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ABSTRACT: BACKGROUND:: We investigated the relationship between the renin/aldosterone profiles of patients with essential hypertension and their prognosis using a long-term follow-up study design. METHODS:: The cohort consisted of 125 Japanese patients with essential hypertension whose plasma-renin activity (PRA) (ng/ml per h), plasma-aldosterone concentration (PAC) (ng/dl), and ratio of PAC to PRA [aldosterone-renin ratio (ARR)] were determined under hospitalization from 1984 to 1993. The patients were divided into two groups according to their ARRs relative to the 50th percentile of the ARR value (ARR = 5.5); the low-ARR group (ARR <5.5, n = 66) and high-ARR group (ARR > 5.5, n = 59). Their clinical outcomes were monitored during follow-up by the attending physicians. RESULTS:: Ninety-six patients with essential hypertension (77% of the original cohort) were eligible for the analyses. The mean follow-up time was 18.6 ± 5.2 years. The cardiovascular morbidity was significantly higher in the high-ARR group than in the low-ARR group 3.2 vs. 2.4 per 100 patient-years, respectively (P = 0.014 by Kaplan-Meier analysis). Among the cardiovascular events, the incidence of stroke was 2.7-fold higher in the high-ARR group than in the low-ARR group. High ARR was an independent risk marker for cardiovascular events by Cox proportional hazards model analysis. CONCLUSION:: High ARR was an independent risk marker for cardiovascular events in patients with essential hypertension.
Journal of hypertension 10/2012; · 4.02 Impact Factor
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ABSTRACT: Heme oxygenase 1 (HO-1) is rapidly induced by stress, degrading pro-oxidant heme into carbon monoxide, bilirubin, and free iron (Fe). Induction of HO-1 is an important defense mechanism against tissue injury. Here, we tested the hypothesis that HO-1 is activated in the myocardium after acute myocardial infarction (AMI) in humans.
Changes in the HO-1 activity after AMI were analyzed by measuring serum levels of bilirubin and Fe. Blood samples were collected in patients with AMI (n = 41) serially after the interventional therapy and compared with non-AMI subjects (n = 18). HO-1 protein levels were measured in a sample of AMI patients (n = 12).
In AMI patients, but not in non-AMI subjects, serum levels of bilirubin (1.57 fold, P < 0.001) and Fe (1.35 fold, P < 0.01) were transiently elevated, both levels peaking 18-21 hours after the start of sampling. The peak changes in the levels of bilirubin and Fe in AMI patients were significantly correlated with each other. Furthermore, the serum HO-1 protein level was elevated, and its change was significantly correlated with the change in bilirubin level (r = 0.82, P < 0.005). Those with a high bilirubin response (peak levels >0.5 mg/dL) had richer collateral flow into the ischemic myocardium.
These results suggest that heme oxygenase (HO) was activated following AMI, and it was detectable in the serum. Our data provide the first evidence of HO-1 induction following stress in humans. The change in bilirubin level may be a novel index for high collateral flow formation following AMI.
Southern medical journal 09/2010; 103(9):876-81. · 0.92 Impact Factor
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ABSTRACT: The angiotensin II type 2 (AT2) receptor promotes apoptosis and inhibits cell proliferation. In the present study, we investigated the role of the AT2 receptor in vascular repair and remodeling following severe vascular injury using AT2 knockout (AT2KO) mice. Left femoral arteries of AT2KO mice and wild-type (WT) control mice were injured by a 0.38 mm steel wire inserted from the lumen. Twenty-eight days after the injury, a concentric vascular wall thickening, composed largely of neointima, was noted both in AT2KO and WT mice. The area occupied by the neointima and the cell count within it were not different in the two mouse strains. However, the area of the medial layer and the cell count within it were significantly larger in AT2KO mice than in WT mice. A BrdU incorporation assay showed that the proliferative activity was high in the neointima but it was not different between the strains. On the other hand, apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was significantly inhibited in the neointima and the media of AT2KO mice compared to the levels in WT mice. However, the number of TUNEL-positive cell was much smaller in the neointima than in the medial layer in both strains. Taken together, these results indicate that AT2 receptors promote the apoptosis of vascular cells but have no net effect on the neointimal cell growth or luminal narrowing after wire injury. The AT2 receptor may be involved in the control of medial layer thickness, at least in part, through medial cell apoptosis.
Hypertension Research 07/2008; 31(6):1241-9. · 2.58 Impact Factor
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ABSTRACT: Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1(-/-)) mice. TAC for 3 weeks in wild-type control (Bach1(+/+)) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and betaMHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and betaMHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1(-/-) mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload.
Hypertension 07/2008; 51(6):1570-7. · 6.21 Impact Factor
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ABSTRACT: This study was designed to determine whether Bach1 gene ablation leads to suppression of atherosclerosis in apolipoprotein E (Apo E)/Bach1 double knockout (DKO) mice. Apo E/Bach1 DKO mice were generated by intercrossing Apo E knockout (KO) and Bach1 KO mice. The animals were fed a high-fat diet for 8 weeks, and the atherosclerotic plaques in the thoracic and abdominal aorta were visualized by oil red O staining. In DKO mice, the total plaque area was reduced by 32% compared with that in Apo E KO mice. In DKO mice, heme oxygenase-1 (HO-1) was upregulated in the endothelium and, to a lesser extent, in vascular smooth muscles. In atherosclerotic plaques in Apo E KO mice and DKO mice, HO-1 was abundantly expressed in the endothelium and macrophages. Urine excretion of 8-iso-prostaglandin (PG) F2alpha, a marker for lipid peroxidation, was reduced in DKO mice compared with that in Apo E KO mice. The effects of Bach1 ablation on the plaque area and 8-iso-PG F2alpha excretion were almost completely abolished by treating DKO mice with Sn protoporphyrin, an inhibitor of HO activity. Disruption of the Bach1 gene in Apo E KO mice caused inhibition of atherosclerosis through upregulation of HO-1. Inhibition of Bach1, conversely, may be a novel therapeutic strategy to treat atherosclerotic diseases.
Hypertension Research 04/2008; 31(4):783-92. · 2.58 Impact Factor
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ABSTRACT: Excessive oxidative stress plays an important role in the mechanism of atherosclerosis. An increased level of reactive oxygen speices (ROS) within the vascular endothelium eventually impedes the vasodilatative and cytoprotective actions of nitric oxide (NO). Such a condition is considered to be an early feature of atherosclerosis, and is physiologically detectable as a decrease in endothelium-dependent vasodilatation. Increased intracellular ROS levels are involved in the mechanisms of hypertension, diabetes, and hyperlipidemia, all of which are major risk factors of atherosclerosis; therefore, the assessment of "oxidative status" is obviously relevant to clinical medicine. However, most of the currently available clinical tests just measure oxidized waste. Considering that the ROS level is determined by the balance between production and elimination, assessment of the ability to eliminate ROS may be a major determinant of the oxidative state and may be useful to assess individual susceptibility to atherosclerotic diseases. Focusing on heme oxygenase (HO)-1, one of the major stress defense mechanisms, we found that the capacity to upregulate HO-1 mRNA is tightly associated with the severity of coronary artery disease. Furthermore, individual differences in stress-induced HO-1 levels were determined by HO-1 gene polymorphism. We propose that clinical use of the HO-1 expression profile as a measure of tolerability against oxidative stress may be relevant in the early diagnosis of atherosclerotic diseases.
Rinsho byori. The Japanese journal of clinical pathology 09/2007; 55(8):758-63.
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ABSTRACT: Heme oxigenase-1 (HO-1) is known to be an inducible cytoprotective enzyme that copes with oxidative stress. However, changes in HO-1 expression and their association with human diseases have not been studied. To test the hypothesis that the capacity to upregulate HO-1 in response to oxidative stress is an intrinsic marker for susceptibility to coronary atherosclerosis, we assessed stimulation-induced change in HO-1 expression in blood cells in 110 patients who underwent coronary angiography, comparing the results with the extent of coronary atherosclerosis and (GT)(n) repeat polymorphism in the HO-1 gene promoter region, which is believed to affect the gene expression level. The extent of coronary atherosclerosis was assessed by coronary score. Mononuclear cells were incubated with 10 micromol/l hemin or vehicle for 4 h to maximally stimulate HO-1 expression, then the HO-1 expression level was determined by real-time polymerase chain reaction (PCR). The difference between the HO-1 mRNA levels of hemin- and vehicle-treated cells (DeltaHO-1 mRNA) was taken as an index of the capacity to upregulate HO-1 mRNA. The coefficient of variance of DeltaHO-1 mRNA was 7.2%. Consistent with previous studies, DeltaHO-1 mRNA was significantly lower in patients carrying a long (GT)(n) repeat. DeltaHO-1 mRNA negatively and significantly correlated with the coronary score (r(2)=0.50, p<0.01). In conclusion, the capacity to upregulate HO-1 expression may be determined, at least in part, by genetics, and reduced ability to induce HO-1 may be involved in the mechanism of coronary atherosclerosis.
Hypertension Research 05/2007; 30(4):341-8. · 2.58 Impact Factor
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Miwa Miyoshi,
Yukiko Nakano,
Takemasa Sakaguchi,
Hiroshi Ogi,
Noboru Oda,
Kazuyoshi Suenari,
Katsuhiro Kiyotani, Ryoji Ozono,
Tetsuya Oshima,
Tetsuya Yoshida,
Kazuaki Chayama
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ABSTRACT: Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-associated enzyme that hydrolyzes oxidized phospholipids, thereby preventing the oxidative modification of low-density lipoproteins (LDL). A high-fat diet reduces PON-1 activity, enhancing LDL oxidation. Thus, PON-1 is a candidate for anti-atherogenic gene therapy. In the present study, we investigated the effect of local PON-1 overexpression on the development of atherosclerotic lesions using the Sendai virus-mediated transgenic technique. One-month-old rabbits (n=11) were fed a high-fat diet for 8 weeks and then subjected to balloon injury of the common iliac artery and simultaneous infection with a Sendai virus vector containing the PON-1 gene (n=7) or enhanced green fluorescence protein (EGFP) gene as a control (n=4). The arteries were examined 7-10 days after the operation. Local overexpression of PON-1 almost completely eliminated the immunohistochemical signals of the lectin-like oxidized LDL receptor-1 (LOX-1), thereby inhibiting macrophage accumulation, intimal thickening (by 63% compared with control), or atherosclerotic plaque formation in the vascular lumen (by 87.5%). Decreased levels of oxidative stress in the PON-1-treated arteries were confirmed by 4-hydroxy-2-nonenal (HNE) staining. Local overexpression of PON-1 in the arteries attenuated oxidative stress, thereby inhibiting the atherosclerotic process. Delivery of the PON-1 gene may be a possible therapeutic strategy for preventing atherosclerosis.
Hypertension Research 02/2007; 30(1):85-91. · 2.58 Impact Factor
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ABSTRACT: There are two subtypes of angiotensin (Ang) II receptors, AT1R and AT2R. It is established that clinical use of specific AT1R blocker (ARB) improves the long-term prognosis of heart failure. However, scientific basis for such effects of ARB is incompletely understood. The present study was designed to determine whether ARB inhibits the left ventricular (LV) remodeling that occurs early after myocardial infarction (MI) and whether the benefit of ARB is mediated by blockade of AT1R itself or by stimulation of AT2R resulting from AT1R blockade. MI was induced in AT2R-knockout mice and wild-type mice. Administration of valsartan, an ARB, or vehicle was started soon after the surgery and continued for two weeks. Infarction caused significant increase in end diastolic and end systolic LV dimensions, LV/body weight ratio, and myocyte cross-sectional area (MCSA) in both strains to a similar extent. Lung/body weight ratio, an index of pulmonary congestion, was also significantly increased in both strains, but the magnitude of increase was significantly larger in knockout mice. Valsartan significantly reduced LV dimensions, LV/body weight ratio, MCSA, and lung/body weight ratio in wild-type mice. In knockout mice, however, valsartan failed to inhibit the increases in LV dimensions and LV/body weight ratio. After the treatment, lung/body weight ratio in the mutant strain was significantly larger than that in the wild-type mice. Valsartan attenuates acute phase post-infarction remodeling and ameliorates heart failure, and a large part of its cardioprotective effect was mediated by AT2R.
Life Sciences 01/2007; 80(1):82-8. · 2.53 Impact Factor
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ABSTRACT: Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1(-/-)) and wild-type (Bach1(+/+)) mice. In Bach1(-/-) mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1(+/+) mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice. Pretreatment of Bach1(-/-) mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.
Genes to Cells 08/2006; 11(7):791-803. · 2.68 Impact Factor
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ABSTRACT: Family history and aging are independent risk factors for the development of hypertension as well as for the development of diabetes. However, it is unclear how the family histories influence the rate of age-associated increase in these diseases. Moreover, despite the fact that hypertension and diabetes often occur concomitantly, it is not known whether family history of hypertension increases the risk of diabetes or vice versa. To gain an insight into these questions, we investigated the cross-sectional prevalence and family history of hypertension and diabetes in 1,123 male subjects (mean age, 42.1 +/- 12 years; range, 20-60 years) who participated in annual medical check-ups. The data were analyzed by 10-year age groups (20s, 30s, 40s and 50s). The prevalence of hypertension increased with age group either in the absence (12% in the 20s and 39% in the 50s) or in the presence (21% in the 20s and 59% in the 50s) of family history of hypertension, and thus the increasing rate of prevalence with age was not affected by family history. The prevalence of diabetes in the absence of family history of diabetes was low until the 40s (< 1.2%) but it jumped in the 50s (4.3%). On the other hand, in the presence of family history, the prevalence was 4% in the 20s and progressively increased to 20% in the 50s. The impact of family history on the risk of diabetes was strong and appeared to increase with age. Family history of hypertension did not increase the risk of diabetes, and family history of diabetes did not increase the risk of hypertension. These results suggest that family history of hypertension has an additive impact on the age-associated increase in the risk of hypertension, whereas family history of diabetes has an exponential impact on aging-associated increase in the risk of diabetes.
Hypertension Research 02/2006; 29(2):81-7. · 2.58 Impact Factor
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Nihon Naika Gakkai Zasshi 01/2006; 94(12):2502-7.
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ABSTRACT: Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca2+ channels were detected in the vascular endothelium. The purpose of the present study was to clarify the role of T-type Ca2+ channels in endothelial function. We studied flow-mediated vasodilation (FMD) and sublingual nitroglycerin (NTG)-induced vasodilation in the brachial artery. Forty patients with essential hypertension were randomly assigned to treatment with efonidipine, a T- and L-type Ca2+ channel blocker, or with nifedipine, an L-type Ca2+ channel blocker. Twenty healthy normotensive individuals were included as a control group. In patients with essential hypertension, FMD was attenuated and NTG was similar that of compared to healthy controls. After 12 weeks, the decrease in mean blood pressure in the efonidipine and nifedipine groups were similar. The endothelial function index, a ratio of FMD/NTG, was significantly increased by efonidipine (73 +/- 24 to 94 +/- 20%) but unchanged by nifedipine. Urinary excretion 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (LDL) were decreased by efonidipine but unchanged by nifedipine. These results suggest that a T-type Ca2+ channel blocker, but not an L-type Ca2+ channel blocker, may improve vascular endothelial dysfunction in patients with essential hypertension via a reduction in oxidative stress.
Hypertension Research 12/2005; 28(11):889-94. · 2.58 Impact Factor
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ABSTRACT: The goal of the present study was to determine whether seropositivity to Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV) is associated with systemic inflammation and endothelial dysfunction in healthy male subjects.
Chronic infection with certain bacteria and viruses may play an important role in inflammation as the pathogenesis of atherosclerosis.
The serum levels of immunoglobulin G antibodies to HP, CP, CMV, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were determined in 81 healthy Japanese men (40 +/- 10 years of age). High-frequency ultrasonographic imaging of the brachial artery was used to study endothelium-dependent (flow-mediated vasodilation) and endothelium-independent (nitroglycerin-induced) vasodilation.
Prevalences of seropositive antibodies to HP, CP, and CMV were 67.9%, 61.7%, and 56.8%, respectively. Infection with HP, CP, or CMV had no relationship with age, blood pressure, or level of serum glucose, lipid, or soluble vascular cell adhesion molecule-1. The levels of C-reactive protein and soluble intercellular adhesion molecule-1 were significantly higher, and flow-mediated vasodilation was significantly lower in subjects with seropositive antibodies to HP than in subjects with seronegative antibodies to HP. Endothelium-independent vasodilation was similar in both groups.
Chronic infection with HP may be involved in the development of the atherosclerosis via endothelial dysfunction and systemic and vascular inflammation.
Journal of the American College of Cardiology 05/2005; 45(8):1219-22. · 14.16 Impact Factor
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ABSTRACT: Bach1 is a transcriptional repressor of the cytoprotective enzyme heme oxygenase-1 (HO-1). Although HO-1 protects against atherosclerosis, the function of Bach1 in this process is poorly understood. We isolated peritoneal macrophages and aortic smooth muscle cells (SMC) from wild-type and bach1-deficient mice. bach1-Deficient macrophages expressed increased levels of HO-1 and showed elevated phagocytic activity when incubated with 0.75 microm microspheres. In SMC, bach1-ablation resulted in increased expression of HO-1 and decreased proliferation in bromodeoxyuridine incorporation assay as compared with wild-type cells. The up-regulated phagocytic activity and reduced SMC proliferation of bach1-deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1. In wild-type mice, cuff placement around femoral artery caused pronounced intimal proliferation without affecting the media, thus resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1-deficient mice had less degree of intimal growth (I/M ratio of 45.6%). These results indicate that Bach1 plays a critical role in the regulation of HO-1 expression, macrophage function, SMC proliferation and neointimal formation. Bach1 may regulate gene expression in these cells during inflammation and atherogenesis.
Genes to Cells 04/2005; 10(3):277-85. · 2.68 Impact Factor
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ABSTRACT: Aging is a major risk factor for cardiovascular disease. Chronological aging does not always parallel biological aging, but there is no reliable biomarker for the latter. In the present study, we tested the hypothesis that telomere attrition in white blood cells is related to endothelial dysfunction and the extent of atherosclerosis, and thus may serve as a useful marker for biological aging. We evaluated telomere lengths in white blood cells by measuring the mean telomere restriction fragment length (mTRFL), as well as endothelial function by flow mediated dilatation (FMD) in the brachial artery, in patients with various degrees of cardiovascular damage and in normal subjects. Cardiovascular damage was assessed by a cardiovascular damage (CVD) score, with 1 point being given for the presence of each cardiovascular risk factor (hypertension, hyperlipidemia and diabetes) and for each event (angina, myocardial infarction, cerebrovascular event and peripheral vascular disease). Subset analysis of CVD score groups revealed that mTRFL and FMD decreased in the rank order of CVD score. Although mTRFL was inversely correlated with age, telomere index, defined as the ratio of TRFL to TRFL predicted by age, also decreased with increase in CVD score. These results indicate that telomere attrition in white blood cells is more closely associated with endothelial damage and atherosclerosis than is chronological aging, supporting the hypothesis that mTRFL in white blood cells is a useful marker for biological aging of the cardiovascular system.
Hypertension Research 06/2004; 27(5):319-25. · 2.58 Impact Factor
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ABSTRACT: We have established a clinical routine method for evaluating the endothelial function in forearm circulation in humans. Flow-mediated vasodilation(FMD) was used as the endothelium-dependent and the response to nitroglycerin(NTG) as the endothelium-independent vasodilation. Diameter of the brachial artery was measured by high-frequency ultrasonographic imaging before and after hyperemia following artery occlusion. Because vasodilation reached the maximal level when the artery was occluded for 5 min, this time was selected as the occlusion time. FMD was greater (12 vs 9%) after upper-arm occlusion than after forearm occlusion. The peak time to maximal vasodilation was 50 sec after forearm occlusion and 70 sec after upper-arm occlusion. During NO synthesis inhibitor infusion, vasodilation after forearm occlusion was abolished, whereas that after upper-arm occlusion was attenuated by half. Therefore, the mechanisms for FMD may differ by occlusion position. The response to NTG was attenuated by aging. FMD was significantly decreased by coronary artery disease and coronary risk factors such as hypertension, hyperlipidemia and diabetes, but the response to NTG was not changed by these diseases. These measurements may offer useful tools for assessment of endothelial function.
Rinsho byori. The Japanese journal of clinical pathology 03/2004; 52(2):158-61.
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ABSTRACT: Kinins have been shown to play a cardioprotective role during myocardial ischemia. However, the localization of each of the components of the kallikrein-kinin system in the heart has not been determined in a cell type-specific manner. Recently, mK1 has been identified as the major tissue kallikrein with the strongest bradykinin-forming activity among the products of the mouse tissue kallikrein gene superfamily. In the study presented here, we investigated the localizations of mK1, kininogen and bradykinin B2 receptors (B2Rs) in ischemic and non-ischemic left ventricles by immunohistochemistry. Kininogen, which contains bradykinin as a surface epitope, was detected by an anti-bradykinin antibody. Changes in the amounts of mK1 and B2R were evaluated by Western blot analysis. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery for 60 min followed by reperfusion for 24 h. mK1 and B2Rs were most abundantly expressed in the vascular endothelium and, to a lesser extent, in fibroblasts. No immunohistochemical signal of these molecules was detected in myocytes. Kininogen was localized in the vascular endothelium and the smooth muscle layer. Myocardial ischemia, although it had no effect on the localization of these molecules, increased the amounts of mK1 and B2R. We have obtained immunohistochemical evidence that all components of the tissue kallikrein-kinin system are present in the mouse heart. The coronary artery is the major site of kallikrein-kinin activity both in ischemic and non-ischemic hearts.
Journal of Cardiovascular Pharmacology 01/2004; 42 Suppl 1:S49-53. · 2.29 Impact Factor
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ABSTRACT: Abnormal Ca2+ handling and enhanced aggregation response have been reported in platelets from spontaneously hypertensive rats (SHR) and patients with essential hypertension, and thought to be involved in the progression of target organ damage of hypertension. It is important to examine whether antihypertensive therapy can improve the abnormal platelet response in hypertension. We investigated the effect of antihypertensive treatment such as amlodipine and cilazapril on Ca2+ handling and aggregation response in SHR platelets. Four-week-old male SHR were divided into three groups. Each group was treated with amiodipine (A: 10 mg/kg/day), cilazapril (C: 10 mg/kg/day) or vehicle (V) for 8 weeks by gavage. At 12-week-old, platelet [Ca2+]i was measured with fura-2 in each group of SHR and age-matched Wistar-Kyoto rats (WKY) as normal control. Systolic blood pressure in amlodipine and cilazapril treated groups were similar with WKY and significantly lower than vehicle treated group (A: 124 +/- 9, C: 126 +/- 9, WKY: 122 +/- 10 and V: 180 +/- 9 mmHg, respectively). The basal [Ca2+]i in the three groups of SHR were similar and higher than WKY (A: 47 +/- 1.7, C: 47 +/- 1.2, V: 48 +/- 3.9 and WKY: 40 +/- 4.0 nmol/l, respectively). There were no significant differences in thrombin (0.1 U/ml)-stimulated [Ca2+]i rise in the presence or absence of extracellular Ca2+ among the three groups of SHR and these were higher than WKY. Intracellular Ca2+ discharge capacity, assessed by the ionomycinstimulation was similar in the all groups. Thrombin-induced maximum platelet aggregation responses in the three groups of SHR were similar and higher than WKY. The antihypertensive treatment of Ca2+ antagonist or ACE inhibitor gave no change in intraplatelet Ca2+ metabolism in SHR. These results support the hypothesis that an abnormal Ca2+ handling in SHR platelet is genetically determined and not improved by hypotensive therapy.
Hypertension Research 12/2003; 26(11):901-6. · 2.58 Impact Factor
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ABSTRACT: We have recently demonstrated that a deletion of the dopamine D2 receptor gene caused suppression of urinary sodium excretion and salt-sensitive elevation of blood pressure in mice. In order to understand the mechanisms underlying this impaired sodium excretion, we studied renal dopamine production and dopamine-induced sodium excretion in 20- to 30-week-old male D2-receptor knockout (D2KO) mice and age- and sex-matched wildtype (WT) mice. Renal local dopamine synthesis, examined by 24-h urine free dopamine excretion (UDAV), was significantly (p < 0.05) reduced in D2KO mice compared to that in WT mice (D2KO versus WT: 1.06 +/- 0.2 versus 1.5 +/- 0.3 ng/mg creatinine). Such a difference between D2KO and WT mice was also observed after oral administration of 3,4-dihydroxyphenylalanine (L-DOPA), a precursor of dopamine, at 5 mg/kg per day for 24 h. Furthermore, activity of aromatic 1-amino acid decarboxylase, a dopamine synthetase, was significantly suppressed in D2KO mice. Next, we examined changes in 24-h urine flow (UV) and 24-h sodium excretion (UNaV) during chronic infusion of dopamine at sub-pressor doses (3-4 microg/kg per min, sq.) or a vehicle via an osmotic pump. Urine flow in 24 h and UNaV were significantly (p < 0.05) smaller in D2KO mice infused with vehicle than in WT mice infused with vehicle (UV: 210 +/- 43 versus 650 +/- 163 microl/day; UNaV: 20.6 +/- 13.2 versus 44.4 +/- 21.6 microEq/day). After administration of dopamine, UV and UNaV in D2KO mice were restored to a level similar to that in WT mice. These results indicate that D2-dopamine receptors play a significant role in renal local dopamine synthesis and that a shortage of dopamine was, at least in part, responsible for the suppression of UV and UNaV in D2KO mice. However, we could not conclude from the present study whether renal tubular sodium reabsorption is intact in D2KO mice because the baseline dopamine contents in kidneys of D2KO mice and WT mice may be different.
Journal of Cardiovascular Pharmacology 12/2003; 42 Suppl 1:S75-9. · 2.29 Impact Factor
