RESUMEN
ABSTRACT: This study aimed to determine if açai seed extract (ASE) could reverse pre-existing cardiovascular and renal injury in an experimental model of renovascular hypertension (2 kidney, 1 clip, 2K1C). Young male rats (Wistar) were used to obtain 2K1C and sham groups. Animals received the vehicle, ASE (200 mg/kg/d), or enalapril (30 mg/kg/d) in drinking water from the third to sixth week after surgery. We evaluated systolic blood pressure by tail plethysmography, vascular reactivity in the rat isolated mesenteric arterial bed (MAB), serum and urinary parameters, plasma inflammatory cytokines by ELISA, MAB expression of endothelial nitric oxide synthase and its active form peNOS by Western blot, plasma and MAB oxidative damage and antioxidant activity by spectrophotometry, and vascular and cardiac structural changes by histological analysis. ASE and enalapril reduced the systolic blood pressure, restored the endothelial and renal functions, and decreased the inflammatory cytokines and the oxidative stress in 2K1C rats. Furthermore, both treatments reduced vascular and cardiac remodeling. ASE substantially reduced cardiovascular remodeling and recovered endothelial dysfunction in 2K1C rats probably through its antihypertensive, antioxidant, and anti-inflammatory actions, supplying a natural resource for the treatment of renovascular hypertension.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Enalapril/farmacología , Euterpe , Hipertensión Renovascular/tratamiento farmacológico , Extractos Vegetales/farmacología , Remodelación Vascular/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Antihipertensivos/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Biomarcadores/sangre , Biomarcadores/orina , Modelos Animales de Enfermedad , Euterpe/química , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Mediadores de Inflamación/sangre , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Ratas WistarRESUMEN
OBJECTIVES: Alterations in cardiovascular and skeletal muscle function are hallmarks of ageing that lead to exercise intolerance. We aimed to examine whether the treatment with Euterpe oleracea Mart. seed extract (ASE) associated with exercise training improves aerobic exercise performance by promoting healthy ageing in the elderly. METHODS: Male Wistar rats were divided into five groups: Young (3 months), Old (18 months), Old+ASE (ASE 200 mg/kg/day), Old+Training (exercise training 30 min/day; 5 days/week) and Old+Training+ASE, for 4 weeks. KEY FINDINGS: ASE treatment increased the exercise time and the running distance concerning the initial maximal treadmill stress test (MTST) in the Old+Training+ASE group. Exercise training or ASE treatment restored the aorta oxidative damage and antioxidant defence. It reduced the acetylcholine (ACh)-induced vasodilation in the aorta of old animals to the same values as the young and improved hypertension. Only the association of both strategies restored the ACh-induced vasodilation in mesentery arteries. Remarkably, exercise training associated with ASE increased the antioxidant defence, nitrite levels and expression of the mitochondrial SIRT-1, PGC1α in soleus muscle homogenates. CONCLUSIONS: ASE treatment associated with exercise training contributes to better exercise performance and tolerance in ageing by improving vascular function, oxidative stress and activating the muscle SIRT-1/PGC-1α pathway.
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Euterpe , Ratas , Masculino , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ratas Wistar , Extractos Vegetales/farmacología , Extractos Vegetales/metabolismo , Estrés Oxidativo , Músculo Esquelético , Rendimiento Físico FuncionalRESUMEN
This study investigated the endothelium-dependent vasorelaxant effects of the essential oil of Ocimum gratissimum (EOOG) in aortas and mesenteric vascular beds isolated from rats. EOOG (3-300 µg/mL) relaxed the tonic contractions induced by phenylephrine (0.1 µmol/L) in isolated aortas in a concentration-dependent manner in both endothelium-containing and endothelium-denuded preparations. This effect was partially reversed by L-NAME (100 µmol/L) but not by indomethacin (10 µmol/L) or TEA (5 mmol/L). In mesenteric vascular beds, bolus injections of EOOG (30, 50, 100, and 300 ng) decreased the perfusion pressure induced by noradrenaline (6 µmol/L) in endothelium-intact preparations but not in those treated with deoxycholate. L-NAME (300 µmol/L) but not TEA (1 mmol/L) or indomethacin (3 µmol/L) significantly reduced the vasodilatory response to EOOG at all of the doses tested. Our data showed that EOOG exerts a dose-dependent vasodilatory response in the resistance blood vessels of rat mesenteric vascular beds and in the capacitance blood vessel, the rat aorta. This action is completely dependent on endothelial nitric oxide (NO) release in the mesenteric vascular beds but only partially dependent on NO in the aorta. These novel effects of EOOG highlight interesting differences between resistance and capacitance blood vessels.
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Aorta Torácica/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Venas Mesentéricas/efectos de los fármacos , Ocimum/química , Aceites Volátiles/farmacología , Vasodilatadores/farmacología , Animales , Aorta Torácica/enzimología , Aorta Torácica/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Endotelio Vascular/fisiología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/enzimología , Arterias Mesentéricas/metabolismo , Venas Mesentéricas/enzimología , Venas Mesentéricas/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Norepinefrina/antagonistas & inhibidores , Norepinefrina/metabolismo , Aceites Volátiles/química , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar , Capacitancia Vascular/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Vasoconstrictores/antagonistas & inhibidores , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/antagonistas & inhibidoresRESUMEN
Many studies suggest a protective role of phenolic compounds in mood disorders. We aimed to assess the effect of Euterpe oleracea (açaí) seed extract (ASE) on anxiety induced by periodic maternal separation (PMS) in adult male rats. Animals were divided into 6 groups: control, ASE, fluoxetine (FLU), PMS, PMS+ASE, and PMS+FLU. For PMS, pups were separated daily from the dam for 3 h between postnatal day (PN) 2 and PN21. ASE (200 mg·kg-1·day-1) and FLU (10 mg·kg-1·day-1) were administered by gavage for 34 days after stress induction, starting at PN76. At PN106 and PN108, the rats were submitted to open field (OF) and forced swim tests, respectively. At PN110, the rats were sacrificed by decapitation. ASE increased time spent in the center area in the OF test, glucocorticoid receptors in the hypothalamus, tropomyosin receptor kinase B (TRKB) levels in the hippocampus, and nitrite levels and antioxidant activity in the brain stem (PMS+ASE group compared with PMS group). ASE also reduced plasma corticotropin-releasing hormone levels, adrenal norepinephrine levels, and oxidative damage in the brain stem in adult male offspring submitted to PMS. In conclusion, ASE treatment has an anti-anxiety effect in rats submitted to PMS by reducing hypothalamic-pituitary-adrenal axis reactivity and increasing the nitric oxide (NO)-brain-derived neurotrophic factor (BDNF)-TRKB pathway and antioxidant defense in the central nervous system. Novelty ASE has anti-anxiety and antioxidant effects in early-life stress. ASE reduces hypothalamic-pituitary-adrenal axis reactivity. The anxiolytic effect of ASE may involve activation of the NO-BDNF-TRKB pathway in the central nervous system.
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Ansiolíticos/farmacología , Antioxidantes/farmacología , Privación Materna , Extractos Vegetales/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo , Euterpe/química , Sistema Hipotálamo-Hipofisario , Masculino , Óxido Nítrico , Estrés Oxidativo , Sistema Hipófiso-Suprarrenal , Ratas , Ratas Wistar , Receptor trkB , Semillas/química , Estrés PsicológicoRESUMEN
BACKGROUND/AIMS: Drinking red wine is associated with a decreased mortality from coronary heart diseases. This study examined whether polyphenols contained in a grape skin extract (GSE) triggered the endothelial formation of nitric oxide (NO) and investigated the underlying mechanism. METHODS: Vascular reactivity was assessed in organ chambers using porcine coronary artery rings in the presence of indomethacin (a cyclooxygenase inhibitor) and charybdotoxin plus apamin (inhibitors of endothelium-derived hyperpolarizing factor-mediated responses). The phosphorylation level of Src, Akt and endothelial NO synthase (eNOS) were assessed by Western blot analysis, and the formation of reactive oxygen species (ROS) was investigated using dihydroethidine and dichlorodihydrofluorescein. RESULTS: GSE-induced endothelium-dependent relaxations were abolished by N(G)-nitro-L-arginine (an eNOS inhibitor) and ODQ (a soluble guanylyl cyclase inhibitor), and they were reduced by MnTMPyP, polyethyleneglycol catalase, PP2 (an inhibitor of Src kinase) and wortmannin (an inhibitor of phosphoinositide 3-kinase). GSE caused phosphorylation of Src, which was prevented by MnTMPyP. It also caused phosphorylation of Akt and eNOS, which were prevented by MnTMPyP, polyethyleneglycol catalase, PP2, wortmannin and LY294002. GSE elicited the formation of ROS in native and cultured endothelial cells, which was prevented by MnTMPyP. CONCLUSIONS: GSE causes endothelium-dependent NO-mediated relaxations of coronary arteries. This effect involves the intracellular formation of ROS in endothelial cells leading to the Src kinase/phosphoinositide 3-kinase/Akt-dependent phosphorylation of eNOS.
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Vasos Coronarios/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Flavonoides/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenoles/farmacología , Extractos Vegetales/farmacología , Vitis , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Vasos Coronarios/citología , Vasos Coronarios/enzimología , Células Endoteliales/citología , Células Endoteliales/enzimología , Activación Enzimática/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Óxido Nítrico/metabolismo , Técnicas de Cultivo de Órganos , Oxidación-Reducción , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Polifenoles , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Porcinos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Familia-src Quinasas/metabolismoRESUMEN
OBJECTIVE: To investigate the effects of sildenafil on noradrenaline- and potassium-induced contractions of isolated human seminal vesicles (SVs), as premature ejaculation is a relatively common male sexual dysfunction that currently lacks an adequate therapy, and recent in vitro tests showed that sildenafil induces relaxation of rodent isolated SVs, but it is not known whether it also inhibits isolated human SV. MATERIAL AND METHODS: Isolated strips of human SVs were suspended in an organ bath and cumulative concentration-response curves to either noradrenaline or KCl were constructed in the presence and absence of sildenafil to evaluate its inhibitory actions. RESULTS: Sildenafil (25-100 microm) induced concentration-dependent inhibitory effects on the human SV contracted by either noradrenaline or KCl. These actions of sildenafil do not therefore appear to be mediated via a competitive antagonism of alpha-adrenoceptors and are consistent with its recognized ability to inhibit phosphodiesterase-5. CONCLUSIONS: The present results show an important inhibitory action of sildenafil in the isolated human SV, supporting the therapeutic indication of this drug for treating premature ejaculation.
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Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Vesículas Seminales/efectos de los fármacos , Sulfonas/farmacología , Anciano , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Músculo Liso/fisiología , Norepinefrina/metabolismo , Cloruro de Potasio/metabolismo , Purinas/farmacología , Vesículas Seminales/fisiología , Citrato de SildenafilRESUMEN
This study investigated the therapeutic potential of Euterpe oleracea extract (açaí) on the growth and survival of endometriotic lesions using an experimental model. Twenty female Sprague-Dawley rats were randomized into two groups after the implantation and establishment of autologous endometrium onto the peritoneum abdominal wall and treated with 200 mg/kg hydroalcoholic solution extract from açaí stone or vehicle via gastric tube for 30 consecutive days. Body weight, lesion surface areas, histological and immunohistochemistry analyses of vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2) and F4-80 were performed. Levels of VEGF, VEGFR-2, MMP-9 and COX-2 mRNA were measured. Flow cytometry of F4-80 was performed, and ELISA immunoassays measured prostaglandin E2 (PGE2), VEGF and nitric oxide (NO) and concentrations. Macrophage cell line J774.G8 was treated with 10, 20, and 40 µg/mL of açaí for 24, 48 and 72 h, and cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Açaí treatment significantly decreased the implant size, and histological examination indicated atrophy and regression. A reduction in immunostaining and mRNA expression of VEGF, MMP-9 and COX-2 was observed, and F4-80 was lower in the treated group than the control group. The treated group also exhibited lower concentrations of PGE2, VEGF and NO compared to the control group. Macrophages cells treated with 20 and 40 µg/ml of açaí reduced cell viability in about 50% after 24, 48 and 72 h. Our results suggest that açaí effectively suppressed the establishment and growth of endometriotic lesions, and this agent is a promising novel pharmacological therapeutic treatment for endometriosis.
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Endometriosis/tratamiento farmacológico , Euterpe/química , Extractos Vegetales/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Línea Celular , Endometriosis/patología , Femenino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Neovascularización Patológica/tratamiento farmacológico , Peritoneo/efectos de los fármacos , Peritoneo/patología , Extractos Vegetales/farmacología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
The possible involvement of the endothelium in the vasodilator action of eugenol was investigated in the mesenteric vascular bed (MVB) of the rat. Bolus injections of eugenol (0.2, 2 and 20 micromol) and acetylcholine (ACh; 10, 30 and 100 pmol) induced dose-dependent vasodilator responses in noradrenaline-precontracted beds that were partially inhibited by pretreatment of the MVB with deoxycholate (1 mg mL(-1)) to remove the endothelium (approximately 14% and approximately 30% of the control response remaining at the lowest doses of ACh and eugenol, respectively). The vasodilator effect of glyceryl trinitrate (1 micromol) was unaltered by deoxycholate. In the presence of either N(omega)-nitro-L-arginine methyl ester (300 microM) or tetraethylammonium (1 mM)the response to ACh was partially reduced, whereas eugenol-induced vasodilation was unaffected. Similarly the vasodilator effect of eugenol was not inhibited by indometacin (3 microM). Under calcium-free conditions the vasoconstrictor response elicited by bolus injections of noradrenaline (10 nmol) was dose-dependently and completely inhibited by eugenol (0.1-1 mM). Additionally, the pressor effects of bolus injections of calcium chloride in potassium-depolarized MVBs were greatly reduced in the presence of eugenol (0.1 mM), with a maximal reduction of approximately 71% of the control response. Our data showed that eugenol induced dose-dependent, reversible vasodilator responses in the rat MVB, that were partially dependent on the endothelium, although apparently independent of nitric oxide, endothelium-derived hyperpolarizing factor or prostacyclin. Furthermore, an endothelium-independent intracellular site of action seemed likely to participate in its smooth muscle relaxant properties.
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Endotelio Vascular/fisiología , Eugenol/farmacología , Circulación Esplácnica/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Presión Sanguínea/efectos de los fármacos , Calcio/fisiología , Ácido Desoxicólico/farmacología , Inhibidores Enzimáticos/farmacología , Indometacina/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Norepinefrina/farmacología , Perfusión , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar , Tetraetilamonio/farmacología , Trinitrotolueno/farmacología , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
OBJECTIVES: This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin-signalling cascade in alloxan-treated mice. METHODS: Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. KEY FINDINGS: Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan-treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan-treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan-treated group. The glucose transporter (GLUT-4) content was reduced in alloxan-treated mice compared with the control group, while alloxan + ACH09 and ACH09-treated mice showed a significant increase in GLUT-4 content. ACH09 treatment did not change glucose-induced insulin secretion in isolated pancreatic islets. CONCLUSIONS: The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin-signalling cascade in skeletal muscle.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/sangre , Extractos Vegetales/farmacología , Vitis/química , Aloxano , Animales , Glucemia/metabolismo , Western Blotting , Peso Corporal , Diabetes Mellitus Experimental/sangre , Modelos Animales de Enfermedad , Hiperglucemia/sangre , Masculino , Ratones , Músculo Esquelético/metabolismo , Receptor de Insulina/metabolismoRESUMEN
An alcohol-free grape-skin extract (GSE) obtained from skins of Vitis labrusca has significant anti-hypertensive, antioxidant and vasodilator effects. According to our previous results, the vasodilator effect of GSE in the isolated mesenteric vascular bed (MVB) of the rat is dependent on endothelium and partially dependent on nitric oxide (NO). In the MVB of the rat pre-contracted with norepinephrine (NE), bolus injections of GSE induced a long-lasting dose-dependent vasodilation that is significantly reduced after the treatment with 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ). Additionally, in vessels pre-contracted with norepinephrine and depolarized with KCl (25 mM) or treated with Ca(2+)-dependent K(+)-channel blockers charybdotoxin (ChTx) plus apamin, the vasodilator effect of GSE was significantly reduced and almost abolished by ChTx plus apamin plus L-NAME. However, the vasodilator effect of GSE was unaffected by D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (HOE-140), atropine, yohimbine, pyrilamine and 4-aminopyridine (4-AP). The vasoconstriction response elicited by bolus injection of KCl was not affected by GSE, whereas the vasoconstrictor response induced by NE was dose-dependently and completed inhibited by GSE in the presence but not in the absence of endothelium. However, NE-induced vasoconstriction in calcium-free condition or without endothelium was not reduced by GSE. The present results demonstrate that GSE induces a vasodilator effect in the rat MVB, which is dependent on NO in combination with endothelium-derived hyperpolarizing factor (EDHF). Additionally, our results indicated that extracellular Ca(2+) has an important role on the endothelium-dependent vasodilator effect induced by GSE.
Asunto(s)
Factores Relajantes Endotelio-Dependientes/farmacología , Arterias Mesentéricas/efectos de los fármacos , Extractos Vegetales/farmacología , Vitis/química , Alcoholes , Animales , Técnicas In Vitro , Masculino , Arterias Mesentéricas/fisiología , Norepinefrina/farmacología , Ratas , Ratas Wistar , Vasoconstrictores/farmacologíaRESUMEN
L-Arginine is the precursor of NO (nitric oxide), a key endogenous mediator involved in endothelium-dependent vascular relaxation and platelet function. Although the concentration of intracellular L-arginine is well above the Km for NO synthesis, in many cells and pathological conditions the transport of L-arginine is essential for NO production (L-arginine paradox). The present study was designed to investigate the modulation of L-arginine/NO pathway in systemic arterial hypertension. Transport of L-arginine into RBCs (red blood cells) and platelets, NOS (NO synthase) activity and amino acid profiles in plasma were analysed in hypertensive patients and in an animal model of hypertension. Influx of L-arginine into RBCs was mediated by the cationic amino acid transport systems y+ and y+L, whereas, in platelets, influx was mediated only via system y+L. Chromatographic analyses revealed higher plasma levels of L-arginine in hypertensive patients (175+/-19 micromol/l) compared with control subjects (137+/-8 micromol/l). L-Arginine transport via system y+L, but not y+, was significantly reduced in RBCs from hypertensive patients (60+/-7 micromol.l(-1).cells(-1).h(-1); n=16) compared with controls (90+/-17 micromol.l(-1).cells(-1).h(-1); n=18). In human platelets, the Vmax for L-arginine transport via system y+L was 86+/-17 pmol.10(9) cells(-1).min(-1) in controls compared with 36+/-9 pmol.10(9) cells(-1).min(-1) in hypertensive patients (n=10; P<0.05). Basal NOS activity was decreased in platelets from hypertensive patients (0.12+/-0.02 pmol/10(8) cells; n=8) compared with controls (0.22+/-0.01 pmol/10(8) cells; n=8; P<0.05). Studies with spontaneously hypertensive rats demonstrated that transport of L-arginine via system y+L was also inhibited in RBCs. Our findings provide the first evidence that hypertension is associated with an inhibition of L-arginine transport via system y+L in both humans and animals, with reduced availability of L-arginine limiting NO synthesis in blood cells.