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1.
J Vasc Res ; 59(4): 239-250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35439760

RESUMO

OBJECTIVES: Atherosclerosis severely damages the arterial wall. The aim of this study was to assess in vivo, for the first time, arterial dynamic properties, reactivity, and stiffness in atherosclerotic (ATH) rabbits. METHODS: The rabbits were fed with 0.3% cholesterol diet. Femoral artery (FA) or abdominal aorta (AA) diameter was recorded by echotracking, together with blood pressure. Arterial reactivity after local administration of agents and stiffness were measured as diameter or pulsatile diameter changes. RESULTS: FA dilation induced by acetylcholine was reduced in the function of diet duration (9-65 weeks). With mid-term diet duration (35-45 weeks), the dilation to nitroprusside was greatly reduced; the constriction to norepinephrine was reduced but not that to serotonin, thromboxane agonist, or angiotensin II. After 17- and 28-week diet AA and FA stiffness were increased while distensibility was reduced. Arterial stiffness measured by regional pulse wave velocity was unaltered. We observed that after 28-week diet, FA exhibited a stiffened wall at the plaque level and higher distensibility at the upstream site. DISCUSSION/CONCLUSION: Arterial reactivity and compliance were greatly modified by atherosclerosis, at various degrees dependent on diet duration. ATH rabbit is therefore a suitable model for in vivo investigations of treatments targeting dynamic properties of arterial wall.


Assuntos
Aterosclerose , Rigidez Vascular , Animais , Pressão Sanguínea , Artéria Femoral , Análise de Onda de Pulso , Coelhos
2.
Mol Ther ; 25(3): 694-704, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28202391

RESUMO

MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.


Assuntos
Antagomirs/genética , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Estresse Fisiológico/genética , Animais , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Interferência de RNA , Ratos , Suínos
3.
J Vasc Res ; 49(4): 309-18, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22572574

RESUMO

INTRODUCTION: Age and hypertension are two major determinants of arterial stiffness, as well as endothelial dysfunction. The present study was designed to test whether a chronic reduction of endogenous nitric oxide (NO) produces arterial stiffening close to that observed in old spontaneously hypertensive rats (SHR), and also to study the effect of an acute or a chronic decrease in blood pressure (BP) on aortic distensibility. METHODS: BP, aortic stiffness, endothelial dysfunction and remodelling were measured in male adult (20-week-old) SHR, in adult SHR treated with a nonspecific NO synthase inhibitor L-NAME (SHR/L-NAME) for 2 weeks, in adult SHR/L-NAME cotreated with perindopril (1 mg/kg/day) and in old SHR (55-week-old). Age-matched WKY were used as a normotensive group. RESULTS: Aortic endothelial dysfunction, remodelling and stiffening appeared in old SHR. Reduction of NO production in adult SHR caused similar alterations. Acute decreases in BP in SHR/L-NAME did not improve isobaric aortic distensibility but a chronic reduction of BP prevented endothelial dysfunction, aortic remodelling and aortic wall stiffening. CONCLUSION: NO reduction in adult SHR induces aortic alterations similar to those observed during aging, which supports the major role of NO in the development of arterial stiffening. These aortic alterations can be prevented by angiotensin-converting enzyme inhibitor treatment.


Assuntos
Envelhecimento/patologia , Aorta/fisiopatologia , Hipertensão/fisiopatologia , Óxido Nítrico/antagonistas & inibidores , Rigidez Vascular/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Clonidina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Perindopril/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
4.
Am J Physiol Heart Circ Physiol ; 301(2): H382-90, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21602465

RESUMO

Large-artery stiffening is a major risk factor in aging and hypertension. Elevated blood pressure (BP) and vascular wall properties participate in arterial stiffening; we aimed to evaluate their respective role by combining echo-tracking and the spontaneously hypertensive rats (SHR) treated with low doses of a nitric oxide synthase inhibitor, shown to have arterial stiffening. Normotensive [Wistar-Kyoto (WKY)], SHR, and SHR treated for 2 wk with N(G)-nitro-L-arginine methyl ester (SHRLN) were anesthetized; BP and distension (pulsatile displacement) of the aortic walls with the ArtLab echo-tracking device were measured. Stiffness index increased in SHRLN vs. SHR; compliance, distensibility, and the slopes and area of the distension-pressure loop curve decreased. The pulsatile distension and pressure waveforms were strongly altered in SHRLN. Maximal values were decreased and increased, respectively, and the waveform kinetics also differed. Thus the area under the curve adjusted to heart rate (AUC/ms) was calculated. Acute BP reductions were induced by diltiazem in SHR and SHRLN, to levels similar to those of WKY. In SHR, compliance, distensibility, stiffness index, and the ascending slope of the distension-pressure loop reached the values of WKY, whereas they were only partially improved in SHRLN. Aortic distension (maximal value and AUC/ms) and the area of the distension-pressure loop were improved in SHR, but not in SHRLN. These data confirm the aortic stiffening induced by nitric oxide reduction in SHR. They show that the ArtLab system analyzes aortic stiffness in rats, and that the aortic pulsatile distension waveform is a parameter strongly dependent on the vascular wall properties.


Assuntos
Aorta/diagnóstico por imagem , Pressão Sanguínea , Hipertensão/diagnóstico por imagem , Fluxo Pulsátil , Processamento de Sinais Assistido por Computador , Análise de Variância , Animais , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Complacência (Medida de Distensibilidade) , Diltiazem/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Fluxo Pulsátil/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de Tempo , Ultrassonografia
5.
Int J Hypertens ; 2019: 8070198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016040

RESUMO

The spontaneously hypertensive rat model with reduced NO synthesis (SHRLN) shares features with aging and hypertension in humans, among other a severe aortic stiffening. The present in vivo study aimed to compare thoracic (TA) and abdominal (AA) aortic stiffness in the SHRLN (treated 5 weeks with L-NAME), SHR, and normotensive Wistar Kyoto (WKY). Dynamic properties of TA and AA were measured in the same rats, using echotracking recording of aortic diameter coupled with blood pressure (BP). Measurements were performed first at operating BP and then after BP reduction in hypertensive rats, thus in isobaric conditions. Histological staining and immunohistochemistry were used for structural analysis at both sites. At operating pressure, BP and pulse pressure (PP) were higher in SHRLN compared with SHR. Stiffness index was also increased and distensibility decreased in both TA and AA in SHRLN. At WKY-matched blood pressure, isobaric AA parameters remained specifically altered in SHRLN, whereas TA recovered to values identical to WKYs. Collagen, fibronectin, α5-selectin, and FAK were increased in SHRLN compared with SHR or WKY. Nevertheless, only the strong accumulations of fibronectin and collagen at the AA site in SHRLN were associated with intrinsic stiffening. In conclusion, we confirm that NO restriction associated with hypertension induces a severe pathological phenotype and shows that L-NAME induced stiffening is more pronounced in AA than in TA as a result of greater fibrosis.

6.
Cardiovasc Res ; 67(4): 699-704, 2005 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15936005

RESUMO

OBJECTIVE: We assessed whether alpha1-adrenoreceptor (alpha1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction. METHODS AND RESULTS: After 7 days of cocaine injection (2 x 7.5 mg/kg/day, i.p., Coc), NADPH activity assessed by chemiluminescence increases as well as phosphorylation of p47phox, one of the cytosolic components of NADPH oxidase. The alpha1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 x 1 mg/kg/day, i.p., Coc+Prz), prevents these effects. Moreover, Prz pretreatment reduces left ventricular/body weight (LV/BW) ratio and partially prevents the cocaine-induced alterations in fractional shortening and cardiac index assessed by echocardiography. In order to confirm the involvement of alpha1-AR stimulation in NADPH oxidase up-regulation in vivo, we used phenylephrine (Phe) administration with the same protocol of injections as that used with cocaine (2 x 5 microg/kg/day, i.p.). After Phe administration, as expected, NADPH oxidase activity increases as well as phosphorylation of p47phox. These effects occur in the absence of sustained hemodynamic changes. CONCLUSION: This study demonstrates the involvement of the alpha1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that alpha1-AR stimulation, at least in part via NADPH oxidase induction, plays a critical role in the events leading to the cardiomyopathy observed after cocaine abuse.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Cardiomiopatias/induzido quimicamente , Cocaína/farmacologia , NADPH Oxidases/metabolismo , Prazosina/farmacologia , Vasoconstritores/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomiopatias/metabolismo , Masculino , Miocárdio/enzimologia , Fenilefrina/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/metabolismo
7.
J Hypertens ; 34(4): 666-75, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26938811

RESUMO

BACKGROUND: Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear. Our objectives were to determine the temporal evolution of both BPV and pulse wave velocity (PWV), a surrogate measure of arterial stiffness, using an animal model of remodeling-dependent aortic stiffening. METHOD: We thus, developed a new telemetric technique allowing continuous measurement of PWV in conscious, unrestrained rats. Studies were performed in spontaneously hypertensive rats (SHR) treated for 2 weeks with N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (SHR-LN). BPV was evaluated conventionally or with a new device composed of two pressure transducers in two different sets of rats. This allowed a continuous monitoring of telemetered PWV, systolic (SPV), diastolic (DPV), and pulse pressure variability (PPV). Aortic structure was then characterized by immunohistochemical analysis. RESULTS: SPV, DPV, and PPV were increased in SHR-LN, when calculated by 24-h SD or using average real variability a parameter used to assess short-term variability in man. We observed rapid and simultaneous increases in BP, SPV, and PWV. Interestingly, PPV was the most increased parameter resulting mainly from different time course of SPV and DPV. Structural alterations of the aortic wall were observed, with a eutrophic inward remodeling and accumulation of fibronectin and its two main receptors (α5 and αv integrins). CONCLUSION: This offers unequivocal evidence of a significant relationship between PWV, BPV, and arterial structure.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea/fisiologia , Rigidez Vascular/fisiologia , Animais , Modelos Cardiovasculares , Análise de Onda de Pulso , Ratos
8.
Cardiovasc Res ; 59(4): 834-43, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14553823

RESUMO

OBJECTIVE: Contractility alterations and LV hypertrophy after chronic cocaine administration have been shown to be accompanied by an increase in oxidative stress. This study was carried out to investigate whether the production of reactive oxygen species is an early event of primary importance in cocaine-induced myocardial injury or simply occurs as a consequence of the ventricular dysfunction itself. METHODS AND RESULTS: After 2 days of cocaine administration to rats, no differences were observed in echocardiographic parameters between the cocaine-treated group and the control group. However, an increase in oxidative stress in the myocardium was indicated by an increase in lipid peroxidation (+35%, cocaine vs. control), an increase in antioxidant enzymes (catalase +110%, glutathione peroxidase +40% and superoxide dismutase +38%) and of NADPH-driven superoxide production (assessed by chemiluminescence). Furthermore, higher gp91phox and p22phox mRNA expression, measured by quantitative real-time RT-PCR, was found in the cocaine group. On day 8, cocaine administration induced a cardiac dysfunction, characterized by a decrease in cardiac index (-30%, cocaine vs. controls) and left ventricular (LV) fractional shortening (-23%, cocaine vs. controls). This LV dysfunction was prevented by antioxidant treatment (100 mg/kg/day vitamin C and 100 U/kg/day vitamin E). Moreover, in these animals, antioxidant treatment decreased lipid peroxides and decreased the activity of NADPH oxidase, associated with the downregulation of gp91phox. CONCLUSION: These data indicate that cocaine administration induces early NADPH-driven O2-. release which may play an important role in the development and progression of the LV dysfunction observed after chronic cocaine abuse.


Assuntos
Cocaína/farmacologia , Miocárdio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Vasoconstritores/farmacologia , Disfunção Ventricular Esquerda/induzido quimicamente , Animais , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ecocardiografia , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , RNA Mensageiro/análise , Distribuição Aleatória , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo , Vitamina E/administração & dosagem
9.
Fundam Clin Pharmacol ; 18(4): 431-6, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15312149

RESUMO

Chronic cocaine abuse causes cardiac dysfunction and induces oxidative stress. The goal of this study was to evaluate whether an enhanced antioxidant pool, induced by the administration of selenium, may prevent the myocardial dysfunction induced by cocaine. Cocaine was administered for 7 days (15 mg/kg/day, i.p.) to rats pretreated for 4 weeks with selenium (1.16 mg/L/day, p.o.). Cardiac function was evaluated by cardiac index and left ventricular (LV) fractional shortening (FS) measured by echocardiography. The redox ratio and enzymatic activities of glutathione peroxidase (GPX) and superoxide dismutase (SOD) were measured in the LV myocardium. Cocaine administration induced a cardiac dysfunction, as evidenced by a decrease in cardiac index and LV FS as well as by an increase in LV diameters. Moreover, antioxidant markers and redox ratio were altered in rats after cocaine exposure. Selenite supplementation induced a significant limitation of cardiac index and FS alterations observed after cocaine administration. This improvement in cardiac function was associated with a redox ratio recovery while SOD and GPX activities remained unchanged. Thus, selenite reversed both the oxidative stress and the contractile dysfunction induced by cocaine administration. These results suggest a major role of oxidative stress in the cocaine-induced cardiotoxicity.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/complicações , Estresse Oxidativo/efeitos dos fármacos , Selênio/uso terapêutico , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Transtornos Relacionados ao Uso de Cocaína/enzimologia , Dieta , Glutationa Peroxidase/metabolismo , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Selênio/administração & dosagem , Superóxido Dismutase/metabolismo , Disfunção Ventricular Esquerda/etiologia
10.
Br J Pharmacol ; 167(4): 854-67, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22646737

RESUMO

BACKGROUND AND PURPOSE: The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury. EXPERIMENTAL APPROACH: Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18-week-old Wistar-Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with N(ω) -nitro-L-arginine methyl ester in the drinking water (L-NAME-treated SHR, 6 mg·kg(-1) ·day(-1) ). KEY RESULTS: Acetylcholine caused similar dose-dependent renal dilatation in the three groups. In vitro administration of indomethacin did not alter the vasodilatation, while the addition of N(w) -nitro-L-arginine (L-NA) produced a differential inhibition of the vasodilatation, (inhibition in WKY > SHR > L-NAME-treated SHR). Further addition of ODQ, an inhibitor of soluble guanylyl cyclase, abolished the responses to sodium nitroprusside but did not affect the vasodilatation to acetylcholine. However, the addition of TRAM-34 (or charybdotoxin) inhibitors of Ca(2+) -activated K(+) channels of intermediate conductance (K(Ca) 3.1), blocked the vasodilatation to acetylcholine, while apamin, an inhibitor of Ca(2+) -activated K(+) channels of small conductance (K(Ca) 2.3), was ineffective. Dilatation induced by an opener of K(Ca) 3.1/K(Ca) 2.3 channels, NS-309, was also blocked by TRAM-34, but not by apamin. The magnitude and duration of NS-309-induced vasodilatation and the renal expression of mRNA for K(Ca) 3.1, but not K(Ca) 2.3, channels followed the same ranking order (WKY < SHR < L-NAME-treated SHR). CONCLUSIONS AND IMPLICATIONS: In SHR kidneys, an EDHF-mediated response, involving activation of K(Ca) 3.1 channels, contributed to the mechanism of endothelium-dependent vasodilatation. In kidneys from L-NAME-treated SHR, up-regulation of this pathway fully compensated for the decrease in NO availability.


Assuntos
Endotélio Vascular/fisiologia , Hipertensão/fisiopatologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/fisiologia , Rim/fisiologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Animais , Apamina/farmacologia , Fatores Biológicos/fisiologia , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Indometacina/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Rim/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Nitroprussiato/farmacologia , Oximas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
11.
J Mol Cell Cardiol ; 42(2): 326-32, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17217956

RESUMO

Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.


Assuntos
Acetofenonas/farmacologia , Alopurinol/farmacologia , Anestésicos Locais/toxicidade , Cardiomiopatias/prevenção & controle , Cocaína/toxicidade , Inibidores Enzimáticos/farmacologia , NADPH Oxidases/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos , Xantina Desidrogenase/biossíntese , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/enzimologia , Masculino , Miocárdio/enzimologia , NADPH Oxidases/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/prevenção & controle
12.
Hypertension ; 48(6): 1088-94, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17075035

RESUMO

Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear. Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44 degrees C), during the local infusion of saline and inhibitors of NO synthase (N(G)-monomethyl-l-arginine [l-NMMA]: 8 to 20 micromol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 micromol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 micromol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter-wall shear stress relationship was constructed. During heating, compared with saline, the diameter-shear stress relationship was shifted downward by l-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of l-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62+/-0.03 mm), was decreased under our experimental conditions by l-NMMA (-39+/-4%), tetraethylammonium chloride (-14+/-4%), fluconazole (-18+/-6%), and to a greater extent, by the combinations of l-NMMA with tetraethylammonium (-64+/-4%) or with fluconazole (-71+/-3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways.


Assuntos
Fatores Biológicos/fisiologia , Óxido Nítrico/fisiologia , Artéria Radial/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Resistência ao Cisalhamento , Vasodilatação/efeitos dos fármacos
13.
Eur Heart J ; 26(15): 1544-50, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15872033

RESUMO

AIMS: Oxidative stress, i.e. imbalance between reactive oxygen species (ROS) and antioxidant defences, contributes to the progression of chronic heart failure (CHF). Acute inhibition of xanthine oxidase (XO), which produces ROS, improves mechanical efficiency of the failing heart, but whether long-term XO inhibition exerts beneficial effects in CHF is unknown. METHODS AND RESULTS: In rats with established CHF induced by left coronary ligation, we assessed the effects of a 5-day and a 10-week treatment with the XO inhibitor allopurinol (50 mg kg(-1) day(-1)) on haemodynamics and left ventricular (LV) function and structure. Both acute and chronic allopurinol treatment increase cardiac output without modification of arterial pressure, but only chronic allopurinol treatment reduces LV end-diastolic pressure and LV relaxation constant. Chronic allopurinol treatment decreases both LV systolic and diastolic diameters, but acute allopurinol treatment only decreases LV systolic diameter. Moreover, chronic allopurinol decreases LV weight and collagen density. Despite XO inhibition after acute and chronic allopurinol treatment, as both treatments reduce uric acid plasma levels, only acute allopurinol treatment reduces LV ROS determined using electron spin resonance spectroscopy. However, the CHF-enhanced myocardial thiobarbituric acid reactive substances levels were never modified. CONCLUSION: In experimental CHF, long-term allopurinol treatment, initiated in a pathological state of overt CHF, improves LV haemodynamics and function and prevents LV remodelling. These long-term effects are, at least partially, caused by a transient reduction of myocardial ROS shortly after initiation of allopurinol treatment, but whether other mechanism(s), independent of myocardial redox 'status', such as reduced inflammation, are implicated remains to be confirmed.


Assuntos
Alopurinol/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Radicais Livres/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Oxigênio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Coronários , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Ligadura , Peroxidação de Lipídeos , Masculino , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
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