Search

BackgroundThe present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT1) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes.MethodshRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks.ResultsCompared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg. Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine.ConclusionsThese results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human renin-angiotensin system. The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.6 [ABSTRACT FROM AUTHOR]

BackgroundTo explore the metabolic actions of nifedipine on diabetes, we examined glucose intolerance and white adipose tissue changes in type 2 diabetic KK-Ay mice.MethodsMale KK-Ay mice were treated with nifedipine (1.5 mg/kg/day in lab chow) for 5 weeks, which did not affect blood pressure or feeding of KK-Ay mice.ResultsAfter treatment with nifedipine, body weight tended to decrease and the weight of white adipose tissue was reduced. Without food restriction, nifedipine decreased plasma insulin level, while plasma glucose level tended to decrease. In oral glucose tolerance test, nifedipine suppressed the increase in glucose level after a glucose load without affecting plasma insulin concentration. Nifedipine also improved the result of insulin tolerance test. In white adipose tissue, nifedipine increased adipocyte number and the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and adipocyte fatty acid-binding protein related to adipocyte differentiation. In addition, expression of adiponectin, insulin receptor, insulin receptor substrate-1, and glucose transporter type-4 was also increased by nifedipine. Nifedipine also increased the expression of NO synthase in white adipose tissue. Nifedipine did not affect expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in white adipose tissue. Such changes in white adipose tissue were apparent in retroperitoneal adipose tissue. Nifedipine did not change the expression of angiotensin receptors, renin receptor, and angiotensinogen in white adipose tissue. Moreover, nifedipine attenuated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased superoxide dismutase (SOD) activity in white adipose tissue.ConclusionThese results suggest that nifedipine can enhance insulin sensitivity and reduce white adipose tissue, possibly related to stimulation of adipocyte differentiation.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.198 [ABSTRACT FROM AUTHOR]

BackgroundPrevious reports indicated that blockade of AT1 receptor stimulation attenuated adipocyte dysfunction. However, the effects of AT2 receptor stimulation on adipose tissue were not yet clear. In the present study, we examined the adipose tissue dysfunction in atherosclerotic apolipoprotein E knockout (ApoEKO) mice with AT2 receptor deficiency.MethodsMale ApoEKO and AT2 receptor/ApoE knockout (AT2/ApoEKO) mice at 6 weeks of age were treated with a normal diet or a high-cholesterol diet (HCD: 1.25% cholesterol). Markers for adipocyte differentiation and inflammation in adipose tissue were assayed with real-time reverse-transcription-PCR and western blot.ResultsCompared with ApoEKO mice, AT2/ApoEKO mice with a normal diet showed only a decrease in expression of adiponectin and CCAAT/enhancer binding protein δ (C/EBPδ) in epididymal adipose tissue without changes in body weight, adipose tissue weight, and adipocyte number even at 6 months of age. After HCD for 4 weeks, the weight of both epididymal and retroperitoneal adipose tissue in AT2/ApoEKO mice was greater than that in ApoEKO mice without a change in body weight. Plasma concentrations of cholesterol and fatty acids were higher in AT2/ApoEKO mice than in ApoEKO mice. In adipose tissue of AT2/ApoEKO mice, the adipocyte number was decreased and the expression of peroxisome proliferator–activated receptor γ (PPARγ), C/EBPα, and aP2 was lower than that in ApoEKO mice, in association with an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.ConclusionsThese results suggest that AT2 receptor stimulation in adipose tissue is involved in the improvement of adipocyte differentiation and adipose tissue dysfunction in atherosclerotic model.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.85American Journal of Hypertension 2009; 22, 7, 784–791. doi:10.1038/ajh.2009.85 [ABSTRACT FROM AUTHOR]

BackgroundA combination of different types of antihypertensive drugs is widely used for the treatment of hypertension. We examined the inhibitory effects of a combination of an AT1 receptor blocker (ARB), olmesartan, with various calcium channel blockers (CCBs) on inflammatory vascular remodeling.MethodsInflammatory vascular remodeling was induced by polyethylene-cuff placement around the femoral artery of C57BL/6J mice at 10 weeks of age. Olmesartan (0.5 mg/kg/day) was administered intraperitoneally using an osmotic minipump. CCBs (nifedipine 1.0 mg/kg/day, amlodipine 0.1 mg/kg/day, azelnidipine 0.1 mg/kg/day), and hydrochlorothiazide (HCTZ 0.5 mg/kg/day) were administered orally.ResultsIn the injured artery, superoxide anion production and expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47phox and Rac-1 were markedly increased, together with expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-α. Administration of a single drug alone at each concentration did not significantly inhibit these changes in the injured artery. However, a combination of olmesartan with various CCBs inhibited neointimal formation as well as oxidative stress and inflammatory markers in the injured artery. Moreover, among these CCBs, inhibition of these markers by olmesartan with azelnidipine was stronger than that caused by a combination with other CCBs. On the other hand, a combination of subeffective doses of olmesartan and HCTZ did not significantly affect vascular changes after cuff placement.ConclusionsThese results suggest that the combination of ARB with CCB synergistically inhibits vascular remodeling and that the inhibitory actions of ARB on vascular remodeling may vary depending on the combined CCB.American Journal of Hypertension (2009). doi:10.1038/ajh.2008.344American Journal of Hypertension (2009); 22, 2, 145–150. doi:10.1038/ajh.2008.344 [ABSTRACT FROM AUTHOR]

BACKGROUND The roles of the angiotensin (Ang) II type 1 (AT1) receptor in the changes in white adipose tissue were explored in an animal model of atherosclerosis using apolipoprotein E-deficient (ApoEKO) mice. METHODS Apolipoprotein E-deficient (ApoEKO) mice and KK-Ay mice were used. Expression of markers for adipocyte differentiation and inflammation was determined by real-time reverse-transcription polymerase chain reaction. RESULTS Adipose tissue weight and adipocyte size in epididymal white adipose tissue were increased in ApoEKO mice and KK-Ay mice. In the adipose tissue of these models, expression of adiponectin and peroxisome proliferator-activated receptor-γ (PPARγ), which induce adipocyte differentiation, and expression of transcription factors of adipocyte differentiation, such as CCAAT-enhancer-binding protein-α (C/EBPα) and aP2, were decreased. Expression of inflammatory markers and nicotinamide adenine dinucleotide phosphate oxidase subunits was also increased. Deletion of AT1a receptor in ApoEKO mice and administration of an AT1 receptor blocker, valsartan, to KK-Ay mice reduced epididymal adipose tissue weight and adipocyte size significantly. Blockade of the AT1 receptor also reduced the expression of inflammatory chemokines and oxidative stress markers. Moreover, AT1a receptor deletion in ApoEKO mice and AT1 receptor blockade in KK-Ay mice prevented the decrease in expression of adiponectin, PPARγ, C/EBPα, and aP2. Valsartan also increased glucose uptake induced by insulin in adipose tissue of KK-Ay mice. CONCLUSIONS These results suggest that enlargement and weakened differentiation of adipocytes are observed in atherosclerosis and diabetes, and that AT1 receptor blockade prevented adipocyte enlargement and promoted adipocyte differentiation in these models. [ABSTRACT FROM AUTHOR]

Background: The effect of a calcium channel blocker (CCB) on the expression of monocyte chemoattractant protein (MCP)-1 was explored in inflammatory vascular injury, focusing on the role of nuclear factor (NF)-κB. Methods: Vascular injury was induced by cuff placement. Expression of MCP-1 was determined by real-time RT-PCR. NF-κB expression and its activity were detected by Western blot and electrophoretic mobility shift assay. Results: Polyethylene cuff placement around the mouse femoral artery increased MCP-1 expression, together with proliferation of vascular smooth muscle cells and neointimal formation in the injured artery. The content of NF-κB was decreased in the cytosolic fraction but increased in the nuclear fraction prepared from the injured artery. In the nuclear fraction, the binding activity of NF-κB to the promoter region of MCP-1 was markedly increased. On the other hand, IκB content in the cytosolic fraction was decreased in the injured artery after cuff placement, accompanied by an increase in IκB kinase (IKK) phosphorylation. Treatment of mice with a CCB, nifedipine, at a dose of 5 mg/kg/day, significantly decreased vascular smooth muscle cell proliferation and neointimal formation without affecting blood pressure. This dose of nifedipine inhibited the increase in MCP-1 expression in the injured artery. Moreover, nifedipine reduced the nuclear content and DNA-binding activity of NF-κB in the injured artery. In contrast, the decrease in IκB content and the increase in IKK phosphorylation in the cytosolic fraction were attenuated by nifedipine. Conclusions: These results indicate that MCP-1 expression in inflammatory vascular injury is regulated by activation of NF-κB. The results also suggest that nifedipine attenuates MCP-1 expression in the injured artery via inhibition of the nuclear translocation and DNA-binding activity of NF-κB, and thereby improves vascular remodeling. [Copyright &y& Elsevier]

Objectives: This study evaluated the feasibility of a model-based iterative reconstruction technique (MBIR) tuned for the myocardium on myocardial computed tomography late enhancement (CT-LE)., Methods: Twenty-eight patients who underwent myocardial CT-LE and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) within 1 year were retrospectively enrolled. Myocardial CT-LE was performed using a 320-row CT with low tube voltage (80 kVp). Myocardial CT-LE images were scanned 7 min after CT angiography (CTA) without additional contrast medium. All myocardial CT-LE images were reconstructed with hybrid iterative reconstruction (HIR), conventional MBIR (MBIR&#95;cardiac), and new MBIR tuned for the myocardium (MBIR&#95;myo). Qualitative (5-grade scale) scores and quantitative parameters (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) were assessed as image quality. The sensitivity, specificity, and accuracy of myocardial CT-LE were evaluated at the segment level using an American Heart Association (AHA) 16-segment model, with LGE-MRI as a reference standard. These results were compared among the different CT image reconstructions., Results: In 28 patients with 448 segments, 160 segments were diagnosed with positive by LGE-MRI. In the qualitative assessment of myocardial CT-LE, the mean image quality scores were 2.9 ± 1.2 for HIR, 3.0 ± 1.1 for MBIR&#95;cardiac, and 4.0 ± 1.0 for MBIR&#95;myo. MBIR&#95;myo showed a significantly higher score than HIR (P < 0.001) and MBIR&#95;cardiac (P = 0.018). In the quantitative image quality assessment of myocardial CT-LE, the median image SNR was 10.3 (9.1-11.1) for HIR, 10.8 (9.8-12.1) for MBIR&#95;cardiac, and 16.8 (15.7-18.4) for MBIR&#95;myo. The median image CNR was 3.7 (3.0-4.6) for HIR, 3.8 (3.2-5.1) for MBIR&#95;cardiac, and 6.4 (5.0-7.7) for MBIR&#95;myo. MBIR&#95;myo significantly improved the SNR and CNR of CT-LE compared to HIR and MBIR&#95;cardiac (P < 0.001). The sensitivity, specificity, and accuracy for the detection of myocardial CT-LE were 70%, 92%, and 84% for HIR; 71%, 92%, and 85% for MBIR&#95;cardiac; and 84%, 92%, and 89% for MBIR&#95;myo, respectively. MBIR&#95;myo showed significantly higher image quality, sensitivity, and accuracy than the others (P < 0.05)., Conclusions: MBIR tuned for myocardium improved image quality and diagnostic performance for myocardial CT-LE assessment., Competing Interests: Conflict of interest: Shota Nakano is an employee of Canon Medical Systems Corporation. The rest of the authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) stabilizes hemodynamics in an electrical storm leading to cardiogenic shock. However, adverse effects of VA-ECMO are increased left ventricular (LV) afterload and LV end-diastolic pressure due to retrograde blood return. These adverse effects could be ameliorated by LV unloading with Impella insertion. This case illustrates the possible efficacy of adjunctive Impella insertion for a refractory electrical storm that is resistant to defibrillation under mechanical support with VA-ECMO for cardiogenic shock., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Akazawa et al.)

Background: Sarcoidosis is a systemic inflammatory disorder and can often affect any other organs beyond the heart. Whole-body 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is used to detect not only cardiac but also extra-cardiac involvement of sarcoidosis. However, the features and clinical impact of extra-cardiac lesions have not yet been fully elucidated. Therefore, this study aimed to clarify these using FDG-PET., Methods and Results: We enrolled 120 consecutive patients with abnormal findings clinically suggesting cardiac sarcoidosis who underwent whole-body FDG-PET. In this study, a patient with suspected cardiac sarcoidosis was defined as one having both clinically suspected findings and FDG-PET positive cardiac uptake. Subsequently, a total of 36 patients with suspected cardiac sarcoidosis were found and analyzed. Extra-cardiac involvement was detected in 35 lesions of 14 patients (39% per patient). In particular, the extra-cardiac lesions were widely distributed throughout the body, and mediastinal/hilar lymph node involvement was most commonly observed. In most of the patients (93% per patient, 13/14), the extra-cardiac lesions were localized in the regions that were considered more accessible with less risk of complication compared with endomyocardial biopsy (EMB). Based on the FDG-PET findings, 8 patients underwent extra-cardiac biopsy without complication, and its diagnostic sensitivity for histological sarcoidosis was high (75%, 6/8). Moreover, FDG-PET-guided extra-cardiac biopsy could confirm histological sarcoidosis in 4 lesions that EMB failed to prove., Conclusions: Extra-cardiac involvement in patients with suspected cardiac sarcoidosis was relatively high. FDG-PET-guided extra-cardiac biopsy may be safe and useful for the imaging based diagnosis of cardiac sarcoidosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Aims: Several studies have demonstrated that type 2 diabetes mellitus (T2DM) is associated with accelerated atherosclerosis, which results in an increased risk of coronary vascular events. However, serial changes in plaque characteristics have not been reported in vivo. We evaluated the progression of coronary atherosclerosis in patients with T2DM using an integrated backscatter intravascular ultrasound (IB-IVUS) examination., Methods and Results: Forty-two T2DM and 48 non-diabetic patients who underwent percutaneous coronary intervention were enrolled in the study. Non-culprit 20-mm length coronary lesions with mild-to-moderate stenosis were measured using a 40-MHz (motorized pullback of 0.5 mm/s) IVUS catheter. IVUS examinations were performed on one target lesion in each patient. Six months later, a follow-up IVUS examination was repeated in the same coronary segment imaged at the baseline examination. T2DM patients demonstrated a greater total plaque volume (TPV; 139 ± 53 vs. 114 ± 45 mm(3), P = 0.02) and total lipid volume (TLV; 67 ± 26 vs. 55 ± 30 mm(3), P = 0.039) at the baseline examination. The progression of TPV (8.6 ± 15.4 vs. -2.2 ± 16.0%, P < 0.01) and TLV (10.8 ± 28.8 vs. -2.5 ± 20.0%, P < 0.05) from the baseline was observed in T2DM patients, but not in non-diabetic patients. The increase in TLV was blunted in T2DM patients who achieved HbA1c levels of <6.5%., Conclusion: Accelerated plaque progression with an increase in the lipid-rich component of non-culprit plaques was observed in T2DM, despite the use of standard medical treatment. Better glycaemic control ameliorated the worsening of plaque characteristics in T2DM.

Aims: Late gadolinium enhancement (LGE) on contrast-enhanced magnetic resonance imaging (MRI) in hypertrophic cardiomyopathy (HCM) has been reported to be associated with myocardial fibrosis and cardiac events. In patients with HCM, two-dimensional (2D) strain can identify subclinical global systolic dysfunction despite normal left ventricular (LV) chamber function. Therefore, this study tested the hypothesis that global 2D strain could detect subtle myocardial fibrosis and serve as a novel prognostic parameter in HCM patients., Methods and Results: Echocardiography and MRI were performed in 48 consecutive patients with HCM and normal chamber function. We measured global longitudinal strain (GLS) in apical two-chamber, four-chamber, and long-axis views using speckle-tracking analysis. The extent of LGE (%LGE = LGE volume/total LV volume) and LV mass index were calculated by MRI using Simpson's rule and custom software. All patients were followed up for major cardiac events. Global longitudinal strain in patients with LGE was significantly lower than that without LGE (-11.8 ± 2.8 vs. -15.0 ± 1.7%, P < 0.001). Multivariate analysis showed that GLS was an independent predictor of %LGE (standard coefficient = 0.627, P < 0.001). During a mean follow-up period of 42 ± 12 months, five patients had cardiac events. When the patients were stratified based on the median level of GLS (-12.9%), all events were observed in the worse GLS group (P = 0.018)., Conclusion: These results suggest that global 2D strain might provide useful information on myocardial fibrosis and cardiac events in HCM patients with normal chamber function.

Background: Activity of renin substrate cleavage (renin-like activity) was measured in vitro in plasma samples obtained from healthy human volunteers., Methods: Renin-like activity was determined using FRET (Fluorescence Resonance Energy Transfer) human renin substrate. Recombinant human renin and human plasma showed dose-dependent cleavage activity of FRET human renin substrate., Results: Activity of recombinant human renin was completely inhibited by either a peptidergic or a non-peptidergic renin inhibitor. However, renin-like activity in human plasma was not inhibited by these renin inhibitors. In a mixture of recombinant renin and human plasma, renin inhibitors inhibited only that part of the activity caused by recombinant renin, while the activity in plasma still remained. Human plasma did not show cleavage activity of rat FRET renin substrate. Native human prorenin showed cleavage activity of human renin substrate. This activety was also completely inhibited by renin inhibitors. Immunoprecipitation with anti-renin or anti-prorenin antibodies did not reduce the activity in human plasma. Renin-like activity in human plasma was abolished by degeneration of protein when sample was heated to 95 degrees C. Activity of both recombinant renin and human plasma was significantly inhibited by a protease inhibitor cocktail., Conclusions: These results suggest that the activity of renin substrate cleavage in human plasma is not mainly caused by the renin or prorenin molecule, but probably by other proteases.

Background: To explore the metabolic actions of nifedipine on diabetes, we examined glucose intolerance and white adipose tissue changes in type 2 diabetic KK-A(y) mice., Methods: Male KK-A(y) mice were treated with nifedipine (1.5 mg/kg/day in lab chow) for 5 weeks, which did not affect blood pressure or feeding of KK-A(y) mice., Results: After treatment with nifedipine, body weight tended to decrease and the weight of white adipose tissue was reduced. Without food restriction, nifedipine decreased plasma insulin level, while plasma glucose level tended to decrease. In oral glucose tolerance test, nifedipine suppressed the increase in glucose level after a glucose load without affecting plasma insulin concentration. Nifedipine also improved the result of insulin tolerance test. In white adipose tissue, nifedipine increased adipocyte number and the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and adipocyte fatty acid-binding protein related to adipocyte differentiation. In addition, expression of adiponectin, insulin receptor, insulin receptor substrate-1, and glucose transporter type-4 was also increased by nifedipine. Nifedipine also increased the expression of NO synthase in white adipose tissue. Nifedipine did not affect expression of angiotensin II type 1 (AT₁) and type 2 (AT₂) receptors in white adipose tissue. Such changes in white adipose tissue were apparent in retroperitoneal adipose tissue. Nifedipine did not change the expression of angiotensin receptors, renin receptor, and angiotensinogen in white adipose tissue. Moreover, nifedipine attenuated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased superoxide dismutase (SOD) activity in white adipose tissue., Conclusion: These results suggest that nifedipine can enhance insulin sensitivity and reduce white adipose tissue, possibly related to stimulation of adipocyte differentiation.

Background: Previous reports indicated that blockade of AT(1) receptor stimulation attenuated adipocyte dysfunction. However, the effects of AT(2) receptor stimulation on adipose tissue were not yet clear. In the present study, we examined the adipose tissue dysfunction in atherosclerotic apolipoprotein E knockout (ApoEKO) mice with AT(2) receptor deficiency., Methods: Male ApoEKO and AT(2) receptor/ApoE knockout (AT(2)/ApoEKO) mice at 6 weeks of age were treated with a normal diet or a high-cholesterol diet (HCD: 1.25% cholesterol). Markers for adipocyte differentiation and inflammation in adipose tissue were assayed with real-time reverse-transcription-PCR and western blot., Results: Compared with ApoEKO mice, AT(2)/ApoEKO mice with a normal diet showed only a decrease in expression of adiponectin and CCAAT/enhancer binding protein delta (C/EBPdelta) in epididymal adipose tissue without changes in body weight, adipose tissue weight, and adipocyte number even at 6 months of age. After HCD for 4 weeks, the weight of both epididymal and retroperitoneal adipose tissue in AT(2)/ApoEKO mice was greater than that in ApoEKO mice without a change in body weight. Plasma concentrations of cholesterol and fatty acids were higher in AT(2)/ApoEKO mice than in ApoEKO mice. In adipose tissue of AT(2)/ApoEKO mice, the adipocyte number was decreased and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), C/EBPalpha, and aP2 was lower than that in ApoEKO mice, in association with an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity., Conclusions: These results suggest that AT(2) receptor stimulation in adipose tissue is involved in the improvement of adipocyte differentiation and adipose tissue dysfunction in atherosclerotic model.

Background: A combination of different types of antihypertensive drugs is widely used for the treatment of hypertension. We examined the inhibitory effects of a combination of an AT(1) receptor blocker (ARB), olmesartan, with various calcium channel blockers (CCBs) on inflammatory vascular remodeling., Methods: Inflammatory vascular remodeling was induced by polyethylene-cuff placement around the femoral artery of C57BL/6J mice at 10 weeks of age. Olmesartan (0.5 mg/kg/day) was administered intraperitoneally using an osmotic minipump. CCBs (nifedipine 1.0 mg/kg/day, amlodipine 0.1 mg/kg/day, azelnidipine 0.1 mg/kg/day), and hydrochlorothiazide (HCTZ 0.5 mg/kg/day) were administered orally., Results: In the injured artery, superoxide anion production and expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47(phox) and Rac-1 were markedly increased, together with expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-alpha. Administration of a single drug alone at each concentration did not significantly inhibit these changes in the injured artery. However, a combination of olmesartan with various CCBs inhibited neointimal formation as well as oxidative stress and inflammatory markers in the injured artery. Moreover, among these CCBs, inhibition of these markers by olmesartan with azelnidipine was stronger than that caused by a combination with other CCBs. On the other hand, a combination of subeffective doses of olmesartan and HCTZ did not significantly affect vascular changes after cuff placement., Conclusions: These results suggest that the combination of ARB with CCB synergistically inhibits vascular remodeling and that the inhibitory actions of ARB on vascular remodeling may vary depending on the combined CCB.

Hypertension has long been recognized as a major risk factor of several cardiovascular diseases. It is well known that the renin-angiotensin system(RAS) is involved in the pathogenesis of both hypertension and hypertensive end-organ damage. Untreated hypertension is self-accelerating condition through RAS stimulation. Activation of RAS contributes to the transition from borderline hypertension to established hypertension. Recently, "the Seventh Report of Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)" proposed a new classification of borderline blood pressure levels, as "prehypertension". The therapeutic focus has begun to shift from the therapy of established hypertension to the prevention of hypertension. This review addressed the relationship between hypertension, prehypertension and the role of RAS.

Background: The roles of the angiotensin (Ang) II type 1 (AT(1)) receptor in the changes in white adipose tissue were explored in an animal model of atherosclerosis using apolipoprotein E-deficient (ApoEKO) mice., Methods: Apolipoprotein E-deficient (ApoEKO) mice and KK-A(y) mice were used. Expression of markers for adipocyte differentiation and inflammation was determined by real-time reverse-transcription polymerase chain reaction., Results: Adipose tissue weight and adipocyte size in epididymal white adipose tissue were increased in ApoEKO mice and KK-A(y) mice. In the adipose tissue of these models, expression of adiponectin and peroxisome proliferator-activated receptor-gamma (PPARgamma), which induce adipocyte differentiation, and expression of transcription factors of adipocyte differentiation, such as CCAAT-enhancer-binding protein-alpha (C/EBPalpha) and aP2, were decreased. Expression of inflammatory markers and nicotinamide adenine dinucleotide phosphate oxidase subunits was also increased. Deletion of AT(1)a receptor in ApoEKO mice and administration of an AT(1) receptor blocker, valsartan, to KK-A(y) mice reduced epididymal adipose tissue weight and adipocyte size significantly. Blockade of the AT(1) receptor also reduced the expression of inflammatory chemokines and oxidative stress markers. Moreover, AT(1)a receptor deletion in ApoEKO mice and AT(1) receptor blockade in KK-A(y) mice prevented the decrease in expression of adiponectin, PPARgamma, C/EBPalpha, and aP2. Valsartan also increased glucose uptake induced by insulin in adipose tissue of KK-A(y) mice., Conclusions: These results suggest that enlargement and weakened differentiation of adipocytes are observed in atherosclerosis and diabetes, and that AT(1) receptor blockade prevented adipocyte enlargement and promoted adipocyte differentiation in these models.

Background: The effect of a calcium channel blocker (CCB) on the expression of monocyte chemoattractant protein (MCP)-1 was explored in inflammatory vascular injury, focusing on the role of nuclear factor (NF)-kappaB., Methods: Vascular injury was induced by cuff placement. Expression of MCP-1 was determined by real-time RT-PCR. NF-kappaB expression and its activity were detected by Western blot and electrophoretic mobility shift assay., Results: Polyethylene cuff placement around the mouse femoral artery increased MCP-1 expression, together with proliferation of vascular smooth muscle cells and neointimal formation in the injured artery. The content of NF-kappaB was decreased in the cytosolic fraction but increased in the nuclear fraction prepared from the injured artery. In the nuclear fraction, the binding activity of NF-kappaB to the promoter region of MCP-1 was markedly increased. On the other hand, IkappaB content in the cytosolic fraction was decreased in the injured artery after cuff placement, accompanied by an increase in IkappaB kinase (IKK) phosphorylation. Treatment of mice with a CCB, nifedipine, at a dose of 5 mg/kg/day, significantly decreased vascular smooth muscle cell proliferation and neointimal formation without affecting blood pressure. This dose of nifedipine inhibited the increase in MCP-1 expression in the injured artery. Moreover, nifedipine reduced the nuclear content and DNA-binding activity of NF-kappaB in the injured artery. In contrast, the decrease in IkappaB content and the increase in IKK phosphorylation in the cytosolic fraction were attenuated by nifedipine., Conclusions: These results indicate that MCP-1 expression in inflammatory vascular injury is regulated by activation of NF-kappaB. The results also suggest that nifedipine attenuates MCP-1 expression in the injured artery via inhibition of the nuclear translocation and DNA-binding activity of NF-kappaB, and thereby improves vascular remodeling.