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1.
Nitric Oxide ; 94: 48-53, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669041

RESUMO

Taurine is a semiessential amino acid found at high concentrations in mammalian plasma and cells, where it regulates cellular functions such as ion flux, controls cell volume and serves as a substrate for conjugated bile acids (BAs). Exogenous administration of both taurine and taurine-conjugated BAs have also been implicated in the modulation of cardiovascular functions. This brief review summarizes the role of taurine and taurine-conjugated BAs in vascular relaxation through the modulation of endothelium-derived nitric oxide (NO). The effects of taurine on vascular health are controversial. However, in the presence of cardiometabolic risk factors, it has been proposed that taurine can increase vascular NO levels by increasing eNOS expression, eNOS phosphorylation on Ser1177, NO bioavailability, the level of antioxidative defense, and the l-arginine/NOS inhibitor asymmetric dimethylarginine (ADMA) ratio. The taurine-conjugated BA-mediated activation of Farnesoid X receptor (FXR), G protein-coupled BA receptor (TGR5) and/or muscarinic 3 receptor (M3) was also reported to increase vascular NO production. FXR activation increases eNOS expression and may reduce ADMA formation, while TGR5 increases mobilization of Ca2+ and phosphorylation of eNOS and Akt in endothelial cells. Furthermore, taurine and taurine-conjugated BAs might regulate NO synthesis and activity by enhancing H2S generation. Several studies have demonstrated the beneficial effects of both taurine and taurine-conjugated BAs in reversing the endothelial dysfunction associated with diabetes, atherosclerosis, hypertension, obesity, malnutrition, and smoking. In addition, taurine-conjugated BAs have emerged as a potential treatment for portal hypertension. Despite these favorable findings, there is a need to further explore the mechanisms and signaling pathways underlying the endothelial effects of taurine and taurine-conjugated BAs. Here, we summarize the main findings regarding the effects of taurine and taurine-conjugated BAs on the endothelial dysfunction associated with altered NO metabolism in cardiovascular diseases.

2.
Curr Hypertens Rev ; 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30968777

RESUMO

Most of the systemic blood vessels are surrounded by the perivascular adipose tissue (PVAT). Healthy PVAT is anticontractile and anti-inflammatory, but a dysfunctional PVAT has been suggested to link cardiometabolic risk factors to vascular dysfunction. Vascular oxidative stress is an important pathophysiological event in cardiometabolic complications of obesity, type 2 diabetes, and hypertension. PVAT-derived adipocytes generate reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide that might signal to vascular wall. Therefore, an abnormal generation of ROS by PVAT emerges as a potential pathophysiological mechanism underlying vascular injury. This review summarizes new findings describing ROS production in PVAT of several vascular beds, major sources of ROS in this tissue including mitochondria, NADPH oxidase and eNOS uncoupled, and finally, changes in ROS production affecting vascular function in the presence of cardiometabolic risk factors and diseases.

3.
Am J Physiol Heart Circ Physiol ; 315(4): H989-H999, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29957022

RESUMO

Recent advances in the field of mineralocorticoid receptor (MR) and its ligand aldosterone expanded the role of this hormone and its receptor far beyond their initial function as a regulator of Na+ and K+ homeostasis in epithelial cells. The symposium "New Roles of Aldosterone and Mineralocorticoid Receptors in Cardiovascular Disease: Translational and Sex-Specific Effects" presented at the 38th World Congress of the International Union of Physiological Sciences (Rio de Janeiro, Brazil) highlighted the contribution of extrarenal MRs to cardiovascular disease. This symposium showcased how MRs expressed in endothelial, vascular smooth muscle, and immune cells plays a critical role in the development of vascular disease associated with aging, obesity, and chronic aldosterone stimulation and demonstrated that MR antagonism prevents the acute renal dysfunction and tubular injury induced by ischemia-reperfusion injury. It was also shown that the adipocyte-derived hormone leptin is a new direct regulator of aldosterone secretion and that leptin-mediated aldosterone production is a major contributor to obesity-associated hypertension in women. Sex differences in the role of aldosterone and of endothelial MR in the cardiovascular outcomes of obesity were highlighted. This review summarizes these important emerging concepts regarding the contribution of aldosterone and cell-specific MR to cardiovascular disease in male and female subjects and further supports sex-specific benefits of MR antagonist drugs to be tested in additional populations.


Assuntos
Aldosterona/metabolismo , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Rim/metabolismo , Receptores de Mineralocorticoides/metabolismo , Pesquisa Médica Translacional , Fatores Etários , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/imunologia , Sistema Cardiovascular/fisiopatologia , Congressos como Assunto , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Ligantes , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Receptores de Mineralocorticoides/efeitos dos fármacos , Fatores Sexuais , Transdução de Sinais
4.
J Appl Physiol (1985) ; 123(3): 655-663, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28684598

RESUMO

Progressive fibrosis is a hallmark of the aging heart. Age-related fibrosis is modulated by endurance exercise training; however, little is known concerning the influence of resistance training (RT). Therefore we investigated the chronic effects of high-intensity RT on age-associated alterations of left ventricle (LV) structure, collagen content, matrix metalloproteinase-2 (MMP-2), and extracellular matrix-related gene expression, including transforming growth factor-ß (TGF-ß). Young adult (3 mo) and aged (21 mo) male Wistar rats were submitted to a RT protocol (ladder climbing with 65, 85, 95, and 100% load), three times a week for 12 wk. Forty-eight hours posttraining, arterial systolic and diastolic pressure, LV end-diastolic pressure (LVEDP) and dP/dt were recorded. LV morphology, collagen deposition, and gene expression of type I (COL-I) and type III (COL-III) collagen, MMP-2, tissue inhibitor of metalloproteinases-1 (TIMP-1), and TGF-ß1 were analyzed by quantitative reverse transcriptase-PCR. MMP-2 content was assessed by zymography. Increased collagen deposition was observed in LV from aged rats. These parameters were modulated by RT and were associated with increased MMP-2 activity and decreased COL-I, TGF-ß1, and TIMP-1 mRNA content. Despite the effect of RT on collagen accumulation, there was no improvement on LVEDP and maximal negative LV dP/dt of aged rats. Cardiomyocyte diameter was preserved in all experimental conditions. In conclusion, RT attenuated age-associated collagen accumulation, concomitant to the increase in MMP-2 activity and decreased expression of COL-I, TGF-ß1, and TIMP-1 in LV, illustrating a cardioprotective effect of RT on ventricular structure and function.NEW & NOTEWORTHY We demonstrated the beneficial resistance-training effect against age-related left ventricle collagen accumulation in the left ventricle, which was associated with decreased type I collagen (COL-I), transforming growth factor-ß1 (TGF-ß1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) gene expression and matrix metalloproteinase-2 (MMP-2) activity. Our findings suggest for the first time the potential effects of resistance training in modulating collagen accumulation and possibly fibrosis in the aging heart.


Assuntos
Colágeno Tipo I/metabolismo , Ventrículos do Coração/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Animais , Pressão Sanguínea/fisiologia , Fibrose/metabolismo , Masculino , Ratos , Ratos Wistar , Treinamento de Resistência/métodos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Remodelação Ventricular/fisiologia
6.
Life Sci ; 125: 63-70, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25636591

RESUMO

AIM: To examine the influence of l-arginine supplementation in combination with physical training on mitochondrial biomarkers from gastrocnemius muscle and its relationship with physical performance. MAIN METHODS: Male Wistar rats were divided into four groups: control sedentary (SD), sedentary supplemented with l-arginine (SDLA), trained (TR) and trained supplemented with l-arginine (TRLA). Supplementation of l-arginine was administered by gavage (62.5mg/ml/day/rat). Physical training consisted of 60min/day, 5days/week, 0% grade, speed of 1.2km/h. The study lasted 8weeks. Skeletal muscle mitochondrial enriched fraction as well as cytoplasmic fractions were obtained for Western blotting and biochemical analyses. Protein expressions of transcriptor coactivator (PGC-1α), transcriptor factors (mtTFA), ATP synthase subunit c, cytochrome oxidase (COXIV), constitutive nitric oxide synthases (eNOS and nNOS), Cu/Zn-superoxide dismutase (SOD) and manganese-SOD (Mn-SOD) were evaluated. We also assessed in plasma: lipid profile, glycemia and malondialdehyde (MDA) levels. The nitrite/nitrate (NOx(-)) levels were measured in both plasma and cytosol fraction of the gastrocnemius muscle. KEY FINDINGS: 8-week l-arginine supplementation associated with physical training was effective in promoting greater tolerance to exercise that was accompanied by up-regulation of the protein expressions of mtTFA, PGC-1α, ATP synthase subunit c, COXIV, Cu/Zn-SOD and Mn-SOD. The upstream pathway was associated with improvement of NO bioavailability, but not in NO production since no changes in nNOS or eNOS protein expressions were observed. SIGNIFICANCE: This combination would be an alternative approach for preventing cardiometabolic diseases given that in overt diseases a profound impairment in the physical performance of the patients is observed.


Assuntos
Arginina/farmacologia , Suplementos Nutricionais , Músculo Esquelético/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais/análise , Ingestão de Alimentos/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Lipídeos/sangue , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/fisiologia , Óxido Nítrico Sintase/metabolismo , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Esforço Físico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
7.
Horm Mol Biol Clin Investig ; 18(2): 113-22, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25390007

RESUMO

AIM: The purpose of this study was to compare the effect of long-term ouabain treatment on the vascular reactivity and Na+, K+-ATPase activity of a conductance artery from normotensive and hypertensive rats. METHODS: Male Wistar rats were treated with ouabain (~8.0 µg/day, subcutaneously) or vehicle for 5 and 20 weeks, and spontaneously hypertensive rats (SHRs) for 5 weeks. Vasoconstrictor response to phenylephrine (10-10 to 10-4 M) and relaxation curves to KCl (1-10 mM) were analyzed in thoracic aorta. The effects of endothelial removal, L-NAME (100 µM), and indomethacin (10 µM) were used to evaluate the endothelial, nitric oxide (NO), and cyclooxygenase (COX) modulation of phenylephrine response, respectively. Protein expression of endothelial and neuronal NO synthase (NOS) and COX-2 were also investigated. RESULTS: The phenylephrine-induced contraction was reduced, whereas the relaxation to KCl was enhanced in the aorta of ouabain-treated Wistar rats and SHRs. In both strains, endothelial modulation of α-adrenergic response was enhanced, related to an increased NO and reduced COX-derived vasoconstrictor factor modulation. Aortas from 20-week ouabain-treated Wistar rats showed reduced COX-2 and enhanced eNOS protein expression. In SHRs, 5-week ouabain treatment reduced COX-2 and increased nNOS protein expression. CONCLUSIONS: The results suggest that long-term ouabain treatment reduces the α-adrenergic response of aorta from normotensive rats and SHRs, associated with an increase of NO synthesis, reduced COX-2-derived vasoconstrictor factors, and enhanced ouabain-sensitive Na+, K+-ATPase activity. These aortic mechanisms could be adjustments to the elevated blood pressure induced by ouabain, even in the presence of preexisting hypertension.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Ouabaína/farmacologia , Fenilefrina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Vasoconstritores/farmacologia , Animais , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/fisiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Contração Muscular , Músculo Liso Vascular/fisiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos SHR , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Especificidade da Espécie , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
8.
J Sex Med ; 11(11): 2661-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25196910

RESUMO

INTRODUCTION: Cardiovascular and endocrine-metabolic diseases associated with increased oxidative stress such as obesity lead to erectile dysfunction (ED). Activators of soluble guanylyl cyclase (sGC) such as BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases. AIM: This study aimed to evaluate the effects of 2-week oral intake with BAY 60-2270 on a murine model of obesity-associated ED. METHODS: C57BL/6 male mice were fed for 12 weeks with standard chow or high-fat diet. Lean and obese mice were treated with BAY 60-2770 (1 mg/kg/day, 2 weeks). MAIN OUTCOME MEASURES: Measurements of intracavernosal pressure (ICP), along with acetylcholine (10(-9) to 10(-5) M) and electrical field stimulation (EFS; 4-10 Hz)-induced corpus cavernosum relaxations in vitro, were obtained. Levels of cyclic guanosine monophosphate (cGMP), reactive oxygen species (ROS), and sGC protein expressions in cavernosal tissues were measured. RESULTS: Cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P < 0.05). Two-week therapy with BAY 60-2770 fully reversed the decreased ICP in obese group. Acetylcholine-induced cavernosal relaxations were 45% lower (P < 0.001) in obese mice, which were fully restored by BAY 60-2770 treatment. Likewise, the EFS-induced relaxations in obese mice were restored by BAY 60-2770. Basal cGMP content in erectile tissue was 68% lower (P < 0.05) in obese mice, an effect normalized by BAY 60-2770. Levels of ROS were 52% higher (P < 0.05) whereas protein expression of α1 sGC subunit was reduced in cavernosal tissue of obese mice, both of which were normalized by BAY 60-2770. In lean group, BAY 60-2770 did not significantly affect any functional, biochemical, or molecular parameter analyzed. CONCLUSIONS: Two-week therapy with BAY 60-2770 restores the erectile function in obese mice that is associated with reduced ROS levels, up-regulation of α1 sGC subunit, and increased cGMP levels in the erectile tissue.


Assuntos
Benzoatos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Ativadores de Enzimas/administração & dosagem , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Hidrocarbonetos Fluorados/administração & dosagem , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , GMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Disfunção Erétil/enzimologia , Disfunção Erétil/etiologia , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Ereção Peniana/efeitos dos fármacos , Pênis/irrigação sanguínea , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Guanilil Ciclase Solúvel , Regulação para Cima
9.
Am J Physiol Heart Circ Physiol ; 307(10): H1393-400, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25217652

RESUMO

Impairment of nitric oxide (NO)-mediated cavernosal relaxations in middle age contributes to erectile dysfunction. However, little information is available about the alterations of sympathetic neurotransmission and contraction in erectile tissue at middle age. This study aimed to evaluate the alterations of the contractile machinery associated with tyrosine hydroxylase (TH) in rat corpus cavernosum (RCC) at middle age, focusing on the role of superoxide anion. Male Wistar young (3.5-mo) and middle-aged (10-mo) rats were used. Electrical-field stimulation (EFS)- and phenylephrine-induced contractions were obtained in RCC strips. Levels of reactive-oxygen species (ROS) and TH mRNA expression, as well as protein expressions for α1/ß1-subunits of soluble guanylyl cyclase (sGC), in RCC were evaluated. The neurogenic contractile responses elicited by EFS (4-32 Hz) were greater in RCC from the middle-aged group that was accompanied by elevated TH mRNA expression (P < 0.01). Phenylephrine-induced contractions were also greater in the middle-aged group. A 62% increase in ROS generation in RCC from middle-aged rats was observed. The mRNA expression for the α1A-adrenoceptor remained unchanged among groups. Protein levels of α1/ß1-sGC subunits were decreased in RCC from the middle-aged compared with young group. The NADPH oxidase inhibitor apocynin (85 mg·rat(-1)·day(-1), 4 wk) fully restored the enhanced ROS production, TH mRNA expressions, and α1/ß1-subunit sGC expression, indicating that excess of superoxide anion plays a major role in the sympathetic hyperactivity and hypercontractility in erectile tissue at middle age. Reduction of oxidative stress by dietary antioxidants may be an interesting approach to treat erectile dysfunction in aging population.


Assuntos
Envelhecimento/metabolismo , Guanilato Ciclase/metabolismo , Impotência Vasculogênica/fisiopatologia , Contração Muscular , Músculo Liso/inervação , Estresse Oxidativo , Ereção Peniana , Pênis/inervação , Receptores Citoplasmáticos e Nucleares/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Fatores Etários , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Impotência Vasculogênica/enzimologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/enzimologia , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Pênis/irrigação sanguínea , RNA Mensageiro/metabolismo , Ratos Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Guanilil Ciclase Solúvel , Superóxidos , Sistema Nervoso Simpático/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
10.
J Pharmacol Exp Ther ; 349(1): 2-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24421320

RESUMO

Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 µM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of ß1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.


Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/uso terapêutico , Óxido Nítrico/metabolismo , Obesidade/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Uretra/efeitos dos fármacos , Animais , Benzoatos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Relação Dose-Resposta a Droga , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Hidrocarbonetos Fluorados/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/metabolismo , Obesidade/complicações , Obesidade/enzimologia , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Guanilil Ciclase Solúvel , Uretra/enzimologia , Uretra/metabolismo , Bexiga Urinária Hiperativa/enzimologia , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/prevenção & controle
11.
J Urol ; 191(2): 539-47, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24050894

RESUMO

PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and ß1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and ß1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.


Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Guanilato Ciclase/efeitos dos fármacos , Hidrocarbonetos Fluorados/uso terapêutico , Obesidade/epidemiologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Western Blotting , Hidrocarbonetos Fluorados/farmacologia , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio , Bexiga Urinária Hiperativa/epidemiologia , Bexiga Urinária Hiperativa/prevenção & controle
12.
J Neuroinflammation ; 11: 218, 2014 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-25551197

RESUMO

BACKGROUND: Ouabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects. Lipopolysaccharide (LPS), via toll-like receptor 4 activation, is a widely used model to induce systemic inflammation. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats. METHODS: Adult male Wistar rats received acute intraperitoneal (ip) OUA (1.8 µg/kg) or saline 20 minutes before LPS (200 µg/kg, ip) or saline injection. Some of the animals had their femoral artery catheterized in order to assess arterial blood pressure values before and after OUA administration. Na,K-ATPase activity, cytokine mRNA levels, apoptosis-related proteins, NF-κB activation brain-derived neurotrophic factor BDNF, corticosterone and TNF-α levels were measured. RESULTS: OUA pretreatment decreased mRNA levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and IL-1ß, which are activated by LPS in the hippocampus, but with no effect on serum measures of these factors. None of these OUA effects were linked to Na,K-ATPase activity. The involvement of the inflammatory transcription factor NF-κB in the OUA effect was indicated by its prevention of LPS-induced nuclear translocation of the NF-κB subunit, RELA (p65), as well as the decreased cytosol levels of the NF-κB inhibitor, IKB, in the hippocampus. OUA pretreatment reversed the LPS-induced glial fibrillary acidic protein (GFAP) activation and associated inflammation in the dentate gyrus. OUA also prevented LPS-induced increases in the hippocampal Bax/Bcl2 ratio suggesting an anti-apoptotic action in the brain. CONCLUSION: Our results suggest that a low dose of OUA has an important anti-inflammatory effect in the rat hippocampus. This effect was associated with decreased GFAP induction by LPS in the dentate gyrus, a brain area linked to adult neurogenesis.


Assuntos
Inibidores Enzimáticos/farmacologia , Hipocampo/imunologia , Inflamação/tratamento farmacológico , Ouabaína/farmacologia , Transdução de Sinais/imunologia , ATPase Trocadora de Sódio-Potássio/imunologia , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/imunologia , Masculino , Ouabaína/administração & dosagem , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos
13.
Int J Cardiol ; 168(4): 3829-36, 2013 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-23849970

RESUMO

BACKGROUND/OBJECTIVES: Therapy using bone marrow (BM) cells has been tested experimentally and clinically due to the potential ability to restore cardiac function by regenerating lost myocytes or increasing the survival of tissues at risk after myocardial infarction (MI). In this study we aimed to evaluate whether BM-derived mononuclear cell (MNC) implantation can positively influence the post-MI structural remodeling, contractility and Ca(2+)-handling proteins of the remote non-infarcted tissue in rats. METHODS AND RESULTS: After 48 h of MI induction, saline or BM-MNC were injected. Six weeks later, MI scars were slightly smaller and thicker, and cardiac dilatation was just partially prevented by cell therapy. However, the cardiac performance under hemodynamic stress was totally preserved in the BM-MNC treated group if compared to the untreated group, associated with normal contractility of remote myocardium as analyzed in vitro. The impaired post-rest potentiation of contractile force, associated with decreased protein expression of the sarcoplasmic reticulum Ca(2+)-ATPase and phosphorylated-phospholamban and overexpression of Na(+)/Ca(2+) exchanger, were prevented by BM-MNC, indicating preservation of the Ca(2+) handling. Finally, pathological changes on remodeled remote tissue such as myocyte hypertrophy, interstitial fibrosis and capillary rarefaction were also mitigated by cell therapy. CONCLUSIONS: BM-MNC therapy was able to prevent cardiac structural and molecular remodeling after MI, avoiding pathological changes on Ca(2+)-handling proteins and preserving contractile behavior of the viable myocardium, which could be the major contributor to the improvements of global cardiac performance after cell transplantation despite that scar tissue still exists.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Contração Miocárdica/fisiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Animais , Transplante de Medula Óssea/métodos , Feminino , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Endogâmicos Lew
14.
Acta sci., Biol. sci ; 35(3): 437-443, jul.-set. 2013. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-859261

RESUMO

Activation of ß2 adrenergic receptors by catecholamine or catecholamine-mimetic substances may enhance insulin secretion. We herein investigated KCl- and nutrient-stimulated insulin secretion in pancreatic islets isolated from ß2 knockout (ß2KO) mice. ß2KO mice showed reduced body weight, fasting hypoglycaemia associate to a similar fasting insulinemia compared to control. ß2KO mice also showed reduced glucose tolerance despite the higher sensitivity to insulin. Glucose-induced insulin secretion was impaired in pancreatic islets isolated from ß2KO mice. Leucine-induced (20mM) insulin secretion was diminished in pancreatic islets isolated from ß 2KO mice when compared to control one. The depolarizing effect of KCl on insulin secretion was also impaired in pancreatic islets from ß2KO mice. These results suggested a possible role of ß2 adrenergic receptors on nutrient-induced insulin secretion.


A ativação dos receptores ß2-adrenérgicos por catecolaminas ou miméticos a catecolaminas podem aumentar a secreção de insulina. Nós investigamos a secreção de insulina estimulada por nutrients e KCl em ilhotas pancreáticas isoladas de camundongos com deleção dos receptores ß2-adrenérgicos (ß2KO). Camudongos ß2KO apresentaram reduzido peso corporal, hipoglicemia de jejum associada a semelhante concentração de insulina plasmática de jejum comparada ao grupo controle. Camundongos ß2KO apesar de apresentarem aumento da sensibilidade a insulina também apresentaram reduzida tolerância a glicose. A secreção de insulina induzida com glicose foi alterada em ilhotas pancreáticas isoladas de camundongos ß2KO. Secreção de insulina induzida por leucina (20mM) foi diminuída em ilhotas pancreáticas isoladas de camundongos ß2KO quando comparado ao controle. O efeito despolarizante do KCl sobre a secreção de insulina também foi alterado em ilhotas pancreáticas de camundongos ß2KO. Estes resultados sugerem um possível papel dos receptores ß2-adrenérgicos na secreção de insulina induzida por nutrientes.


Assuntos
Camundongos , Glucose , Células Secretoras de Insulina , Leucina , Receptores Adrenérgicos
15.
Arq. bras. cardiol ; 98(3): 243-251, mar. 2012. tab
Artigo em Português | LILACS | ID: lil-622515

RESUMO

FUNDAMENTO: A Contração Pós-Repouso (CPR) do músculo cardíaco fornece informações indiretas sobre a manipulação de cálcio intracelular. OBJETIVO: Nosso objetivo foi estudar o comportamento da CPR e seus mecanismos subjacentes em camundongos com infarto do miocárdio. MÉTODOS: Seis semanas após a oclusão coronariana, a contratilidade dos Músculos Papilares (MP) obtidos a partir de camundongos submetidos à cirurgia sham (C, n = 17), com infarto moderado (MMI, n = 10) e grande infarto (LMI, n = 14), foi avaliada após intervalos de repouso de 10 a 60 segundos antes e depois da incubação com cloreto de lítio (Li+) em substituição ao cloreto de sódio ou rianodina (Ry). A expressão proteica de SR Ca(2+)-ATPase (SERCA2), trocador Na+/Ca2+ (NCX), fosfolambam (PLB) e fosfo-Ser (16)-PLB foi analisada por Western blotting. RESULTADOS: Os camundongos MMI apresentaram potenciação de CPR reduzida em comparação aos camundongos C. Em oposição à potenciação normal para camundongos C, foram observadas degradações de força pós-repouso nos músculos de camundongos LMI. Além disso, a Ry bloqueou a degradação ou potenciação de PRC observada em camundongos LMI e C; o Li+ inibiu o NCX e converteu a degradação em potenciação de CPR em camundongos LMI. Embora os camundongos MMI e LMI tenham apresentado diminuição no SERCA2 (72 ± 7% e 47 ± 9% de camundongos controle, respectivamente) e expressão protéica de fosfo-Ser16-PLB (75 ± 5% e 46 ± 11%, respectivamente), a superexpressão do NCX (175 ± 20%) só foi observada nos músculos de camundongos LMI. CONCLUSÃO: Nossos resultados mostraram, pela primeira vez, que a remodelação miocárdica pós-IAM em camundongos pode mudar a potenciação regular para degradação pós-repouso, afetando as proteínas de manipulação de Ca(2+) em miócitos.


BACKGROUND: Post-rest contraction (PRC) of cardiac muscle provides indirect information about the intracellular calcium handling. OBJECTIVE: Our aim was to study the behavior of PRC, and its underlying mechanisms, in rats with myocardial infarction. METHODS: Six weeks after coronary occlusion, the contractility of papillary muscles (PM) obtained from sham-operated (C, n=17), moderate infarcted (MMI, n=10) and large infarcted (LMI, n=14) rats was evaluated, following rest intervals of 10 to 60 seconds before and after incubation with lithium chloride (Li+) substituting sodium chloride or ryanodine (Ry). Protein expression of SR Ca(2+)-ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLB) and phospho-Ser(16)-PLB were analyzed by Western blotting. RESULTS: MMI exhibited reduced PRC potentiation when compared to C. Opposing the normal potentiation for C, post-rest decays of force were observed in LMI muscles. In addition, Ry blocked PRC decay or potentiation observed in LMI and C; Li+ inhibited NCX and converted PRC decay to potentiation in LMI. Although MMI and LMI presented decreased SERCA2 (72±7% and 47±9% of Control, respectively) and phospho-Ser16-PLB (75±5% and 46±11%, respectively) protein expression, overexpression of NCX (175±20%) was only observed in LMI muscles. CONCLUSION: Our results showed, for the first time ever, that myocardial remodeling after MI in rats may change the regular potentiation to post-rest decay by affecting myocyte Ca(2+) handling proteins.


FUNDAMENTO: La Contracción pos pausa (CPP) del músculo cardíaco provee informaciones indirectas sobre la manejo del calcio intracelular. OBJETIVO: Nuestro objetivo fue estudiar el comportamiento de la CPP y sus mecanismos subyacentes en Ratas con infarto de miocardio. MÉTODOS: Seis semanas después de la oclusión coronaria, la contractilidad de los Músculos Papilares (MP) obtenidos a partir de Ratas sometidos a falsa cirurgia (C, n = 17), con infarto moderado (MMI, n = 10) y gran infarto (LMI, n = 14), fue evaluada después de pausas de estímulos de 10 a 60 segundos antes y después de la incubación con cloruro de litio (Li+) en substitución del cloruro de sodio o rianodina (Ry). La expresión proteica de SR Ca(2+)-ATPasa (SERCA2), intercambiador Na+/Ca2+ (NCX), fosfolamban (PLB) y fosfo-Ser (16)-PLB fue analizada por Western blotting. RESULTADOS: Los Ratas MMI presentaron potenciación de CPP reducida en comparación a los Ratas C. En oposición a la potenciación normal para Ratas C, fueron observadas decaimientos de fuerza post-reposo en los músculos de Ratas LMI. Además de eso, la Ry bloqueó la decaimiento o potenciación de PRC observada en Ratas LMI y C; el Li+ inhibió el NCX y convirtió la decaimiento en potenciación de CPP en Ratas LMI. Aunque los Ratas MMI y LMI hayan presentado disminución en el SERCA2 (72 ± 7% y 47 ± 9% de Ratas control, respectivamente) y expresión proteica de fosfo-Ser16-PLB (75 ± 5% y 46 ± 11%, respectivamente), la superexpresión del NCX (175 ± 20%) sólo fue observada en los músculos de Ratas LMI. CONCLUSIÓN: Nuestros resultados mostraron, por primera vez, que el remodelado miocárdico post-IAM en Ratas puede cambiar la potenciación regular para decaimiento post-reposo, afectando las proteínas de manejo del Ca(2+) en miocitos.


Assuntos
Animais , Ratos , Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Remodelação Ventricular/fisiologia , Modelos Animais de Doenças , Cloreto de Lítio/farmacologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/classificação , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Distribuição Aleatória , Ratos Wistar , Rianodina/farmacologia
16.
Exp Physiol ; 97(6): 710-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22327331

RESUMO

Persistent ß-adrenergic receptor stimulation with isoproterenol is associated with cardiac hypertrophy as well as cardiac synthesis of angiotensin II. Serum- and glucocorticoid-regulated kinase type 1 (SGK-1) is a key mediator in structural, functional and molecular cardiac effects of aldosterone in rats. This study was designed to investigate the cardiac effects of the mineralocorticoid receptor antagonist spironolactone on the response to isoproterenol treatment in rats, as well as the involvement of the main mediator of cellular aldosterone action, SGK-1, in the heart. Male Wistar rats received isoproterenol (3 mg kg(-1) day(-1)) or vehicle for 15 days. Half of the animals in each group were simultaneously treated with spironolactone (200 mg kg(-1) day(-1)). Systolic and diastolic blood pressures were not significantly different among groups. Treatment with spironolactone normalized the increased left ventricular end-diastolic pressure observed in isoproterenol-treated rats. Isoproterenol treatment induced cardiac hypertrophy and increased collagen content, both of which were normalized by spironolactone treatment. The mRNA levels of transforming growth factor ß, connective tissue growth factor, matrix metalloprotease 2, matrix metalloprotease inhibitor 2, tumour necrosis factor α, interleukin 1ß, p22phox and xanthine dehydrogenase were increased (P < 0.05) in isoproterenol-treated rats, and this effect was prevented by spironolactone (P < 0.05). Spironolactone also reduced the elevated SGK-1 expression in isoproterenol-treated rats. The observed reduction of the principal mediator of aldosterone cellular actions, SGK-1, by spironolactone in hearts from isoproterenol-treated rats suggests a role of mineralocorticoids in the cardiac hypertrophy, fibrosis, inflammation, oxidation and diastolic dysfunction induced by isoproterenol treatment in rats.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Proteínas Imediatamente Precoces/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Espironolactona/farmacologia , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Coração/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Isoproterenol , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/metabolismo
17.
Arq Bras Cardiol ; 98(3): 243-51, 2012 Mar.
Artigo em Inglês, Português, Espanhol | MEDLINE | ID: mdl-22344675

RESUMO

BACKGROUND: Post-rest contraction (PRC) of cardiac muscle provides indirect information about the intracellular calcium handling. OBJECTIVE: Our aim was to study the behavior of PRC, and its underlying mechanisms, in rats with myocardial infarction. METHODS: Six weeks after coronary occlusion, the contractility of papillary muscles (PM) obtained from sham-operated (C, n=17), moderate infarcted (MMI, n=10) and large infarcted (LMI, n=14) rats was evaluated, following rest intervals of 10 to 60 seconds before and after incubation with lithium chloride (Li(+)) substituting sodium chloride or ryanodine (Ry). Protein expression of SR Ca(2+)-ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLB) and phospho-Ser(16)-PLB were analyzed by Western blotting. RESULTS: MMI exhibited reduced PRC potentiation when compared to C. Opposing the normal potentiation for C, post-rest decays of force were observed in LMI muscles. In addition, Ry blocked PRC decay or potentiation observed in LMI and C; Li(+) inhibited NCX and converted PRC decay to potentiation in LMI. Although MMI and LMI presented decreased SERCA2 (72±7% and 47±9% of Control, respectively) and phospho-Ser(16)-PLB (75±5% and 46±11%, respectively) protein expression, overexpression of NCX (175±20%) was only observed in LMI muscles. CONCLUSION: Our results showed, for the first time ever, that myocardial remodeling after MI in rats may change the regular potentiation to post-rest decay by affecting myocyte Ca(2+) handling proteins.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Cloreto de Lítio/farmacologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/classificação , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Rianodina/farmacologia
18.
Toxicology ; 295(1-3): 39-46, 2012 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-22361244

RESUMO

Clinical evidence has identified the pulmonary circulation as an important target of air pollution. It was previously demonstrated that in vitro exposure to fine particulate matter (aerodynamic diameter≤2.5 µm, PM2.5) induces endothelial dysfunction in isolated pulmonary arteries. We aimed to investigate the effects of in vivo exposure to urban concentrated PM2.5 on rat pulmonary artery reactivity and the mechanisms involved. For this, adult Wistar rats were exposed to 2 weeks of concentrated São Paulo city air PM2.5 at an accumulated daily dose of approximately 600 µg/m3. Pulmonary arteries isolated from PM2.5-exposed animals exhibited impaired endothelium-dependent relaxation to acetylcholine without significant changes in nitric oxide donor response compared to control rats. PM2.5 caused vascular oxidative stress and enhanced protein expression of Cu/Zn- and Mn-superoxide dismutase in the pulmonary artery. Protein expression of endothelial nitric oxide synthase (eNOS) was reduced, while tumor necrosis factor (TNF)-α was enhanced by PM2.5 inhalation in pulmonary artery. There was a significant positive correlation between eNOS expression and maximal relaxation response (Emax) to acetylcholine. A negative correlation was found between vascular TNF-α expression and Emax to acetylcholine. Plasma cytokine levels, blood cells count and coagulation parameters were similar between control and PM2.5-exposed rats. The present findings showed that in vivo daily exposure to concentrated urban PM2.5 could decrease endothelium-dependent relaxation and eNOS expression on pulmonary arteries associated with local high TNF-α level but not systemic pro-inflammatory factors. Taken together, the present results elucidate the mechanisms underlying the trigger of cardiopulmonary diseases induced by urban ambient levels of PM2.5.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Inflamação/induzido quimicamente , Material Particulado/toxicidade , Artéria Pulmonar/efeitos dos fármacos , Animais , Endotélio Vascular/fisiologia , Masculino , Óxido Nítrico Sintase Tipo III/análise , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/análise
19.
PLoS One ; 7(12): e53318, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285277

RESUMO

BACKGROUND: The majority of studies have investigated the effect of exercise training (TR) on vascular responses in diabetic animals (DB), but none evaluated nitric oxide (NO) and advanced glycation end products (AGEs) formation associated with oxidant and antioxidant activities in femoral and coronary arteries from trained diabetic rats. Our hypothesis was that 8-week TR would alter AGEs levels in type 1 diabetic rats ameliorating vascular responsiveness. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats were divided into control sedentary (C/SD), sedentary diabetic (SD/DB), and trained diabetic (TR/DB). DB was induced by streptozotocin (i.p.: 60 mg/kg). TR was performed for 60 min per day, 5 days/week, during 8 weeks. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (PHE) and tromboxane analog (U46619) were obtained. The protein expressions of eNOS, receptor for AGEs (RAGE), Cu/Zn-SOD and Mn-SOD were analyzed. Tissues NO production and reactive oxygen species (ROS) generation were evaluated. Plasma nitrate/nitrite (NO(x)⁻), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS) and N(ε)-(carboxymethyl) lysine (CML, AGE biomarker). A rightward shift in the concentration-response curves to ACh was observed in femoral and coronary arteries from SD/DB that was accompanied by an increase in TBARS and CML levels. Decreased in the eNOS expression, tissues NO production and NO(x)⁻ levels were associated with increased ROS generation. A positive interaction between the beneficial effect of TR on the relaxing responses to ACh and the reduction in TBARS and CML levels were observed without changing in antioxidant activities. The eNOS protein expression, tissues NO production and ROS generation were fully re-established in TR/DB, but plasma NO(x)⁻ levels were partially restored. CONCLUSION: Shear stress induced by TR fully restores the eNOS/NO pathway in both preparations from non-treated diabetic rats, however, a massive production of AGEs still affecting relaxing responses possibly involving other endothelium-dependent vasodilator agents, mainly in coronary artery.


Assuntos
Vasos Coronários , Diabetes Mellitus Experimental , Endotélio Vascular/fisiopatologia , Artéria Femoral , Produtos Finais de Glicação Avançada/metabolismo , Condicionamento Físico Animal , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/terapia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Fatores Relaxantes Dependentes do Endotélio/farmacologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/metabolismo , Artéria Femoral/fisiopatologia , Produtos Finais de Glicação Avançada/farmacologia , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Estreptozocina
20.
J Physiol ; 589(Pt 10): 2585-96, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21486789

RESUMO

Cardiovascular disease is less frequent in premenopausal women than in age-matched men or postmenopausal women. Moreover, the marked age-related decline in serum dehydroepiandrosterone (DHEA) level has been associated to cardiovascular disease. The aim of this study was to evaluate the effects of DHEA treatment on vascular function in ovariectomized rats. At 8 weeks of age, female Wistar rats were ovariectomized (OVX) or sham (SHAM) operated and 8 weeks after surgery both groups were treated with vehicle or DHEA (10mg kg⁻¹ week⁻¹) for 3 weeks. Aortic rings were used to evaluate the vasoconstrictor response to phenylephrine (PHE) and the relaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP). Tissue reactive oxygen species (ROS) production and SOD, NADPH oxidase and eNOS protein expression were analysed. PHE-induced contraction was increased in aortic rings from OVX compared to SHAM, associated with a reduction in NO bioavailability. Furthermore, the relaxation induced by ACh was reduced in arteries from OVX, while SNP relaxation did not change. The incubation of aortic rings with SOD or apocynin restored the enhanced PHE-contraction and the impaired ACh-relaxation only in OVX. DHEA treatment corrected the increased PHE contraction and the impaired ACh-induced relaxation observed in OVX by an increment in NO bioavailability and decrease in ROS production. Besides, DHEA treatment restores the reduced Cu/Zn-SOD protein expression and eNOS phosphorylation and the increased NADPH oxidase protein expression in the aorta of OVX rats. The present results suggest an important action of DHEA, improving endothelial function in OVX rats by acting as an antioxidant and enhancing the NO bioavailability.


Assuntos
Desidroepiandrosterona/farmacologia , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetofenonas/farmacologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Fármacos Cardiovasculares/farmacologia , Endotélio Vascular/enzimologia , Feminino , NADPH Oxidases/biossíntese , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/biossíntese , Nitroprussiato/farmacologia , Ovariectomia , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/biossíntese
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