RESUMO

Activation of the peripheral angiotensin-(1-7)/Mas axis of the renin-angiotensin system produces important cardioprotective actions, counterbalancing the deleterious actions of an overactivity of Ang II/AT1 axis. In the present study we evaluated whether the chronic increase in Ang-(1-7) levels in the brain could ameliorate cardiac disorders observed in transgenic (mRen2)27 hypertensive rats through actions on Mas receptor. Sprague Dawley (SD) and transgenic (mRen2)27 hypertensive rats, instrumented with telemetry probe for arterial pressure (AP) measurement were subjected to 14 days of ICV infusion of Ang-(1-7) (200 ng/h) or Ang-(1-7) associated with Mas receptor antagonist (A779, 1 µg/h) or 0.9% sterile saline (0.5 µl/h) through osmotic mini-pumps. Ang-(1-7) infusion in (mRen2)27 rats reduced blood pressure, normalized the baroreflex control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy and pre-fibrotic alterations and decreased the altered imbalance of Ang II/Ang-(1-7) in the heart. In addition, there was an attenuation of the increased levels of atrial natriuretic peptide, brain natriuretic peptide, collagen I, fibronectin and TGF-ß in the heart of (mRen2)27 rats. Furthermore, most of these effects were mediated in the brain by Mas receptor, since were blocked by its selective antagonist, A779. These data indicate that increasing Ang-(1-7) levels in the brain can attenuate cardiovascular disorders observed in (mRen2)27 hypertensive rats, probably by improving the autonomic balance to the heart due to centrally-mediated actions on Mas receptor.

Assuntos

Angiotensina II/análogos & derivados , Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Angiotensina II/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Miocárdio/patologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia

RESUMO

We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), Sprague-Dawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose. Compared with control rats, FF rats had increased mean arterial pressure and cardiac sympathetic tone with impaired baroreflex sensitivity. FF rats also presented increased circulating triglycerides, leptin, insulin, and glucose with impaired glucose tolerance. Furthermore, relative weights of liver and retroperitoneal adipose tissue were increased in FF rats. Glycogen content was reduced in liver, but increased in muscle. In contrast, fructose-fed rats subjected to chronic intracerebroventricular infusion of Ang-(1-7) presented reduced cardiac sympathetic tone with normalized mean arterial pressure, baroreflex sensitivity, glucose and insulin levels, and improved glucose tolerance. Relative weight of liver, and hepatic and muscle glycogen contents were also normalized in FF+A7 rats. In addition, FF+A7 rats had reduced mRNA expression for neuronal nitric oxide synthase and NR1 subunit of N-methyl-d-aspartate receptor in hypothalamus and dorsomedial medulla. Ang-(1-7) infusion did not alter fructose-induced hyperleptinemia and increased relative weight of retroperitoneal adipose tissue. There were no differences in body weights, neither in liver mRNA expression of phosphoenolpyruvate carboxykinase or glucose-6-phosphatase among the groups. These data indicate that chronic increase in Ang-(1-7) levels in the brain may have a beneficial role in fructose-fed rats by ameliorating cardiovascular and metabolic disorders.

Assuntos

Angiotensina I/uso terapêutico , Encéfalo/metabolismo , Carboidratos da Dieta/efeitos adversos , Frutose/efeitos adversos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/administração & dosagem , Angiotensina I/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Carboidratos da Dieta/farmacologia , Modelos Animais de Doenças , Frutose/farmacologia , Glicogênio/metabolismo , Infusões Intraventriculares , Insulina/metabolismo , Síndrome Metabólica/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Risco

RESUMO

Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

Assuntos

Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Estresse Oxidativo , Peptidil Dipeptidase A/metabolismo , Vasodilatação/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ativação Enzimática , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Peptidil Dipeptidase A/efeitos dos fármacos , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos , Xantonas/farmacologia

RESUMO

The renin-angiotensin (Ang) system (RAS) plays an important role in the control of glucose metabolism and glycemia. Several studies demonstrated that the effects of angiotensin-(1-7) are mainly opposite to the actions of biological angiotensin II. Recent studies have demonstrated that rats with increased circulating angiotensin-(1-7), acting through the G protein coupled receptor Mas, have enhanced glucose tolerance and insulin sensitivity, presenting improved metabolic parameters. However, there is no data regarding the role of angiotensin-(1-7)-Mas axis in hepatic glycemic metabolism. In the present study, the gluconeogenesis and glycogenolysis was investigated in Sprague-Dawley (SD) and in TGR(A1-7)3292 (TGR) rats which present approximately twofold increase in plasma Ang-(1-7) levels compared to SD. The pyruvate administration in fasted rats showed a decreased synthesis of glucose in TGR compared to the SD rats, pointing to a downregulation of gluconeogenesis. Supporting this data, the mRNA evaluation of gluconeogenic enzymes showed a significant reduction in phosphoenolpyruvate carboxykinase reinforced by a significantly diminished expression of hepatocyte nuclear factor 4α (HNF-4α), responsible for the regulation of gluconeogenic enzymes. In conclusion our data show that the improved glucose metabolism induced by Ang-(1-7) could be due, at least in part, to a downregulation of hepatic gluconeogenesis.

Assuntos

Angiotensina I/sangue , Gluconeogênese , Fígado/metabolismo , Fragmentos de Peptídeos/sangue , Animais , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos

RESUMO

Hypertension is associated to an increase in central oxidative stress and an attenuation of the baroreflex control of arterial pressure. The present study evaluated the effect of alterations in the levels of nitric oxide (NO) and superoxide anion in the caudal ventrolateral medulla (CVLM), a key area of the brainstem for the baroreflex control of arterial pressure, in renovascular hypertensive rats (2K1C). Baseline mean arterial pressure (MAP), heart rate (HR), and reflex bradycardia were evaluated 30 days after renal artery occlusion in anesthetized (urethane, 1.2 g/kg, i.p.) 2K1C or normotensive (SHAM) rats. The MAP, HR, and baroreflex control of HR were evaluated before and after CVLM microinjections of the non-selective NOS inhibitor L-NAME (10 nmol), the NO precursor L-ARG (50 nmol), or the antioxidant ascorbic acid, Vit C (10 nmol). In both 2K1C and SHAM animals, CVLM microinjection of L-NAME produced a decrease in MAP, whereas L-ARG induced a significant increase in MAP. However, microinjection of Vit C into the CVLM produced a decrease in MAP and HR only in 2K1C and not in SHAM rats. Cardiovascular effects produced by microinjection of l-ARG into the CVLM were abolished by prior microinjection of L-NAME in the CVLM of 2K1C and SHAM rats. Microinjection of L-NAME into the CVLM increased the sensitivity of reflex bradycardia in 2K1C animals. In contrast, the CVLM microinjection of L-ARG reduced reflex bradycardia only in SHAM rats. Vit C in the CVLM did not change reflex bradycardia in either 2K1C or in SHAM rats. These results suggest that increased oxidative stress in the CVLM during hypertension contributes to the reduced baroreflex sensitivity and to maintain hypertension in the 2K1C model.

Assuntos

Barorreflexo/fisiologia , Bradicardia/metabolismo , Hipertensão Renovascular/metabolismo , Bulbo/metabolismo , Óxido Nítrico/metabolismo , Análise de Variância , Animais , Arginina/farmacologia , Ácido Ascórbico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Endogâmicos F344 , Análise de Regressão , Superóxidos/metabolismo

RESUMO

AIM: To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes. METHODS: Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS: PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05). In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 +/- 0.08 vs 0.38 +/- 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 +/- 0.02 vs 0.13 +/- 0.02, P < 0.04). Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70). CONCLUSION: Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis.

Assuntos

Angiotensina II/sangue , Angiotensina I/sangue , Hemodinâmica , Cirrose Hepática/sangue , Fragmentos de Peptídeos/sangue , Animais , Estudos Transversais , Feminino , Humanos , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/fisiologia , Circulação Esplâncnica/fisiologia

RESUMO

AIM: To evaluate the effect of beta-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. RESULTS: PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under beta-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

Assuntos

Antagonistas Adrenérgicos beta/uso terapêutico , Angiotensinas/sangue , Cirrose Hepática/tratamento farmacológico , Propranolol/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/sangue , Circulação Esplâncnica , Adulto , Idoso , Angiotensina I/sangue , Angiotensina II/sangue , Estudos Transversais , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Veia Porta

RESUMO

We investigated the expression of specific extracellular matrix (ECM) proteins in cardiac hypertrophy induced by isoproterenol in TGR(A1-7)3292 rats. Additionally, changes in circulating and tissue renin-angiotensin system (RAS) were analyzed. Left ventricles (LV) were used for quantification of collagen type I, III, and fibronectin using immunofluorescence-labeling techniques. Angiotensin (Ang) II levels were measured by radioimmunoassay. Expression of RAS components was assessed by semi-quantitative polymerase chain reaction (PCR) or real-time PCR. Isoproterenol treatment induced an increase in the expression of collagen I, III, and fibronectin in normal rats. Collagen I and fibronectin expression were decreased in TGR(A1-7)3292 at basal conditions and both proteins increased by isoproterenol treatment; however, the levels achieved were still significantly lower than those observed in treated normal rats. The increase in collagen III observed in normal rats was completely blunted in TGR(A1-7)3292. Moreover, TGR(A1-7)3292 presented lower Ang II levels and angiotensinogen expression and a higher angiotensin-converting enzyme 2 (ACE2) expression in LV. Isoproterenol treatment increased cardiac Ang II concentration only in normal rats, which was associated with an increase in ACE2 and a decrease in Mas expression. These observations suggest that Ang-(1-7) specifically modulates the expression of RAS components and ECM proteins in LV.