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Graphical abstract Highlights • Endothelin-1 (ET-1) causes potent vasoconstriction and vasoproliferation. • Cardiomyocytes produce ET-1, which causes a hypertrophic activity of cardiomyocytes. • ET-1 acts via activation of two receptor subtypes, ET A and ET B receptors. • ET receptor antagonists (ERA) are currently in clinical use for pulmonary hypertension. • Heart failure, renal diseases, hypertension, etc are further target diseases of ERA. Abstract Endothelin-1 (ET-1), a 21-amino acid peptide, was initially identified in 1988 as a potent vasoconstrictor and pressor substance isolated from the culture supernatant of porcine aortic endothelial cells. From human genomic DNA analysis, two other family peptides, ET-2 and ET-3, were found. They showed different effects and distribution, suggesting that each peptide may play separate roles in different organs. In the heart, ET-1 also causes positive inotropic and chronotropic responses and hypertrophic activity of the cardiomyocytes. ETs act via activation of two receptor subtypes, ET A and ET B receptors, both of which are coupled to various GTP-binding proteins depending on cell types. Endogenous ET-1 may be involved in progression of various cardiovascular diseases. ET antagonists are currently used clinically in the treatment for patients with pulmonary hypertension, and are considered to have further target diseases as heart failure, cardiac hypertrophy and other cardiac diseases, renal diseases, systemic hypertension, and cerebral vasospasm. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Recent guidelines have emphasized the need for uninterrupted chest compressions. The purpose of this study was to evaluate the rescuer's tolerability of uninterrupted chest compressions. METHODS: Twenty-five healthy subjects performed uninterrupted chest compressions for 7 minutes at a rate of 100 compressions per minute using a training manikin. The quality of chest compressions was assessed in terms of the total number and percentage of chest compressions, compression depth, recoil distance, and duty cycle. Correct chest compression was defined as a depth of 38 to 51 mm. Physiological and laboratory parameters were measured before and after the procedure. Fatigue was measured using a numerical rating scale. Data were compared before and after the procedure. RESULTS: The participants were 10 emergency physicians and 15 medical students. The compression rate was nearly 100 compressions per minute. The number and percentage of correct compressions decreased gradually after 3 minutes. The compression depth decreased significantly after 2 minutes. The recoil distance and duty cycle were unchanged over 7 minutes. Systolic blood pressure, pulse rate, respiratory rate, numerical rating scale, serum lactate, adrenalin, and noradrenalin increased significantly after the procedure. Noradrenalin levels measured before the procedure were significantly and negatively correlated with the total number and percentage of correct compressions (r = -0.587, P = .004; r = -0.549, P = .008, respectively). CONCLUSIONS: Performing uninterrupted chest compressions for 7 minutes is an arduous procedure. Higher noradrenalin levels before the procedure might be associated with incorrect chest compressions. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects.: BackgroundPatients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis.: MethodsTwenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uni-nephrectomized rats as normotensive controls.: ResultsFenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (−dP/dtmax/P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate.: ConclusionsA PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease. [Copyright &y& Elsevier]

Endothelin (ET)-1 and ET-2 are potent vasoconstrictor peptides with mitogenic activity. In this study, we investigated roles of ET system in renin-angiotensin system (RAS)-mediated hypertension, using transgenic hypertensive mice (THM) with over-expression of both human renin and angiotensinogen genes. In the first step, it was revealed that expression of ET system was locally enhanced, i.e. increases in cardiac preproET-1 mRNA and renal preproET-2 mRNA in THM, compared with the control (wild type) mice. In the next step, we studied the chronic effects of an ET antagonist (SB209670) on THM. Blood pressure (BP) in THM was significantly higher than that in the normal mice during the investigation. However, in the later phase of the study, from 12 to 20 weeks of treatment, THM receiving SB 209670 showed significantly lower BP than that in THM receiving saline. SB 209670 treatment for 20 weeks significantly attenuated phenotypes of cardiac hypertrophy, vascular wall thickening and hypertensive nephropathy observed in THM, suggesting that the ETA/B receptor antagonist is also effective even in the extraordinarily activated RAS condition. These findings suggest that organ specifically activated ET system in THM develops the phenotypes, hypertension, cardiac hypertrophy, and hypertensive nephropathy. [Copyright &y& Elsevier]

Objectives: We sought to investigate whether the combination of an oral endothelin (ET)A receptor antagonist and an oral prostacyclin (PGI(2)) analogue is superior to the single use of each drug alone for treating pulmonary hypertension (PH).Background: Treatment with intravenous PGI(2) or an ET(A) receptor antagonist was effective for PH; however, the effect of both agents is unclear.Methods: We administered the oral ET(A) receptor antagonist TA-0201 and/or the oral PGI(2) analogue beraprost sodium (BPS) to rats with monocrotaline-induced PH for 19 days. The groups were: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group) and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group).Results: Right ventricular (RV) systolic pressure and the ratio of RV systolic pressure to systemic systolic blood pressure (Pp/Ps) were markedly higher in the PH group than in the Control group. The increased RV systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA and PH + BPS groups; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indexes of RV hypertrophy showed the same tendency as the increase in RV systolic pressure among the five groups. The expression of beta-myosin heavy chain messenger ribonucleic acid in the RV was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in the PH + TA + BPS group. Combined treatment also ameliorated PH, even if it started after the onset of PH.Conclusions: The combination of an oral ETA receptor antagonist and an oral PGI(2) analogue is superior to the single use of each drug alone in inhibiting the progression of PH. [ABSTRACT FROM AUTHOR]

Presents evidence that an endothelin receptor antagonist is a useful drug for the treatment of heart failure. How endothelin-1 exerts long-term effects, such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes; Thought that myocardial endothelin system appears to be an important target for therapeutic intervention in heart failure.

In Japan, high economic growth after the war brought about disorderly urban sprawl. The government then enforced an "area division system," which divided city planning areas into "urbanization promotion areas" (UPA) and "urbanization control areas" (UCA). This system maintains the existing UPA size almost unconditionally and, in addition, aims to incorporate parts of UCA into UPA by the size corresponding to new housing demands, which is based on an incremental of the future population prediction. Therefore, there was no need for an objective judgment criterion to verify that the total size of the expanded UPA was suitable for the population size; there are also no related previous studies. Nevertheless, this was not recognized as a major problem when local government finances were abundant due to population increase. However, in Japan, the arrival of an era of unprecedented population decline is certain; maintaining a huge number of urban facilities at the current UPA size could seriously damage local government finance. Shrinking UPAs are an urgent issue and it is time to seriously discuss the appropriate UPA size for the size of the population. In this study, we developed a quantitative estimation method of UPA size, commensurate with population size, through regression analysis of the relationship between population and UPA size. This estimation method is based on the strong correlation between population and UPA size, therefore it can be used as a judgment criterion for local governments to reach appropriate UPA sizes when considering compact cities. • Urban size estimation method for compact cities in depopulation era was developed. • Relationship between population and urban size was clarified by regression analysis. • Appropriate urban size commensurate with population can be estimated quantitatively. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Abnormal eating behaviors such as compulsive overeating, eating fast, chewing less, palatable soft food preferences and avoiding hard food are often observed in obese individuals, and these behaviors may affect their masticatory function, but little information of masticatory function in obese subjects are available at present. The present study investigated masticatory function in non-elderly obese Japanese adults and explored the relationships between obesity and masticatory function. Methods: Seventy-five obese subjects (BMI≥25; male: 34, female: 41) and 98 subjects with normal weight (BMI 18.5–25; male: 63, female: 35) aged 25–40 years old were enrolled in the present study. The status of masticatory function was determined using a chewing gum mixing method, a direct method of examining masticatory function, and the numbers of present teeth, untreated decayed teeth, missing teeth, and filled teeth were also examined. Results: Masticatory function was significantly lower in the obese subjects both in male and female, whereas the numbers of present teeth, decayed teeth, missing teeth and filled teeth did not differ significantly between the obese subjects and the controls both in male and female. Multiple regression analysis revealed a significant correlation between obesity and reduced masticatory function after adjustment for gender, age, and numbers of decayed teeth, missing teeth, and filled teeth. Conclusions: Significantly reduced masticatory function was found in male and female non-elderly obese adults based on direct measurement of masticatory function. Multiple regression analysis suggested that obesity might induce reduced masticatory function. [Copyright &y& Elsevier]

Abstract: Background: The transpulmonary thermodilution technique allows the determination of cardiac preload (global end-diastolic volume index) and quantification of pulmonary edema (extravascular lung water index [EVLWI]). Pulmonary edema commonly develops in critically ill patients; however, the underlying pathophysiology, that is, hydrostatic (cardiac) or permeability-induced (noncardiac), often remains unclear. In this study, hemodynamic and serum parameters of osmolarity and oncotic pressure were analyzed to identify risk factors for increased EVLWI. Methods: A retrospective, single-center analysis in an intensive care unit of a university hospital was performed. No interventions were made for the study. Forty-two critically ill patients were included, and 126 simultaneous hemodynamic measurements and serum determinations were analyzed by logistic regression and Spearman rank correlation coefficient analysis. Results: Global end-diastolic volume index (P = .001), serum albumin (P = .006), and serum osmolarity (P = .029) were significant factors for increased EVLWI (defined as >10 mL/kg). Conclusion: Hypervolemia, hypoalbuminemia, and high plasma osmolarity are associated with increased EVLWI. [Copyright &y& Elsevier]

Summary: Objectives: Several recent reports have indicated a high prevalence of periodontitis in obese subjects, but the results have not been consistent. This study was performed to investigate the prevalence of periodontitis in non-elderly obese Japanese adults and to explore the relationship between obesity and periodontitis. Methods: Ninety-five obese subjects (BMI≥25; males: 44, females: 51) and 102 subjects with normal weight (BMI 18.5–25; males: 66, females: 36) were enrolled from April 1997 to March 1999 in the study. All subjects were aged 25–40 years old. The status of periodontitis was evaluated based on the intraoral community periodontal index (CPI) codes of the WHO, and the numbers of present teeth, untreated decayed teeth, missing teeth, and filled teeth were also examined. Results: The prevalence of periodontitis was significantly higher in obese subjects, and particularly in females, compared to controls, whereas the numbers of present teeth, decayed teeth, missing teeth and filled teeth did not differ significantly between the obese subjects and the controls for both males and females. Multiple logistic regression analysis revealed that obesity was significantly related to periodontitis. Conclusion: A high prevalence of periodontitis was found in non-elderly Japanese obese subjects, and particularly in obese female adults. Correlation analysis also suggested that obesity carries a high risk for development of periodontitis. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Although morning hypertension (HT) has been identified as a major cardiovascular risk, susceptible populations remain unknown. This study aimed to clarify the relationship between morning HT and diabetes or obesity in a large-scale population. Main methods: Clinic blood pressure (BP) and BP upon awakening were recorded in 2554 outpatients with HT who attended 101 clinics or hospitals for two weeks. Mean clinic and awakening BP>140/90 and >135/85mmHg, respectively, were considered as HT. The patients were classified according to values for clinic and home BP, into normal BP, white coat HT, masked HT, and sustained HT. Key findings: Morning BP (mmHg) significantly and progressively elevated in the order of normal glucose tolerance, impaired glucose tolerance and diabetes (134.1±12.2, 135.4±13.1 and 137.5±11.5; p<0.0001). The incidence of morning HT significantly increased and progressively in the same order (53.4%, 55.6%, 66.4%, p<0.0001). Morning BP was significantly higher among obese patients with diabetes than among non-obese and non-diabetic patients (138.8±10.5, 133.1±11.9, p<0.0001). In addition, the incidence of morning HT was significantly higher in obese diabetic patients than in non-obese and non-diabetic patients (73.0% vs. 49.9%, p<0.0001). Significance: Diabetic or obese patients frequently have morning HT. [Copyright &y& Elsevier]

Abstract: Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ETA and ETB, which are present – among others – on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target. [Copyright &y& Elsevier]

Abstract: Professor Tomoh Masaki, a Japanese physician-scientist born in 1934, is particularly known for the discovery of endothelium-derived peptide endothelin and its receptors, among many other scientific achievements. In recognition of his work, the Tomoh Masaki Award was established in 2011 by the Endothelin International Advisory Board of The International Conferences on Endothelin as a biannual scientific prize in recognition of Masaki''s innovative and ground-breaking work that has led to new clinical applications. The inaugural Tomoh Masaki Award was presented at The Twelfth International Conference on Endothelin held in Cambridge, UK, to one his former graduate students, Professor Masashi Yanagisawa as the first recipient of this award, who played an instrumental role in the discovery of endothelin at the University of Tsukuba, Japan. The article summarizes the scientific achievements of Masaki and the awardee, Masashi Yanagisawa, also including personal reflections of two of Masaki''s former graduate students on their teacher as well as on the awardee of The First Tomoh Masaki Award 2011 and their work as scientists and their role as mentors. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the prevalence and associated factors of delirium in critically ill patients during an intensive care unit (ICU) stay. Methods: We investigated 103 of 172 patients admitted consecutively to a university-based 20-bed ICU in a 3-month period. Six ICU physicians, who were familiar with the Confusion Assessment Method for the ICU (CAM-ICU), assessed patient delirium daily. Patient demographics, diagnosis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, mechanical ventilation and maximum serum C-reactive protein (max-CRP) level during the ICU stay (max-CRP) were compared between patients who developed delirium and those who did not. Results: Twenty-one (20%) of 103 patients and 13 (76%) of 17 mechanically ventilated patients developed delirium. APACHE II scores and max-CRP were significantly higher in patients who experienced delirium than in those who did not (P<.001). Use of a mechanical ventilator (P=.002), max-CRP (P=.032) and length of ICU stay (P=.043) were identified as independent associations for delirium development. Conclusions: The prevalence of delirium was 20% in ICU patients and 80% in ventilated patients in a Japanese ICU. [Copyright &y& Elsevier]

Abstract: Aim of the study: Serum glial fibrillary acidic protein (GFAP) has recently been identified as a specific predictor of brain damage and neurological outcome in patients with head trauma. In this study, serum GFAP was assessed as a predictor of neurological outcome in post-cardiac-arrest (PCA) patients. Methods: This study was a retrospective, single-medical-center analysis, conducted in the intensive care unit of a university hospital. Forty-four sequential PCA patients with cardiogenic or non-cardiogenic arrest were included. The patients were treated with or without therapeutic hypothermia (TH). Serum samples were collected from the patients at 12, 24, and 48h after the return of spontaneous circulation (ROSC). Serum GFAP concentrations were measured by enzyme-linked immunosorbent assay and compared in patients with good and poor neurological outcomes, evaluated over a period of 6 months using Glasgow Outcome Scale. Results: Serum GFAP was significantly higher in patients with a poor outcome at 12 and 24h without TH and at 48h with TH (P <0.05). GFAP (>0.1ngdL−1) was a specific predictor of poor neurological outcome at 6 months with or without TH treatment. Conclusions: Although this study is preliminary, serum GFAP after ROSC reflected a poor neurological outcome in PCA patients. [Copyright &y& Elsevier]

Aims Vascular remodeling results from aberrations in the balance between cell proliferation and death, which is seen in the obstructive vasculature of pulmonary arterial hypertension (PAH). Endothelin (ET)-1 has a potent proliferative activity on vascular smooth muscle cells, and ET receptor inhibitors are used to treat PAH; however, it remains unclear whether ET receptor inhibition contributes to the apoptosis of pulmonary arterial smooth muscle cells (PASMCs), another cause of pulmonary vascular remodeling. Main methods Cultured human PASMCs were treated with the ET A receptor antagonist BQ-123 (100 μM), or the ET B antagonist A-192621 (1 – 100 μM) or BQ-788 (1 – 100 μM) for 48 h. The cells were then incubated for another 24 h with or without doxorubicin (DOX, 1 μM), an anthracyclin antitumor antibiotic that promotes p53-mediated apoptosis. Cell viability and apoptosis were evaluated by MTT assays, caspase-3/7 activity assays, and Western blots for cleaved caspase-3 expression. Key findings The viability of PASMCs was significantly decreased by A-192621 and BQ-788, in a dose-dependent manner. A-192621 and BQ-788 significantly increased the caspase-3/7 activity and cleaved caspase-3 expression in PASMCs. The PASMCs' susceptibility to DOX-induced apoptosis was significantly higher in the presence of A-192621 and BQ-788 than with vehicle. However, BQ-123 did not affect these parameters. Significance Blockade of the ET B receptor increases the extent of apoptosis and susceptibility to DOX-induced apoptosis in PASMCs. Apoptosis caused by ET B receptor blockade in PASMCs may be one of the mechanisms by which vascular remodeling is reduced in ET receptor inhibitor-based PAH treatments. [ABSTRACT FROM AUTHOR]

Objective: To determine the effects of cardiopulmonary resuscitation (CPR) with AutoPulse™ (LDB-CPR) on post-resuscitation injuries identified by post-mortem computed tomography (PMCT). AutoPulse™ is a novel mechanical chest-compression device with a load-distributing band (LDB) that may affect post-resuscitation injury identified by PMCT.Methods: We conducted a retrospective cohort study of non-traumatic adult out-of-hospital cardiac arrest patients whose death was confirmed in our emergency department between October 2009 and September 2014. Patients were divided according to whether LDB-CPR (LDB-CPR group) or manual CPR only (manual CPR only group) was performed. The background characteristics and post-resuscitation injuries identified by PMCT were compared between both groups. Logistic regression was used to identify risk factors for posterior rib fracture and abdominal injury.Results: Overall, 323 patients were evaluated, with 241 (74.6%) in the LDB-CPR group. The total duration of CPR was significantly longer in the LDB-CPR group than in the manual CPR only group. Posterior rib fracture, hemoperitoneum, and retroperitoneal hemorrhage were significantly more frequent in the LDB-CPR group. The frequencies of anterior/lateral rib and sternum fracture were similar in both groups. Pneumothorax tended to be more frequent in the LDB-CPR group, although not significantly. LDB-CPR was an independent risk factor for posterior rib fracture (odds ratio 30.57, 95% confidence interval 4.15-225.49, P=0.001) and abdominal injury (odds ratio 4.93, 95% confidence interval 1.88-12.95, P=0.001).Conclusions: LDB-CPR was associated with higher frequencies of posterior rib fracture and abdominal injury identified by PMCT. PMCT findings should be carefully examined after LDB-CPR. [ABSTRACT FROM AUTHOR]

Aims Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We investigated the ameliorating effect of CGRP in myocardial ischemia induced by endothelin-1 (ET-1), with special emphasis on myocardial microvascular hemodynamics and levels of energy-related metabolites. Main methods The Langendorff preparations of rat isolated heart were perfused at a constant flow rate. Microvascular blood flow was also visualized in the anterior epicardium of the left ventricle by means of an intravital fluorescence microscope system. Energy-related metabolite contents in the myocardium were measured by means of 31 P-magnetic resonance spectroscopy ( 31 P-MRS). Key findings Intracoronary bolus injections of CGRP caused dose-dependent decreases in coronary perfusion pressure (CPP) in the hearts exposed to ET-1 (30 pmol). The vasodilator potency of CGRP was about 10,000-fold greater than that of nitroglycerin and 1,000-fold greater than that of isobutylmethylxanthine. Vasodilation of the small-sized arterioles (10–40 μm in diameter) in response to CGRP (100 pmol) was confirmed by direct microscopic observation. After ET-1 (30 pmol) plus vehicle administration, high energy phosphates (phosphocreatine (PCr), ATP) were markedly reduced (p < 0.05). CGRP administration significantly (p < 0.05) attenuated the anaerobic changes in the myocardium (decrease in PCr) and macrohemodynamic alterations (increase in CPP, decrease in dP/dt etc.) induced by ET-1. Significance We conclude that CGRP effectively confers hemodynamic and metabolic protections to isolated beating hearts against ET-1-induced myocardial ischemia. [ABSTRACT FROM AUTHOR]

Aims A growing body of evidence shows the cardiovascular benefits of fish oil ingredients, including eicosapentaenoic acid (EPA), in humans and experimental animals. However, the effects of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy and the involved signaling cascade are largely unknown. A previous study has demonstrated that peroxisomal proliferator-activated receptor (PPAR)-α ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Although EPA is a ligand of PPAR-α, to date, no study has examined a relationship between EPA and PPAR-α in cardiomyocyte hypertrophy. Here, we investigated whether EPA can block ET-1-induced cardiomyocyte hypertrophy and the possible underlying mechanisms. Main methods At day 4 of culture, neonatal rat cardiomyocytes were divided into four groups: control, control cells treated with EPA (10 μM), ET-1 (0.1 nM) administered only and EPA-pre-treated ET-1 administered groups. Also, the cardiomyocytes were treated with PPAR-α siRNA in order to elucidate the mechanisms that may underlie suppression of hypertrophy via the EPA-PPAR system. Key findings Following ET-1 treatment, 2.12- and 1.92-fold increases in surface area and total protein synthesis rate in cardiomyocytes, respectively, were observed and these changes were greatly blocked by EPA pre-treatment. Further, the expression of PPAR-α increased in EPA-treated groups. PPAR-PPRE binding activity was suppressed in ET-1 administered cardiomyocyte and this suppression was improved by EPA treatment. Lastly, pre-treatment of cardiomyocytes with PPAR-α siRNA prior to EPA treatment attenuated the suppressing effects of EPA on cardiomyocyte hypertrophy. Significance In conclusion, the present study shows that EPA attenuates ET-1 induced cardiomyocyte hypertrophy by up regulating levels of PPAR-α pathway. [ABSTRACT FROM AUTHOR]

Aims Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Experimental autoimmune myocarditis (EAM) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy. The pathological role of endothelin (ET) in myocarditis has not been elucidated. Main methods EAM was induced by immunization of cardiac myosin peptide with complete Freund's adjuvant on days 0 and 7 in BALB/c mice. An ET A /ET B dual receptor antagonist, SB209670, was administered by a continuous infusion from a subcutaneous pump for 2 weeks. Key findings An increase in the heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. Heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the lesser inflammation in the hearts of vehicle-treated mice. We found that an ET blockade decreased the number of Foxp3 + regulatory T cells in the heart. The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor- and cytokine receptor-mediated signaling. EAM is a CD4 + T cell-mediated disease. CD4 + T cells isolated from SB209670-treated EAM mice produced less IL-10 and more inflammatory cytokines, IL-6 and IL-17, than those isolated from vehicle-treated mice. Significance The ET receptor antagonist exacerbated autoimmune myocarditis in mice. Our novel findings suggest that ET may play an important role in the regulation of inflammation in myocarditis. [ABSTRACT FROM AUTHOR]

Aims Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it. Main methods Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. Key findings Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. Significance We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart. [ABSTRACT FROM AUTHOR]

The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. Main methods Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. Key findings The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. Significance Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase, an enzyme responsible for the generation of NO. Plasma concentrations of ADMA increase in the elderly and in postmenopausal women. In fact, an elevated ADMA level is a risk factor of cardiovascular disease. Aerobic exercise has a beneficial effect on cardiovascular disease. However, the relationship between ADMA and aerobic fitness is unknown. The aim of this study was to determine whether plasma ADMA concentrations correlate with aerobic fitness levels in postmenopausal women. Main methods: Thirty healthy postmenopausal women aged 50–76years participated in this study. We measured plasma concentrations of ADMA and oxygen consumption at the ventilatory threshold (VO2VT) as an index of aerobic fitness. Subjects were divided into the low aerobic fitness (Low fitness) and high aerobic fitness (High fitness) groups, and the dividing line was set at the median VO2VT value. Key findings: VO2VT was significantly higher in the High fitness group than in the Low fitness group (P <0.01). The plasma ADMA concentrations in the High fitness group were significantly lower than those in the Low fitness group (P <0.05). There was a negative correlation between plasma ADMA concentrations and VO2VT (r =−0.532, P <0.01). Significance: We found that plasma ADMA concentrations were associated with aerobic fitness in postmenopausal women. The results of this study suggest that habitual aerobic exercise may decrease plasma ADMA concentrations. [Copyright &y& Elsevier]

Abstract: Aims: Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels. Main methods: Male Wistar rats at 8weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10h). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for 3h to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney. Key findings: An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1h of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels. Significance: The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide. [Copyright &y& Elsevier]

Abstract: Aims: Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of their common intracellular pathways is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions. Main methods: We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [3H]-leucine incorporation. Key findings: Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [3H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it reached basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin. Significance: This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation. [Copyright &y& Elsevier]

Aims: Post-procedural myocardial necrosis manifested by elevated cardiac troponin T (cTnT) often complicates percutaneous coronary intervention (PCI). Plasma pentraxin 3 (PTX3) levels are increased in patients with arterial inflammation and especially unstable angina pectoris (UAP). This study tested whether plasma PTX3 levels can predict post-PCI cTnT elevation. Main methods: We evaluated 94 consecutive patients with AP and normal pre-PCI cTnT levels who underwent PCI. Pre-PCI virtual histology-intravascular ultrasound was performed to assess culprit plaque composition. Plasma PTX3 and serum hs-CRP levels were measured pre-PCI. Patients were divided into 2 groups according to presence (Group I, n=34) or absence (Group II, n=60) of post-PCI cTnT elevation >3× the upper limit of normal at 24h after PCI. Key findings: Plasma PTX3 (4.06±2.05ng/ml vs 2.17±1.02ng/ml, p<0.001), serum hs-CRP levels (0.25±0.03 vs 0.16±0.03mg/dl, p=0.048), plaque burden (80.9±5.3 vs 75.4±10.6%, p=0.047), presence of positive remodeling (59 vs 25%, p=0.034), and percent necrotic core area (19.0±7.4 vs 14.0±5.9%, p=0.046) were significantly higher in Group I than in Group II. Receiver-operating characteristic curve analysis showed that with a best cut-off value of 2.83ng/ml, plasma PTX3 level (AUC 0.823) predicted post-PCI cardiac TnT elevation better than did serum hs-CRP level (AUC 0.618). Multiple logistic regression analysis showed that plasma PTX3 level was the most independent predictor of post-PCI cardiac cTnT elevation (OR: 2.65; 95% CI: 1.56–10.1; p=0.003). Significance: Plasma PTX3 level may be a useful marker for predicting post-PCI cardiac cTnT elevation, which is associated with inflammatory status of culprit lesions. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Big endothelins (pro-endothelin; inactive-precursor) are converted to biologically active endothelins (ETs). Mammals and humans produce three ET family members: ET-1, ET-2 and ET-3, from three different genes. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3, which is produced by neuronal cells and organs such as the thyroid, salivary gland and the kidney. In patients with end-stage renal disease, abnormal vascular endothelial cell function and elevated plasma ET-1 and big ET-1 levels have been reported. It is unknown whether big ET-2 and big ET-3 plasma levels are altered in these patients. The purpose of the present study was to determine whether endogenous ET-1, ET-2, and ET-3 systems including big ETs are altered in patients with end-stage renal disease. Main methods: We measured plasma levels of ET-1, ET-3 and big ET-1, big ET-2, and big ET-3 in patients on chronic hemodialysis (n=23) and age-matched healthy subjects (n=17). Key findings: In patients on hemodialysis, plasma levels (measured just before hemodialysis) of both ET-1 and ET-3 and big ET-1, big ET-2, and big ET-3 were markedly elevated, and the increase was higher for big ETs (Big ET-1, 4-fold; big ET-2, 6-fold; big ET-3: 5-fold) than for ETs (ET-1, 1.7-fold; ET-3, 2-fold). Significance: In hemodialysis patients, plasma levels of the inactive precursors big ET-1, big ET-2, and big ET-3 levels are markedly increased, yet there is only a moderate increase in plasma levels of the active products, ET-1 and ET-3. This suggests that the activity of endothelin converting enzyme contributing to circulating levels of ET-1 and ET-3 may be decreased in patients on chronic hemodialysis. [Copyright &y& Elsevier]

Abstract: Aims: Cardiac hypertrophy is associated with the increase of total amount of RNA, which is in accordance with RNA polymerase II (RNAPII) activation via C-terminal domain (CTD) phosphorylation of the largest subunit of RNAPII. It has been demonstrated that endothelin-1 (ET-1) phosphorylates CTD at the hypertrophic response in cardiomyocytes. However, it is unclear whether ET-1-induced hypertrophy is affected by the CTD phosphatase, transcription factor IIF-interacting CTD phosphatase1 (FCP1). Main methods: We analyzed whether ET-1-induced cardiomyocyte hypertrophy was affected by overexpression of FCP1 or dominant-negative form of FCP1 (dnFCP1) in neonatal rat cardiomyocytes. Key findings: The level of ET-1-induced RNAPII CTD phosphorylation was decreased by FCP1 overexpression, whereas it was sustained by dnFCP1. Global RNA synthesis evaluated by [3H]-uridine incorporation showed that the ET-1-induced increase in RNA synthesis was suppressed by FCP1 and was augmented by dnFCP1. ET-1-induced increase in cell surface area was suppressed by FCP1 and was preserved by dnFCP1. Furthermore, the ET-1-induced increase in molecular markers of cardiac hypertrophy, expression of ANP and β-MHC gene, was suppressed by FCP1 and was not inhibited by dnFCP1. Significance: ET-1-induced cardiac hypertrophy and CTD phosphorylation level are functionally regulated by FCP1. These findings suggest that FCP1 plays an important role in ET-1-induced cardiac hypertrophy via controlling phosphorylation level of the RNAPII CTD. [Copyright &y& Elsevier]

Abstract: Aim of the study: In postcardiac-arrest (PCA) patients, hyperglycemia is a factor reflecting an unfavorable outcome, and might be caused by the inflammation and stress of “sepsis-like” syndrome. In this study, plasma glucagon, a representative glycogenolytic and gluconeogenic hormone, was measured and assessed the correlation for neurological outcome in PCA patients. Methods: This study was a retrospective, single-medical-center analysis, conducted in the intensive care unit of a university hospital. Twenty-four sequential PCA patients were included. Plasma samples were collected from the patients on days 1, 2, and 3 after the return of spontaneous circulation (ROSC). Glucagon was compared in patients with favorable and unfavorable neurological outcomes. Results: At all time points, plasma glucagon was significantly higher in patients with an unfavorable outcome (P <0.05). Glucagon on day 1 had remarkable sensitivity (88.2%) and specificity (85.8%) as an indicator of outcome, and correlated with the collapse–ROSC interval, the start of cardiopulmonary resuscitation (CPR)–ROSC interval, and the epinephrine dose during CPR. Conclusions: Plasma glucagon reflects unfavorable outcomes in PCA patients, and might be related to ischemic and reperfusion stress. [Copyright &y& Elsevier]

Abstract: Background: Regular aerobic exercise improves large artery compliance in middle-aged and older humans. However, the underlying mechanisms are unknown. We tested the hypothesis that the improved central arterial compliance with endurance training is mediated by decreased α-adrenergic tone and/or increased endothelial function. Methods: Seven sedentary healthy adults (60±3 years) underwent systemic α-adrenergic blockade (phentolamine) and nitric oxide synthase (NOS) inhibition using N G-monomethyl-l-arginine in sequence before and after a 3-month moderate endurance training (walk/jog, 4–5 days/week). Phentolamine was given first to isolate the contribution of nitric oxide to arterial compliance by minimizing reflex suppression of sympathetic tone resulting from systemic NOS inhibition as well as to assess the α-adrenergic receptor-mediated modulation of arterial compliance. Results: Baseline arterial compliance (via simultaneous ultrasound and applanation tonometry on the carotid artery) increased 34±12% after exercise training (P <0.01). When α-adrenergic blockade was performed, arterial compliance increased 37±6% (P <0.01) before the exercise training but did not change significantly after the training. Decreases in arterial compliance from the α-adrenergic blockade to the subsequent additional NOS blockade were not different before and after exercise training. Conclusion: Our results suggest that the reduction in α-adrenergic receptor-mediated vascular tone contributes to the improved central arterial compliance with endurance training. [Copyright &y& Elsevier]

Abstract: To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10h) by a single i.p. injection of lipopolysaccharide (LPS) (15mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3h; renal ET-1 protein and its receptors, ET type A (ETA) receptor (vasoconstrictive) and ET type B (ETB) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other. [Copyright &y& Elsevier]