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Item Tratamento com aceturato de diminazeno ou angiotensina-(1-7) em ratas hipertensas gestantes atenua disfunções cardiovasculares na prole(Universidade Federal de Goiás, 2019-04-22) Bessa, Amanda de Sá Martins de; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; Costa, Renata Mazaro; Fonseca, Silvia Carolina GuatimosimIt has been proven that harmful stimuli during gestation can promote deleterious outcomes in offspring. Furthermore, previous studies have observed that the Renin-angiotensin system (RAS) can play a role in this pathological process. TheACE2/Ang-(1-7)/Mas axis presents several protective actions in the cardiovascular system. Thus, the aim of this study was to investigate whether the treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with Angiotensin-(1-7) during the pregnancy could attenuate the development of cardiovascular dysfunctions in the adult offspring of spontaneously hypertensive rats (SHR). For this, pregnant SHR received DIZE or Ang-(1-7) during the gestation. The SBP was measured in the male offspring by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Aortic vascular reactivity was also evaluated by isolated vessel in an organ bath. Samples of the LV were collected for histology and Western blot assay. Maternal treatment with DIZE (SHR: 181 ± 2.03 vs. SHR DIZE: 166.6 ± 0.35 mmHg, P <0.05) or Ang-(1-7) (SHR: 167.3 ± 1.79 vs. SHR Ang-(1-7): 153.8 ± 1.75 mmHg, P <0.05) during pregnancy attenuated the increase of the SBP in adult offspring. Additionally, the treatments reduced the cardiomyocyte diameter (SHR: 16.3 ± 0.11 vs. SHR DIZE: 12.9 ± 0.95 μm, P <0.05) (SHR: 16.6 ± 0.12 vs. SHR Ang-(1-7): 14 ± 0.10 μm, P <0.05) and degradation of the extracellular matrix (SHR: 15.6 ± 0.96 vs. SHR DIZE: 9.0 ± 0.61%, P <0.05) (SHR: 17.2 ± 1.27 vs. SHR Ang- (1-7): 10.3 ± 0,73%, P <0.05) in LV. The maternal treatment with DIZE and Ang-(1-7) improved the coronary vasodilation induced by bradykinin in isolated hearts. The expressions of AT1, Mas, ACE, ACE2, ERK Total, P-ERK, TNF-α, Collagen I, SOD, and Catalase in LV were not modified with Ang-(1-7), but this treatment decreased the AT2 (SHR: 0.90 ± 0.03 vs. SHR Ang- (1-7): 0.74 ± 0.05, P <0.05) expression. These data show that the treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects in attenuating hypertension and cardiac remodeling in adult offspring.Item Efeito do peptídeo Bj-PRO-7a no remodelamento cardíaco em ratos hipertensos(Universidade Federal de Goiás, 2018-04-27) Jesus, Érika Fernandes de; Ianzer, Danielle Alves; http://lattes.cnpq.br/7609262674053858; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Ianzer, Danielle Alves; http://lattes.cnpq.br/7609262674053858; Ferreira, Anderson José; Biancardi, Manoel FranciscoBj-PRO-7a, a proline-rich oligopeptide isolated from Bothrops jararaca snake venom, was able to reduce blood pressure and heart rate in hypertensive animals. However, it is not yet known whether this peptide may have beneficial effects on cardiac remodeling. Herein, we evaluate the effect of the Bj-PRO-7a in spontaneously hypertensive rats. Normotensive (Wistar) and spontaneously hypertensive (SHR) rats were divided into 3 groups: 1) Wistar treated with 0.9% saline, s.c.; 2) SHR treated with 0.9% saline, s.c.; and 3) SHR treated with BjPRO-7a (71 nmol/Kg/day, s.c.). The animals were treated during 28 days. The systolic blood pressure was weekly measured by tail-cuff plethysmography. At the end of the treatment, cardiac function was evaluated in isolated perfused heart preparation. The ventricular mass index was calculated by the ratio between the left ventricular weight and tibia length. The cardiomyocyte diameter and interstitial and perivascular fibrosis of the left ventricle were evaluated using the Picrossirius staining. The detection of collagen III deposition was evaluated by immunofluorescence. Fibroblast proliferation were assessed by immunohistochemistry to detect proliferating cell nuclear antigen (PCNA). The expression of catalase, SOD and ERK1/2, MMP-2 and MMP-9 was assessed by Western Blot. In our protocol, the Bj-PRO-7a was unable to reduce the systolic blood pressure of the SHRs. However, this peptide attenuated the development of the cardiomyocyte hypertrophy in these animals. Additionally, the deposition of the interstitial and perivascular fibrosis in SHR was significantly reduced by the treatment with Bj-PRO-7a. This peptide did not alter the collagen III deposition in hypertensive rat hearts. The Bj-PRO-7a reduced positive PCNA-labeled fibroblasts. The expression of catalase, SOD and ERK1/2 was significantly increased in SHR, but the Bj-PRO-7a attenuates this increase. The expression of MMP-2 and MMP-9 was not different in SHR hearts, but the Bj-PRO-7a increased the expression of the MMP-2 in the heart of these animals. Our findings demonstrate that the Bj-PRO-7a reduced the pathological cardiac remodeling through mechanism mediated by inhibition of the ERK1/2 and increasing MMP-2 expression. This data suggest that the Bj- xxiii PRO-7a could have a potential therapeutic for the treatment of cardiac diseases.Item Avaliação da ação de nanopartículas magnéticas na função cardiovascular de ratos(Universidade Federal de Goiás, 2014-02-27) Nunes, Allancer Divino de Carvalho; Bakuzis, Andris Figueiroa; http://lattes.cnpq.br/3477269475651042; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; Bakuzis, Andris Figueiroa; Colugnati, Diego Basile; Borges, Clayton LuizMagnetic Nanoparticles (MNPs) have been used for various biomedical applications. Importantly, manganese ferrite-based nanoparticles have a useful magnetic resonance imaging characteristics and potential for magnetic hyperthermia treatment, but their effects in the cardiovascular system are poorly reported. Thus, the objectives of this study were to determine the cardiovascular effects of four different types of manganese ferrite-based nanoparticles: albumin-coated (MnFe2O4 Albumin); citrate-coated (MnFe2O4 Citrate); tripolyphosphate-coated (MnFe2O4 Phosphate); and bare nanoparticles (MnFe2O4 Ionic). The direct effects of the MNPs on cardiac contractility were evaluated in isolated perfused rat hearts. The MnFe2O4 Citrate, but not MnFe2O4 Phosphate and MnFe2O4 Ionic induced a transient decreased in the Left Ventricular End Systolic Pressure. The MnFe2O4 Phosphate and MnFe2O4 Ionic, but not MnFe2O4 Citrate induced an increase in Left Ventricular End Diastolic Pressure which resulted decrease in a Left Ventricular End Developed Pressure. Indeed, MnFe2O4 Phosphate and MnFe2O4 Ionic also caused a decrease in the maximum dP/dt and minimum dP/dt. The three MNPs studied induced an increase in the perfusion pressure of isolated hearts. It is important to note that the ionic nanoparticle induced more significant changes in cardiac function. Interestingly, coating the bare nanoparticles with albumin reverted the MnFe2O4 Ionic-induced cardiac effects. MnFe2O4 Ionic, but not MnFe2O4 Phosphate or MnFe2O4 Citratre, induced a slight vasorelaxant effect in the isolated aortic rings. None of the MNPs were able to change heart rate or arterial blood pressure in conscious rats. In summary, the responses on ventricular function were found to be strongly dependent upon the surface nanoparticles coating layer. Also, although the MNPs were able to induce effects ex vivo, no significant changes were observed in vivo. Thus, given the proper dosages, these MNPs should be considered for possible therapeutic applications.Item Influência da Angiotensina-(1-7) na sensibilidade colinérgica cardíaca de ratos normotensos e hipertensos(Universidade Federal de Goiás, 2018-03-02) Pontes, Carolina Nobre Ribeiro; Custódio, Carlos Henrique Xavier; http://lattes.cnpq.br/0207928273284808; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Pansani, Aline Priscila; Pedrino, Gustavo Rodrigues; Castro, Carlos Henrique de; Custódio, Carlos Henrique XavierPrevious studies suggested that the Angiotensin-(1-7) [(Ang-(1-7)] is able to modulate the cardiac sympathetic control and beta-adrenergic sensitivity. However, whether or not Ang-(1- 7) modulates the cholinergic activity in the heart remains unknown. The aim of this study was to evaluate the influence of Ang-(1-7) upon cholinergic sensitivity of hearts from normotensive and hypertensive rats. Wistar and Spontaneously Hypertensive Rats (SHR) were anesthetized with urethane and underwent catheterization of femoral artery and left ventricle to record the arterial and intraventricular pressure, respectively. Following, a dose-response curve of acetylcholine (ACh, 10, 20, 40 and 80 ng/Kg, i.v. into femoral vein) was performed in the absence or presence of Ang-(1-7) (7 x 10-12 mol/min), Mas receptor antagonist A-779 (7 x 10-11 mol/min) or Ang-(1-7)+A-779. Isolated hearts were perfused according to the Langendorff technique. Increasing concentrations of ACh (10-7 to 10-5 mol/L) were added to the hearts in absence or presence of Ang-(1-7), (2 x 10-11 mol/L), A-779, (2 x 10-10 mol/L), Ang-(1-7)+A-779, MrgD receptor antagonist, D-PRO (2 x 10-10 mol/L) or D-PRO+Ang-(1-7). ACh-induced vasorelaxation was assessed in absence or presence of Ang-(1-7) (2 x 10-11 mol/L or 2 x 10-10 mol/L). Ang-(1-7) attenuated the effect of ACh in decreasing the intraventricular systolic, dP/dt max and dP/dt min in anesthetized Wistar and SHR. These effects were blocked by A-779. Ang-(1-7) did not change the amplitude of the hypotensive effect evoked by ACh in Wistar or SHRs. In isolated hearts, Ang-(1-7) also attenuated the reduction of the intraventricular systolic pressure, dP/dt max and dP/dt min evoked by ACh. A-779 blocked the Ang-(1-7) effects in hearts from Wistar. A-779 or D-PRO did not modify the effects of Ang-(1-7) in hearts from SHR, but in presence of D-PRO, Ang-(1-7) effects were equipotent. Ang-(1-7) attenuated the vasorelaxation induced by ACh in aorta from SHR by only in SHR group. These data suggest that Ang-(1-7) exerts differential modulation of cardiac cholinergic sensitivity during experimental primary hypertension, which is independent on blood pressure.Item Receptor Mas contribui para o desenvolvimento do remodelamento cardíaco(Universidade Federal de Goiás, 2016-03-21) Silva, Cintia do Carmo e; Costa, Renata Mazaro e; http://lattes.cnpq.br/5625298314637434; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique dePrevious studies have demonstrated a protective effect of the Ang-(1-7)/Mas receptor axis on pathological cardiac hypertrophy. Also, the involvement of Mas receptor in the exercise-induced cardiac hypertrophy has been suggested. However, the role of the Ang-(1-7)/Mas receptor on pregnancy-induced cardiac remodeling remains unknown. Thus, the aim of this study was to evaluate the participation of the Mas receptor in the development of pregnancy and hypertrophy, fibrosis and cardiac function during pregnancy. Female Wistar rats were randomly shared in 3 groups: control (W-NP), pregnant (W-P), and pregnant treated with A-779 (W-P + A-779). Wild type and Masknockout mice were distributed in non-pregnant (WT and KO) and pregnant (WT-P and KO-P) groups. Gestational parameters such as, maternal weight, placental weight, fetus weight, fetus/placenta ratio, fertility, Loss pre embryonic, Loss pos embryonic were evaluated. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. The medial part of the left ventricle (LV) was collected for cardiomyocytes morphometry analysis and extracellular matrix proteins deposition. Echocardiographic analysis was used to evaluate the cardiac function. Mas receptor blockade or genetic deletion of Mas did not alter the fertility or embryonic and fetal development. However, the Mas receptor antagonist decreased placental weight and increased fetus placenta ratio in rats. The pregnant KO mice presented a decreased maternal and fetal weight and increased fetus/placenta ratio. SBP was not changed by pregnancy or A-779 treatment in the Wistar rats. Pharmacological blockade or genetic deletion of Mas receptor attenuates the pregnancy-induced myocyte hypertrophy. The A-779 treatment or genetic deletion of the Mas receptor increased the collagen III deposition in LV from pregnant animals. KO mice presented a lower ejection fraction, fraction shortening, stroke volume and higher end systolic volume compared to WT. Interestingly, the pregnancy restored these parameters. In conclusion, these data show that Mas receptor can alter gestational and maternal parameters, and this is involved in the cardiomyocyte hypertrophy and in the control of the collagen III deposition in pregnancy condition. These alterations are associated with improvement of the cardiac function through Mas-independent mechanism.Item Avaliação de fármacos anti-hipertensivos na resposta vascular da Angiotensina-(1-7) em ratos submetidos à sobrecarga pressórica(Universidade Federal de Goiás, 2014-09-12) Souza, Álvaro Paulo Silva; Mendes, Elizabeth Pereira; http://lattes.cnpq.br/4901673689321551; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; Mendes , Elizabeth Pereira; Ghedini, Paulo Cesar; Rabelo, Luisa AntasAccording to the World Health Organization (2013),cardiovascular diseases(CVD) are the major causes of death world wide. High blood pressure is the main risk factors for these diseases. The Renin-angiotensin System (RAS) is a important regulator of the cardiovascular functions. Among the components of the RAS, we can highlight the Angiotensin-(1-7) [Ang (1-7)]. It is known that the vasodilator effect of Ang-(1-7) is endothelium-dependent. Hypertension cause changes in the vascular structure and function, especially in the endothelium cells, leading to endothelial dysfunction and, consequently, impairment in the vasodilator effect of Ang (1-7). However, it has been shown that some classes of antihypertensive drugs (Angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors and Calcium channel blocker) improve the endothelial function. However, it is unknown if these drugs are able to improve the vasorelaxant effect of Ang-(1-7) in pressure-overload condition. Since several studies have pointed to Ang-(1-7)/Mas axis as a therapeutic potential for cardiovascular disease, is very important to understand the influence of the anti hypertensive drugs on the vascular effects of Ang-(1-7). Thus, the purpose of this study was to evaluate the influence of anti hypertensive drugs on the vascular effects of Angiotensin-(1-7) in pressure-overload rats. Wistar rats were submitted to abdominal aorta coarctation (ACo). Sham surgery was performed in the controls group. After 21 days of coarctation, blood pressure (BP) was recorded by carotid artery catheterization. Subsequently,the vasorelaxant effect of Ang-(1-7) were evaluated in aortic rings with or without acute pre-treatment (in vitro) of losartan 1µmol/L, captopril 1µmol/L or amlodipine 1µmol/L. To evaluate the effect of chronic treatment (in vivo), the ACo animals received the following treatments after surgery procedure: losartan 1 or 5 mg/kg/day, captopril 1 or 5 mg/kg/day, amlodipine 1 or 5 mg/kg/day, or DIZE 1 or 5 mg/kg/day. At the end of treatment, the aortic rings were isolated and the vasorrelaxant effect of Ang-(1-7) was evaluated. The increase of the BP was confirmed in the ACo rats. None of the treatment was able to reduce the blood pressure in ACo rats. Pressure overload decreased the relaxation induced by Ang (1-7) in isolated aortic rings. The in vitro pre treatment with losartan, captopril or amlodipine restored the vasorelaxant effect promoted by Ang-(1-7).A-779 or L-NAME blunted the vasorelaxant effect of Ang-(1-7) in aortic rings from CoA rats in presence of losartan.The in vivo treatment with losartan 1 mg/kg/day, captopril 1 mg/kg/day, amlodipine 1 mg/kg/day or DIZE 1 and 5 mg/kg/day was not effective in improving the vasorelaxant effect of Ang (1-7) in CoA aortic rings. However, losartan 5 mg/kg/day, captopril 5 mg/kg/day or amlodipine 5 mg/kg/Day improved the vasorelaxant effect of Ang-(1-7) in aortic rings from CoA rats. These results demonstrate that treatment in vitro or in vivo with some antihypertensive drugs (losartan, captopril and amlodipine) was able to improve the vasorelaxation effect of Ang (1-7) in the aorta from pressure-overloaded animals through mechanisms independent of blood pressure reduction. Therefore, the use of Ang-(1-7) associated with sub-pressor doses of antihypertensive agents may be a new therapeutic tool for the hypertension treatment.