RESUMO
PURPOSE: Endothelial dysfunction underlies the pathogenesis of preeclampsia, but its mechanism has not yet been completely understood. In this study we have aimed to measure homocysteine (Hcy), asymmetric dimethylarginine (ADMA), and nitric oxide (NO) levels as endothelial dysfunction markers in preeclamptic women. METHODS: Control-case study with 62 preeclamptic patients and 30 controls without pregnancy complications was conducted. Plasma total Hcy, determined by capillary column gas chromatography/mass spectrometry (GC/MS), was correlated with serum ADMA (determined by liquid chromatography/tandem mass spectrometry using (13)C(6)-L: -arginine as the internal standard) and NO (analyzed by GC/MS). RESULTS: There was a highly significant increase in the plasma concentration of homocysteine (P < 0.001) and ADMA (P < 0.001) and a highly significant decrease in the plasma concentration of nitric oxide (P < 0.001) among the preeclamptic patients. The differences were more significant between mild and severe preeclampsia, with and without eclampsia, with and without HELLP (hemolysis, elevated serum level of liver enzymes, and low platelets). In the combined patients and control groups a highly significant positive correlation was found between the plasma concentrations of homocysteine and ADMA (r = 0.853, P < 0.001). In addition, significant negative correlations were detected between the plasma concentrations of nitric oxide and the plasma concentration of homocysteine (r = -0.870, P < 0.001) and ADMA (r = -0.895, P < 0.001). These significant correlations were found to persist, even when they were restricted to the preeclamptic patients. CONCLUSIONS: The homocysteine-ADMA-NO may be at least partly responsible for etiology in preeclampsia and could be regarded as markers for the severity of the disease. Therefore, L: -arginine may represent a novel therapy for the treatment of preeclampsia.
Assuntos
Arginina/análogos & derivados , Inibidores Enzimáticos/sangue , Homocisteína/sangue , Óxido Nítrico/sangue , Pré-Eclâmpsia/sangue , Arginina/sangue , Arginina/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Endotélio Vascular/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Homocisteína/metabolismo , Humanos , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Terceiro Trimestre da Gravidez , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: To explore the relationship between plasma adipocyte fatty acid-binding protein (A-FABP), adiponectin (APN) levels and A-FABP/APN ratio with femoral intima-media thickness (FA-IMT) and endothelium-dependent vasodilation in patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: Plasma A-FABP and APN in 133 patients with newly diagnosed T2DM were measured by enzyme-linked immunosorbent assays. FA-IMT, endothelium-dependent and independent vasodilation of brachial artery was measured by high-resolution vascular ultrasound. Upper quartile of FA-IMT was regarded as a criterion of elevated FA-IMT, defined as early atherosclerosis (AS). The patients were subdivided into low FA-IMT group (FA-IMT < 0.60 mm, n = 34), middle FA-IMT group (0.60 mm = FA-IMT < 0.73 mm, n = 33), high FA-IMT group (0.73 mm = FA-IMT < 0.80 mm, n = 33) and early AS group (FA-IMT >/= 0.80 mm, n = 33). RESULTS: Plasma A-FABP/APN ratio was higher in early AS group than in low IMT control group [A-FABP/APN x 1000, 3.9(2.8 approximately 6.1) vs 2.9(1.8 approximately 5.7), P < 0.05]. FA-IMT correlated positively with plasma A-FABP/APN ratio (r = 0.216, P = 0.006) and negatively with APN (r = -0.179, P = 0.020). After adjusted for age, gender and BMI, FA-IMT still correlated positively with plasma A-FABP/APN ratio (r = 0.217, P = 0.007) and negatively with APN (r = -0.172, P = 0.026). Endothelium-dependent vasodilation correlated negatively with plasma A-FABP/APN ratio (r = -0.166, P = 0.028). After adjusted for age, gender and BMI, endothelium-dependent vasodilation still correlated negatively with plasma A-FABP/APN ratio (r = -0.153, P = 0.042). CONCLUSION: Plasma A-FABP/APN ratio is closely associated with FA-IMT and endothelium-dependent vasodilation. Plasma A-FABP/APN ratio may be a better clinical marker of AS and endothelial dysfunction than A-FABP or APN alone in patients with newly diagnosed T2DM.
Assuntos
Adiponectina/sangue , Diabetes Mellitus Tipo 2 , Endotélio Vascular/fisiopatologia , Proteínas de Ligação a Ácido Graxo/sangue , Artéria Femoral/patologia , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Asymmetric dimethylarginine (ADMA), which inhibits NO synthase, is inactivated by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH). We tested whether DDAH-1 or -2 regulates serum ADMA (S(ADMA)) and/or endothelium-derived relaxing factor (EDRF)/NO. Small inhibitory (si)RNAs targeting DDAH-1 or -2, or an siRNA control were given intravenously to rats. After 72 hours, EDRF/NO was assessed from acetylcholine-induced, NO synthase-dependent relaxation and 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate for NO activity in isolated mesenteric resistance vessels (MRVs). Expression of mRNA for DDAH-1 versus -2 was 2- and 7-fold higher in the kidney cortex and liver, respectively, whereas expression of DDAH-2 versus -1 was 5-fold higher in MRVs. The proteins and mRNAs for DDAH-1 or -2 were reduced selectively by 35% to 85% in the kidney cortex, liver, and MRVs 72 hours following the corresponding siRNA. S(ADMA) was increased only after siDDAH-1 (266+/-25 versus 342+/-39 [mean+/-SD] nmol x L(-1); P<0.005), whereas EDRF/NO responses and NO activity were not changed consistently by siDDAH-1 but were greatly reduced after siDDAH-2. Mean arterial pressure was not changed significantly by any siRNA. In conclusion, S(ADMA) is regulated by DDAH-1, which is expressed at sites of ADMA metabolism in the kidney cortex and liver, whereas EDRF/NO is regulated primarily by DDAH-2, which is expressed strongly in blood vessels. This implies specific functions of DDAH isoforms.
Assuntos
Amidoidrolases/metabolismo , Arginina/análogos & derivados , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação , Acetilcolina/farmacologia , Amidoidrolases/genética , Animais , Arginina/sangue , Arginina/metabolismo , Relação Dose-Resposta a Droga , Fatores Relaxantes Dependentes do Endotélio/sangue , Regulação Enzimológica da Expressão Gênica , Isoenzimas/metabolismo , Córtex Renal/enzimologia , Fígado/enzimologia , Masculino , Artérias Mesentéricas/citologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Óxido Nítrico/sangue , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Nebivolol (Nomexor) is a third generation, vasodilating beta-blocker with a high beta(1)-adrenoceptor selectivity. Nebivolol acts as an agonist at the beta(3) adrenoceptor as well as the estrogen receptor thereby releasing nitric oxide in blood vessels via eNOS. Pleiotropic effects of nebivolol furthermore include a positive influence on cholesterol and triglycerides and a decrease in thrombocyte activity. Nebivolol is recommended in the guidelines of the European cardiac society (ESC) for patients with metabolic syndrome. Nebivolol's main properties in combination with its broad range of beneficial pleiotropic effects allow it to be clearly distinguished from other second and third generation beta-blockers.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Benzopiranos/uso terapêutico , Etanolaminas/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Vasodilatadores/uso terapêutico , Agonistas Adrenérgicos beta/efeitos adversos , Agonistas Adrenérgicos beta/classificação , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Benzopiranos/efeitos adversos , Benzopiranos/classificação , Pressão Sanguínea/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Fatores Relaxantes Dependentes do Endotélio/sangue , Etanolaminas/efeitos adversos , Etanolaminas/classificação , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Lipídeos/sangue , Síndrome Metabólica/sangue , Camundongos , Nebivolol , Óxido Nítrico/sangue , Agregação Plaquetária/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Pesquisa , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Vasodilatadores/classificaçãoRESUMO
Nitric oxide (NO) released by endothelial cells in response to hemodynamic shear stress is a key controller molecule of the vascular functions and antiatherogenic mechanisms. Endothelial dysfunction is associated with increased cardiovascular events. Therefore, several indirect techniques have been employed to evaluate endothelial function or NO bioavailability. However, a growing body of evidences suggests limitations of the indirect methods for evaluation of NO bioavailability. In years, it has been considered that NO is immediately oxidized or inactivated in blood stream. However, recent studies suggest that NO remain active in blood stream, causing remote biological response. Therefore, measuring plasma NO concentration directly in the circulation will contribute to clarify the kinetics and physiological roles of NO and to evaluate endothelial function. In this article, the measurement of plasma NO concentration using a newly developed catheter-type NO sensor will be described.
Assuntos
Endotélio Vascular/fisiologia , Fatores Relaxantes Dependentes do Endotélio/sangue , Óxido Nítrico/sangue , Cateterismo , Humanos , Estresse MecânicoRESUMO
Experiments with unconscious rats showed that blocking of NO secretion intensifies orthostatic hypotension (mean arterial pressure drops by 72%) and reduces proportionally the calculated total peripheral resistance. A supposition has been made concerning involvement of the endothelial relaxing factor in orthostatic hypotension development, since in orthostasis cardiac output (systemic blood circulation) losses its influence on the endothelial NO secretion.
Assuntos
Fatores Relaxantes Dependentes do Endotélio , Inibidores Enzimáticos/farmacologia , Hipotensão Ortostática/fisiopatologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Pressão Sanguínea , Débito Cardíaco , Interpretação Estatística de Dados , Fatores Relaxantes Dependentes do Endotélio/antagonistas & inibidores , Fatores Relaxantes Dependentes do Endotélio/sangue , Hemodinâmica , Hipotensão Ortostática/etiologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar , Resistência VascularRESUMO
Chronic lead exposure induces hypertension and alters endothelial function. However, treatment with low lead concentrations was not yet explored. We analyzed the effects of 7 day exposure to low lead concentrations on endothelium-dependent responses. Wistar rats were treated with lead (1st dose 4 µg/100 g, subsequent dose 0.05 µg/100 g, i.m. to cover daily loss) or vehicle; blood levels attained at the end of treatment were 9.98 µg/dL. Lead treatment had the following effects: increase in systolic blood pressure (SBP); reduction of contractile response to phenylephrine (1 nM-100 µM) of aortic rings; unaffected relaxation induced by acetylcholine (0.1 nM-300 µM) or sodium nitroprusside (0.01 nM-0.3 µM). Endothelium removal, N(G)-nitro-L-arginine methyl ester (100 µM) and tetraethylammonium (2 mM) increased the response to phenylephrine in treated rats more than in untreated rats. Aminoguanidine (50 µM) increased but losartan (10 µM) and enalapril (10 µM) reduced the response to phenylephrine in treated rats. Lead treatment also increased aortic Na(+)/K(+)-ATPase functional activity, plasma angiotensin-converting enzyme (ACE) activity, protein expression of the Na(+)/K(+)-ATPase alpha-1 subunit, phosphorylated endothelial nitric oxide synthase (p-eNOS), and inducible nitric oxide synthase (iNOS). Our results suggest that on initial stages of lead exposure, increased SBP is caused by the increase in plasma ACE activity. This effect is accompanied by increased p-eNOS, iNOS protein expression and Na(+)/K(+)-ATPase functional activity. These factors might be a compensatory mechanism to the increase in SBP.
Assuntos
Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Fatores Relaxantes Dependentes do Endotélio/sangue , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/fisiopatologia , Chumbo/toxicidade , Animais , Aorta/metabolismo , Aorta/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Masculino , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
Systemic lupus erythematosus is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Objectives were to determine endothelial dysfunction with a non-invasive method in lupus patients and to analyse correlation with risk factors and atherosclerotic complications. Sixty-one SLE patients and 26 healthy age- and sex-matched control subjects were entered into the study. The diameters of brachial artery at rest, during reactive hyperaemia, and after glyceril trinitrate administration, as well as the intima-media thickness of the common carotid artery were measured using high-resolution B-mode ultrasonography. Demographic characteristics, lipid profile, paraoxonase activity, concentration of anti-phospholipid antibodies and anti-oxLDL were assessed together with atherosclerotic complications. The endothelium dependent vasodilation (FMD) was significantly impaired in SLE patients as compared to controls. The absolute difference of vessel diameter (Deltad) was 0.25+/-0.15 mm vs. 0.38+/-0.16 mm (p=0.001), and Deltad as in percent of the rest diameter was 7.31+/-5.2% vs. 9.86+/-3.87% (p=0.013) in lupus patients and controls, respectively. Nitrate mediated dilation (NMD) did not differ. FMD negatively correlated with age, systolic and diastolic blood pressure in SLE, but did not show significant correlation with the other examined parameters. However, FMD significantly differed between SLE patients with (5.54+/-4.36%) and without (8.81+/-5.28%) cardiovascular complications (p=0.01). The determination of flow-mediated vasodilation is a useful method to detect endothelial dysfunction in lupus patients, as reduced capacity of brachial artery may distinguish between SLE patients and healthy subjects, as well as lupus patients with and without atherosclerotic vascular complications.
Assuntos
Aterosclerose/etiologia , Aterosclerose/fisiopatologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/fisiopatologia , Adulto , Aterosclerose/sangue , Artéria Braquial/fisiopatologia , Endotélio Vascular/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/sangue , Fatores Relaxantes Dependentes do Endotélio/uso terapêutico , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Vasodilatação/fisiologiaRESUMO
Static magnetic fields (SMF) in the millitesla (mT) range have been reported to modulate microcirculatory hemodynamics and/or blood pressure (BP) under pharmacologically modified state in mammals. This study was designed to investigate the acute effects of local application of a SMF to neck or pelvic region under pharmacologically modulated BP; norepinephrine (NE)-induced hypertension as well as an L-type voltage-gated Ca(2+) channel blocker, nicardipine (NIC)-induced hypotension in conscious rabbits. Magnetic flux densities were up to 5.5 mT and the spatial magnetic gradient peaked in neck (carotid sinus baroreceptor) region at the level of approximately 0.06 mT/mm. The duration of exposure was 30 min (including 10 min of pretreatment) and the effects on BP were investigated up to 100 min postexposure. Baroreflex sensitivity (BRS) was estimated from invasive recordings of systolic BP and pulse interval. Neck exposure to 5.5 mT significantly attenuated the pharmacologically induced vasoconstriction or vasodilation, and subsequently suppressed the increase or decrease in BP compared with sham exposure. In contrast, pelvic exposure to 5.5 mT did not significantly antagonized NE-elevated BP or NIC-reduced BP. The neck exposure to 5.5 mT has a biphasic and restorative effect on vascular tone and BP acting to normalize the tone and BP. The neck exposure to 5.5 mT caused a significant increase in BRS in NE-elevated BP compared with sham exposure. The buffering effects of the SMF on increased hemodynamic variability under NE-induced high vascular tone and NIC-induced low vascular tone might be, in part, dependent on baroreflex pathways, which could modulate NE-mediated response in conjunction with Ca(2+) dynamics.