RESUMO
BACKGROUND: Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. METHODS: We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. RESULTS: (1) Vascular endothelium-dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. CONCLUSIONS: These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan's higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Oxidiazóis/uso terapêutico , Vasculite/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Oxidiazóis/farmacologia , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Serina/metabolismo , Treonina/metabolismo , Vasculite/tratamento farmacológico , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Brown rice (BR) and white rice (WR) produce different glycaemic responses and their consumption may affect the dietary management of obesity. In the present study, the effects of BR and WR on abdominal fat distribution, metabolic parameters and endothelial function were evaluated in subjects with the metabolic syndrome in a randomised cross-over fashion. In study 1, acute postprandial metabolic parameters and flow- and nitroglycerine-mediated dilation (FMD and NMD) of the brachial artery were determined in male volunteers with or without the metabolic syndrome after ingestion of either BR or WR. The increases in glucose and insulin AUC were lower after ingestion of BR than after ingestion of WR (P= 0·041 and P= 0·045, respectively). FMD values were decreased 60 min after ingestion of WR (P= 0·037 v. baseline), but the decrease was protected after ingestion of BR. In study 2, a separate cohort of male volunteers (n 27) with the metabolic syndrome was randomised into two groups with different BR and WR consumption patterns. The values of weight-based parameters were decreased after consumption of BR for 8 weeks, but returned to baseline values after a WR consumption period. Insulin resistance and total cholesterol and LDL-cholesterol levels were reduced after consumption of BR. In conclusion, consumption of BR may be beneficial, partly owing to the lowering of glycaemic response, and may protect postprandial endothelial function in subjects with the metabolic syndrome. Long-term beneficial effects of BR on metabolic parameters and endothelial function were also observed.
Assuntos
Dieta , Endotélio Vascular/fisiologia , Análise de Alimentos , Obesidade/dietoterapia , Oryza/classificação , Adulto , Glicemia , Estudos Cross-Over , Humanos , Insulina/sangue , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-IdadeRESUMO
Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro. Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro. These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca2+ channels may differ among cells.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Ácidos Graxos não Esterificados/efeitos adversos , Hemorreologia/efeitos dos fármacos , Adulto , Antioxidantes/farmacologia , Linhagem Celular , Estudos Cross-Over , Método Duplo-Cego , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Adulto JovemRESUMO
PURPOSE: To investigate possible differences in the time course of vasodilating effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in humans. METHODS: We measured forearm blood flow (FBF) by strain gauge plethymography and cyclic GMP spillover during and after intra-arterial infusions of BNP and ANP at 16.2 pmol/min for 30 min in healthy subjects. RESULTS: The steady-state responses of FBF and cyclic GMP to the infusion were achieved approximately 20 min after commencement of the infusion of BNP, but within 5 min for ANP, with similar magnitudes of maximum responses. These parameters more slowly returned to the baseline value after withdrawal of the BNP infusion than after the ANP infusion. CONCLUSION: The onset and disappearance of the guanylate cyclase-stimulating and vasodilating effects of BNP were significantly slower than those of ANP. This differing mode of vasodilator action may be relevant to the therapeutic use of natriuretic peptides.
Assuntos
Fator Natriurético Atrial/farmacologia , GMP Cíclico/sangue , Peptídeo Natriurético Encefálico/farmacologia , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adolescente , Fator Natriurético Atrial/sangue , Antebraço/irrigação sanguínea , Guanilato Ciclase/fisiologia , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Adulto JovemRESUMO
Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.80 +/- 0.05 vs. -7.11 +/- 0.05 log(10) mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED(50), -7.16 +/- 0.03 and -7.14 +/- 0.05 log(10) mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Ácidos Graxos não Esterificados/sangue , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Acetofenonas/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatologia , Dislipidemias/metabolismo , Dislipidemias/fisiopatologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiopatologia , Inibidores Enzimáticos/farmacologia , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Masculino , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/fisiopatologia , Quinolinas/farmacologia , Ratos , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Veias Umbilicais/citologia , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: Abnormalities during the postprandial state contribute to the development of atherosclerosis. Reportedly, postprandial hyperglycemia, hypertriglyceridemia, and hyperlipacidemia independently cause postprandial cytokine activation. However, it is not clear which dietary composition preferentially affects postprandial endothelial function in healthy subjects. OBJECTIVE: We aimed to examine the associations of dietary composition and postprandial endothelial function in healthy subjects. DESIGN: The effects of a single ingestion of a high-carbohydrate meal (300 kcal, 100% carbohydrate), a high-fat meal (30 g fat/m(2), 35% fat), or a standard test meal (478 kcal; 16.4% protein, 32.7% fat, 50.4% carbohydrate) on postprandial plasma concentrations of adiponectin and forearm blood flow (FBF) during reactive hyperemia were studied in healthy subjects. RESULTS: The peak FBF response and the total reactive hyperemic flow (flow debt repayment; FDR), indexes of resistance artery endothelial function, were unchanged after ingestion of a high-carbohydrate and standard test meal but decreased 120 and 240 min after a high-fat meal. After a high-fat meal, decreases in peak FBF and FDR were well correlated with an increase in plasma free fatty acid (FFA) concentrations but not with the other biochemical variables, including triacylglycerol, insulin, glucose, total cholesterol, HDL cholesterol, and adiponectin. CONCLUSIONS: Postprandial endothelial function was impaired only after the high-fat diet and not after the high-carbohydrate or standard test meal in healthy subjects. Because such endothelial dysfunction after a high-fat meal was closely correlated with FFA concentrations, postprandial state could be hazardous, mostly through acute hyperlipacidemia in healthy subjects.
Assuntos
Adiponectina/sangue , Dieta , Gorduras na Dieta/metabolismo , Endotélio Vascular/fisiologia , Ácidos Graxos não Esterificados/sangue , Adulto , Braço/irrigação sanguínea , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Velocidade do Fluxo Sanguíneo , Estudos Cross-Over , Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Masculino , Período Pós-Prandial/fisiologiaRESUMO
CONTEXT: Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the alpha-glucosidase inhibitor acarbose was associated with a risk reduction of cardiovascular complications, but effects of acarbose on endothelial function have never been elucidated. DESIGN: This study was aimed to assess the efficacy of acarbose on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peakglucose (14.47 +/- 1.27 vs. 8.50 +/- 0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (DeltaAUC)glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 33.3%; carbohydrate 51.4%) were significantly higher in diet-treated type 2 diabetic patients (n = 14) than age- and sex-matched controls (n = 12). RESULTS: The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in controls. But those of diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of acarbose decreased postprandial peakglucose, PPGE, and DeltaAUCglucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peakglucose, PPGE, and DeltaAUCglucose but not with DeltaAUCinsulin or the other lipid parameters. CONCLUSIONS: Even a single loading of test meal was shown to impair endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of acarbose. Acarbose might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.
Assuntos
Acarbose/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Hipoglicemiantes/uso terapêutico , Área Sob a Curva , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Glicemia/efeitos dos fármacos , Tamanho Corporal , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta para Diabéticos , Endotélio Vascular/efeitos dos fármacos , Feminino , Antebraço/irrigação sanguínea , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-PrandialRESUMO
OBJECTIVE: An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. METHODS AND RESULTS: Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the coinfusion of vitamin C or NG-monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (P=0.0096) without L-NMMA, but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. CONCLUSIONS: Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels.
Assuntos
Endotélio Vascular/fisiologia , Ácidos Graxos não Esterificados/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Acetilcolina/administração & dosagem , Adulto , Anticoagulantes/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Heparina/administração & dosagem , Humanos , Lipídeos/administração & dosagem , Losartan/administração & dosagem , Masculino , Perindopril/administração & dosagem , Pletismografia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Vasodilatadores/administração & dosagem , ômega-N-Metilarginina/administração & dosagemRESUMO
BACKGROUND/OBJECTIVES: Visceral fat obesity plays an essential role in the clustering of cardiovascular risk factors. This study aimed to clarify the effects of miglitol, α-glycosidase inhibitor, on body weight, fat distribution and cardiovascular risk factors in patients with the metabolic syndrome. METHODS AND RESULTS: One hundred and eleven drug naive patients with the metabolic syndrome were continuously recruited and randomly allocated to a group of life style modification (LSM) alone or a group of LSM with miglitol per os 50 mg × 3 (LSM+miglitol). After 12 weeks of treatment, body weight (5.1%), body mass index (4.9%) and waist circumference were greatly reduced in miglitol group (n=42) than in LSM group (n=43). Plasma levels of insulin and glucose during an oral 75 g glucose loading were decreased only in miglitol group. Visceral fat area, determined by abdominal computed tomography, was greatly reduced in miglitol group (baseline 188 vs 12 weeks 161 cm(2), p<0.0001) than in LSM group (184 vs 174 cm(2), p<0.05). Subcutaneous fat area was reduced only in miglitol group (p<0.001). Systolic blood pressure was reduced in miglitol group (142 vs 133 mm Hg, p<0.001), but not in control group (137 vs 134 mm Hg). Serum levels of triglyceride, LDL-cholesterol, γ-GTP, and high-sensitive CRP were decreased and adiponectin was increased only in miglitol group. CONCLUSIONS: Our results indicated that miglitol showed an anti-obesity potential, which was achieved by reducing abdominal fat accumulation and/or enhanced insulin requirement, and then corrected both the metabolic and hemodynamic aberrations seen in patients with the metabolic syndrome (UMIN Clinical Trial Registry UMIN000007650).
Assuntos
1-Desoxinojirimicina/análogos & derivados , Doenças Cardiovasculares/prevenção & controle , Inibidores de Glicosídeo Hidrolases , Gordura Intra-Abdominal/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Comportamento de Redução do Risco , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Adulto , Doenças Cardiovasculares/enzimologia , Feminino , Humanos , Gordura Intra-Abdominal/enzimologia , Masculino , Síndrome Metabólica/enzimologia , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Fatores de Risco , alfa-Glucosidases/metabolismoRESUMO
The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD) and threatens to reduce life expectancy around the world. The concept of the metabolic syndrome (MetS) takes into account that visceral fat plays an essential role in the development of metabolic and cardiovascular diseases. However, MetS cannot be used to assess global CVD risk but is at best one more modifiable CVD risk factor. Thus, global cardiometabolic risk (the global risk of cardiovascular disease resulting from traditional risk factors combined with the additional contribution of the metabolic syndrome and/or insulin resistance) should be considered individually. There is solid evidence supporting the notion that excess abdominal fat is predictive of insulin resistance and the presence of related metabolic abnormalities currently referred to as MetS. Despite the fact that abdominal obesity is a highly prevalent feature of MetS, the mechanisms by which abdominal obesity is causally related to MetS are not fully elucidated. Besides visceral fat accumulation, ectopic lipid deposition, especially in liver and skeletal muscle, has been implicated in the pathophysiology of diabetes, insulin resistance and obesity-related disorders. Also, ectopic fat deposition could be deteriorated in the heart components such as (1) circulatory and locally recruited fat, (2) intra- and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. In this review, the contribution of ectopic lipid deposition to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance and lipotoxicity.
Assuntos
Doenças Cardiovasculares/etiologia , Metabolismo dos Lipídeos , Síndrome Metabólica/complicações , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doença das Coronárias/etiologia , Humanos , Resistência à Insulina , Fatores de RiscoRESUMO
Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middle-aged men with metabolic syndrome. Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area (VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver. Results A significant inverse correlation was observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestyle modification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated with the levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment. On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease after Miglitol treatment. Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and the liver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.
Assuntos
Fígado Gorduroso/metabolismo , Hipoglicemiantes/uso terapêutico , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/terapia , Comportamento de Redução do Risco , Adulto , Idoso , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/terapia , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/fisiopatologia , Masculino , Síndrome Metabólica/diagnóstico por imagem , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Tomografia Computadorizada por Raios XRESUMO
We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ≥220 mg/dL and/or triglycerides ≥150 mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800 mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-γ-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.
RESUMO
Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.
Assuntos
Dieta Hiperlipídica , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Oryza/metabolismo , Fenilpropionatos/farmacologia , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Camundongos , Camundongos Endogâmicos C57BL , Fenilbutiratos/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/metabolismoRESUMO
A nickel-catalyzed reductive deoxygenation of aryl alkyl ethers and aryl pivalates has been developed. Hydrosilanes serve as a mild reducing agent. The present protocol allows the use of a pivalate group as a robust and traceless steering group in arene functionalization reactions.
Assuntos
Hidrocarbonetos Aromáticos/química , Níquel/química , Oxigênio/química , Substâncias Redutoras/química , Silanos/química , Catálise , Ácidos Pentanoicos/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
OBJECTIVE: Glucose intolerance is recognized as a predictor of congestive heart failure (CHF). However, the association of postprandial hyperglycemia or fasting hyperglycemia with CHF has not been clarified. We determined the impact of the total spectrum of glucose abnormalities on left ventricular (LV) geometry and diastolic function. RESEARCH DESIGN AND METHODS: Two hundred and eighty-seven Japanese subjects who visited the university hospital to be checked for glucose intolerance or known type 2 diabetes were consecutively recruited. Participants underwent an oral glucose tolerance test if they had no history of diabetes, and LV geometry and LV systolic and diastolic function were analyzed by Doppler echocardiography. RESULTS: The frequency of LV diastolic dysfunction in subjects with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), newly detected diabetes, and known diabetes were 13, 22, 50, 51, and 61%, respectively (χ(2) = 54.2, P < 0.0001). IGT was a predictor for LV diastolic dysfunction after adjusting for age, sex, systolic blood pressure, and heart rate (odds ratio 3.43 [95% CI 1.09-11.2]), but IFG was not (0.49 [0.06-3.08]). IGT was a predictor after adjusting for established CHF risk factors but was no longer significant after adjusting for BMI and homeostasis model assessment of insulin resistance. CONCLUSIONS: In this hospital-based registry of subjects without CHF, the prevalence of LV diastolic dysfunction was higher in subjects with IGT but not in those with IFG. Results suggest that IGT, as well as newly detected and known diabetes, could be linked to an increased risk of cardiovascular events, partly through LV diastolic dysfunction.
Assuntos
Glicemia/metabolismo , Jejum/sangue , Intolerância à Glucose/sangue , Intolerância à Glucose/fisiopatologia , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/etiologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Feminino , Intolerância à Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Ventricular Esquerda/metabolismoRESUMO
Release of free fatty acid (FFA) from adipose tissue is implicated in insulin resistance and endothelial dysfunction in patients with visceral fat obesity. We demonstrated previously that increased FFA levels cause endothelial dysfunction that is prevented by inhibition of the renin-angiotensin system (RAS) in humans. However, the mechanisms for FFA-mediated activation of RAS and the resultant endothelial dysfunction were not elucidated. We investigated effects of elevated FFA on activity of circulating and vascular RAS, angiotensin II-forming activity of leukocytes, and leukocyte activation of normotensive subjects. We showed that increased FFA levels significantly enhanced angiotensin II-forming activity in human mononuclear (mean fold increase: 3.5 at 180 minutes; P=0.0016) and polymorphonuclear (2.0; P=0.0012) cells, whereas parameters of the circulating and vascular RAS were not affected. We also showed that FFA caused angiotensin II- dependent leukocyte activation, which impaired endothelial function partly via increased myeloperoxidase release and presumably enhanced adhesion of leukocytes. We propose that the enhanced production of angiotensin II by FFA in mononuclear and polymorphonuclear cells causes activation of leukocytes that consequently impairs endothelial function. RAS in leukocytes may regulate the leukocyte-vasculature interaction as the mobile RAS in humans.
Assuntos
Angiotensina II/biossíntese , Endotélio Vascular/fisiopatologia , Ácidos Graxos não Esterificados/sangue , Leucócitos Mononucleares/metabolismo , Neutrófilos/metabolismo , Obesidade/sangue , Sistema Renina-Angiotensina/fisiologia , Adulto , Endotélio Vascular/metabolismo , Emulsões Gordurosas Intravenosas/administração & dosagem , Humanos , Masculino , Obesidade/fisiopatologia , Valores de Referência , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto JovemRESUMO
We studied whether urinary oxalate excretion after an acute oral load of oxalic acid is influenced by concomitant administration of calcium in rats. Male Wistar rats weighing approximately 180 g were divided into six groups of five animals each. After inducing anesthesia, the animals were orally (via a gastrostomy) given 110 micromol of oxalic acid along with 0, 27.5, 55, 110, or 220 micromol of calcium (0, 27.5, 55, 110, or 220 micromol Ca group, respectively). Saline was given to the control group instead of oxalic acid. Urine specimens were collected before administration and then at hourly intervals up to 5 h afterward. Urinary oxalate and citrate levels were measured by capillary electrophoresis, while urinary calcium, magnesium, and phosphorus levels were measured by ICP spectrophotometry. Urinary oxalate excretion peaked at 1 h after administration and was higher in the 0, 27.5, and 55 micromol Ca groups than in the control group. The urinary recovery of oxalate in these groups was 10-15%, while the recovery rate was less than 3% in other groups. Urinary Ca excretion showed no significant changes, either over time or between groups. Free oxalic acid is absorbed more readily from the gastrointestinal tract than calcium oxalate, while simultaneous administration of calcium appears to block intestinal oxalic acid absorption in a dose-dependent manner.