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Am J Physiol Renal Physiol ; 310(11): F1295-307, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26962104


Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor.

Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Rim/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/irrigação sanguínea , Losartan/farmacologia , Masculino , Natriurese/efeitos dos fármacos , Ratos , Ratos Wistar , Resistência Vascular/efeitos dos fármacos
Horm Mol Biol Clin Investig ; 18(2): 113-22, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25390007


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.

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
PLoS One ; 9(5): e98012, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24859374


BACKGROUND: Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1-7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1-7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF. METHODS/MAIN RESULTS: Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1-7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1-7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle. CONCLUSIONS: Exercise training causes a shift in RAS towards the Ang-(1-7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal muscle.

Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Sistema Renina-Angiotensina , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Masculino , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar
Shock ; 40(3): 203-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23846411


INTRODUCTION: It has been shown that the innate immune system mediates acute lung inflammation triggered by intestinal trauma. Sexual dimorphism modulates the profile of TH1 and TH2 lymphocytes, and accordingly sex hormones may modulate acute lung inflammation by intestinal ischemia/reperfusion (I/R). Studies indicate that female rats are relatively resistant to organ injury caused by hemorrhagic shock and that the gut of female is more resistant than that of the male to deleterious effects of ischemic injury. At the present study, we investigated the effect of estradiol (E(2)) on the lung inflammation after intestinal I/R and its interaction with the nitric oxide (NO) pathway. METHODS: Anesthetized female rats submitted or not to 7 days ovariectomy (OVx) were subjected to occlusion of the superior mesenteric artery during 45 min, followed by 2 h of reperfusion. Groups of rats were treated with E(2) (17ß-estradiol, 280 µg/kg, s.c.) 24 h before ischemia and/or with the nonselective NO synthase inhibitor L-NAME (Nω-nitro-L-arginine methyl ester hydrochloride) (5 mg/kg, i.v.). In a parallel set of experiments, the selective NO synthase inhibitor, aminoguanidine (50 mg/kg i.v.), was given 1 h before ischemia. In all groups, lung vascular permeability (LVP) was assessed using the Evans blue dye extravasation method, neutrophil recruitment to the tissues by the standard myeloperoxidase (MPO) method, and endothelial NO synthase (eNOS) protein expression by Western blot. RESULTS: In OVx rats, LVP and MPO were increased after intestinal I/R as compared with intact controls. Estradiol reverted the LVP, but not MPO. Aminoguanidine reduced LVP in OVx rats. The E(2) protective effect on LVP was abolished by L-NAME; moreover, an increase in LVP even when compared with OVx rats treated only with L-NAME was observed. In addition, lung eNOS protein expression was reduced in OVx-I/R rats in comparison to intact controls and the E(2) inhibited this effect. CONCLUSIONS: Estradiol treatment is able to reduce lung inflammation due to intestinal I/R, but with the concomitant blockade of NOS activity, this effect is abolished. Nitric oxide probably reduces the vascular deleterious effects of intestinal I/R, and E(2) pretreatment reduces lung inflammation after intestinal I/R and exerts these effects by modulating eNOS protein expression in the lungs.

Estradiol/uso terapêutico , Intestinos/irrigação sanguínea , Óxido Nítrico/metabolismo , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Wistar
PLoS One ; 7(12): e53318, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285277


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.

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