR three times a week for 10 wk. More than 30% of the irradiated mice developed tumors of melanocyte origin that metastasized to the lymph nodes. Histologically, proliferated cells exhibited lentigo maligna melanoma or nodular melanoma. Immunohistochemistry confirmed that the tumor cells were characteristic of melanoma. Non-irradiated mice did not develop skin tumors spontaneously. The newly generated model mouse might be useful for studying the photobiological aspects of human melanoma, because the mice developed melanoma from epidermal melanocytes only after UVR exposures.

Animals↗
PubMed2005

The photocarcinogenesis of antibiotic lomefloxacin and UVA radiation is enhanced in xeroderma pigmentosum group A gene-deficient mice.

Lomefloxacin (LFLX) is phototoxic and phototumorigenic, but the mechanisms of phototumorigenesis of quinolone drugs have not been fully elucidated. Formation of cyclobutane pyrimidine dimers (CPD) by UVB radiation is primarily involved in the carcinogenesis of ultraviolet (UV) radiation. On the other hand, UVA region is responsible to photobiologic reactions of quinolone drugs. To know if CPD can be formed by UVA radiation in the presence of LFLX and is involved in the phototumorigenesis, we used xeroderma pigmentosum (XP) group A gene-deficient (XPA-/-) mouse, which is defective in nucleotide excision repair. XPA-/- and XPA+/+ mice were irradiated to 5 J per cm2-UVA with or without the administration of LFLX. In XPA-/- mice treated with LFLX, the first skin tumor appeared after exposures to 75 J per cm2 in 5 wk. In XPA+/+ mice treated with LFLX, the first tumor appeared after exposures to 345 J per cm2 in 23 wk. Immunohistochemically, CPD formation was observed after UVA-exposure in the skin of XPA+/+ as well as XPA-/- mice which had been given LFLX. The CPD disappeared, however, earlier from XPA+/+ mice than from XPA-/- mice. The acute inflammatory reaction after LFLX administration and exposure to UVA were greatly enhanced in XPA-/- mice. These results indicate that UVA exposure induces DNA damage in the form of CPD in the presence of LFLX, which exerts phototoxicity and phototumorigenesis.

Animals↗
PubMed2005

Adrenomedullin reflects cardiac dysfunction, excessive blood volume, and inflammation in hemodialysis patients.

BACKGROUND: Plasma adrenomedullin (AM) reflects cardiac dysfunction and predicts survival after myocardial infarction. The present study was designed to investigate whether the mature AM (mAM) reflects status of cardiac function, systemic blood volume, or inflammation in hemodialysis patients with cardiovascular disease, and whether mortality and additional cardiovascular morbidity can be predicted by mAM. METHODS: Plasma levels of mAM, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), norepinephrine (NE), and C-reactive protein (CRP) before hemodialysis were measured in 67 chronic hemodialysis patients with cardiovascular disease, along with 2-dimensional and Doppler echocardiographic variables. RESULTS: By univariate regression analysis, mAM correlated negatively with pulmonary venous flow velocity ratio and left ventricular (LV) ejection fraction and positively with LV inflow velocity ratio, LV end-diastolic, end-systolic volume indexes, plasma CRP level, and removal fluid volume by ultrafiltration. Multivariate stepwise regression analysis revealed that mAM reflected all variables better than log [ANP], log [BNP], and log [NE]. During a 1-year follow-up period, 7 patients died and 8 had additional cardiovascular events. Event-free Kaplan-Meier curves based on the median mAM (4.55 pmol/L) showed that patients with high plasma mAM levels had higher mortality and morbidity than those with low plasma mAM levels (P = 0.0056). By Cox multivariate proportional hazard analysis, mAM was related to mortality and morbidity [hazard ratio (HR) 4.55, 95% CI 1.2-16.8, P= 0.023). CONCLUSION: Plasma mAM reflects cardiac dysfunction, excessive blood volume, and inflammation better than ANP, BNP, and NE, resulting in a predictor of mortality and cardiovascular morbidity in hemodialysis patients with cardiovascular disease.

Adrenomedullin↗
PubMed2005

Effects of calcium concentration on the SOD activity and UVB-induced cytotoxicity in cultured human keratinocytes.

BACKGROUND/PURPOSE: Cellular differentiation due to the extracellular calcium (Ca(2+)) concentration affects the level of several antioxidant enzymes in cultured human keratinocytes. Because the epidermis includes well- and un-differentiated keratinocytes, we expected that keratinocytes possess different antioxidant capacity and sensitivity to damaging effects of ultraviolet-B (UVB) depending on the differentiation. We examined the effects of Ca(2+) concentration of culture medium (DMEM (Dulbecco's modified Eagle's medium)) on the superoxide dismutase (SOD) activity and UVB-induced cytotoxicity in cultured human keratinocytes in order to investigate the relationship between cell differentiation and antioxidant defense. METHODS: Human keratinocytes (HaCaT cells) were incubated in high Ca(2+) (>1 mM) or low Ca(2+) (<0.1 mM) concentration DMEM for 24 h at 37 degrees C in 5% CO(2). Then, we measured total SOD activity and also individual Cu,Zn- and Mn-SOD activities in keratinocytes. Furthermore, after incubation in high or low Ca(2+) concentration DMEM, human keratinocytes were irradiated with 10, 20 or 30 mJ/cm(2) UVB. The quantity of lactate dehydrogenase (LDH) leaked in the supernatant from damaged keratinocytes, cell viability and TdT-mediated dUTP nick end labelings (TUNEL) positive keratinocytes were measured at 24 h after UVB irradiation. RESULTS: Total SOD activity and Cu,Zn-SOD activity in human keratinocytes cultured in low Ca(2+) were significantly lower than in keratinocytes cultured in high Ca(2+) concentration DMEM. In contrast, Mn-SOD activity was not affected. LDH leakage in the supernatant from keratinocytes cultured in low Ca(2+) concentration was significantly higher than that from keratinocytes cultured in high Ca(2+) concentration DMEM after UVB irradiation. The cell viability of keratinocytes cultured in low Ca(2+) concentration DMEM was significantly decreased compared to that of keratinocytes cultured in high Ca(2+) concentration DMEM after UVB irradiation. Furthermore, UVB-induced apoptosis was increased in keratinocytes cultured in low Ca(2+) concentration DMEM by the TUNEL method. CONCLUSIONS: These results suggest that cellular differentiation due to the change of Ca(2+) concentration of culture medium affects the Cu,Zn-SOD activity and UVB-induced cytotoxicity in cultured human keratinocytes.

Apoptosis↗
PubMed2005

Therapeutic and prophylactic effects of PUVA photochemotherapy on atopic dermatitis-like lesions in NC/Nga mice.

BACKGROUND: Psoralens and ultraviolet A radiation (PUVA) photochemotherapy has been used for severe cases of atopic dermatitis (AD). To understand the mechanisms of action is important for the choice of treatments. AD-like lesions can be induced experimentally in NC/Nga mice. OBJECTIVES: To evaluate clinically and histologically the therapeutic and prophylactic effects of PUVA on AD-like dermatitis using NC/Nga mice. METHODS: PUVA therapy was performed with intraperitoneal injection of 4 mg/kg of 8-methoxypsoralen (8-MOP) and 4 J/cm(2)-UVA irradiation before and after development of AD-like lesions in NC/Nga mice which had been maintained in a conventional room (Conv-NC/Nga mice). Clinical skin conditions were evaluated periodically by a clinical severity score defined. Lesions were histologically examined in haematoxylin-eosin or toluidine blue-stained sections. Plasma levels of total IgE were measured at various time points. RESULTS: In Conv-NC/Nga mice infested with mite, AD-like lesions started to develop at 8 week of age and thereafter increased in severity score. PUVA therapy at lower does than minimal phototoxic dose suppressed the development of dermatitis and was also therapeutically effective against established lesions. Proliferation of dermal mast cells in AD-like lesions was suppressed, but IgE hyperproduction was not changed after PUVA. CONCLUSIONS: These observations suggest that PUVA photochemotherapy reveals not only therapeutic but also prophylactic effects on human AD.

Animals↗
PubMed2005

Primary aldosteronism combined with preclinical Cushing's syndrome in an elderly patient.

Pre-clinical Cushing's syndrome (pre-CS) is sometimes seen with adrenal cortical tumors. An 80-year-old woman had severe hypertension and hypokalemia, the typical clinical features of primary aldosteronism, but detailed hormonal examinations revealed the accompanying pre-CS. After adrenalectomy by laparoscopy, her blood pressure was remarkably reduced and the hypokalemia also recovered. The tumor consisted of mostly light clear cells and scattered dark compact cells resembling islands. Abundant expression of cytochrome P450 aldosterone synthase in the clear cells and cytochrome P450 11beta-hydroxylase in the dark cells was detected by immunohistochemical studies, which confirmed that clear cells can produce aldosterone and compact cells can produce cortisol.

Adrenal Cortex Neoplasms↗
PubMed2005

A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.

A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.

Aged↗
PubMed2005

Clinical implications of assessing coronary flow velocity reserve and plasma endothelin-1 in hypertensive patients.

Previous reports have indicated that hypertensive patients who have angina-like chest pain and normal coronary arteriograms have reduced coronary flow velocity reserve (CFVR) levels. In addition, elevated plasma endothelin-1 (ET-1) levels have been reported to be associated with microvascular angina. The purpose of this study was to evaluate the plasma ET-1 levels and CFVR in patients with chest pain but without coronary artery disease (CAD). A total of 66 patients were included in this study. CAD was ruled out by exercise stress test or coronary angiogram. Plasma ET-1 and CFVR measurements were performed in patients with (n=35) and without (n=31) a history of angina-like chest pain. CFVR was measured using adenosine-triphosphate stress transthoracic Doppler echocardiography. The mean ET-1 level was significantly higher and the CFVR was significantly lower in patients in the symptomatic group than in those in the asymptomatic group (ET-1: 3.85 +/- 1.24 pg/ml vs. 2.98 +/- 1.27 pg/ml, CFVR: 2.26 +/- 0.48 vs. 2.77 +/- 0.11, respectively). Plasma ET-1 level and CFVR were significantly correlated with each other (-r = 0.265, p = 0.033). Age, blood pressure, cardiovascular risk factors, and left ventricular mass index were similar between the two groups. The results of multiple regression analysis indicate that age (p = 0.008) and plasma ET-1 concentration (p = 0.031) had statistically independent associations with CFVR. Attenuated CFVR in the symptomatic hypertensive patients was associated with endothelial dysfunction, which results in elevated plasma ET-1 levels. The link between these two parameters may play a role in the genesis of chest pain in hypertensive patients without CAD.

Aged↗