Navegando por Autor "Santos, Robson Augusto Souza dos"
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Item Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats.(2013) Castro, Uberdan Guilherme Mendes de; Santos, Robson Augusto Souza dos; Silva, Marcelo Eustáquio; Lima, Wanderson Geraldo de; Santos, Maria José Campagnole dos; Alzamora, Andréia CarvalhoBackground: The metabolic syndrome (MS) is characterized by variable coexistence of metabolic and pathophysiological alterations which are important risk factors for developing of type II diabetes and/or cardiovascular diseases. Increased of MS patients in worldwide has stimulated the development of experimental models. However, it is still challenging to find an dietetic model that most closely approximates human MS and, in addition, is not yet fully established the effect of different diets of MS in lipid metabolism in rats of different ages. The aim of this study was to evaluate the effect of different diets of MS in lipid metabolism and ectopic fat deposition and define the most appropriate diet for inducing the characteristic disturbances of the human MS in rats of different ages. Methods: Young (4 weeks old) and adult rats (12 weeks old) were given a high-fat (FAT) or high-fructose diet (FRU) for 13 weeks and biochemical, physiological, histological and biometric parameters were evaluated. Results: In young rats, the FAT diet induced increased mean blood pressure (MAP) and heart rate (HR), body weight after 6 to 10 weeks, and in the 13th week, increased the liver, mesenteric, retroperitoneal and epididymal fat weights,fasting glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and reduced HDL cholesterol; and also induced non-alcoholic fatty liver disease (NAFLD) and renal inflammatory infiltrates. In adult rats, the FRU diet induced transient elevations of MAP and HR in the 6th week, and, at 13 weeks, increased fasting glucose, triglycerides, total cholesterol, AST and ALT; increased liver, kidneys and retroperitoneal fat weights; and induced macrovesicular and microvesicular NAFLD, the presence of fat cells in the kidney, glomerular sclerosis, and liver and kidney inflammation. Additionally, the FAT and FRU diets induced, respectively, increases in liver glycogen in adults and young rats. Conclusions: Our data show that FRU diet in adult rats causes biggest change on metabolism of serum lipids and lipid accumulation in liver and kidney, while the FAT diet in young rats induces elevation of MAP and HR and higher increased visceral lipid stores, constituting the best nutritional interventions to induce MS in rats.Item Altered renal response to acute volume expansion in transgenic rats harboring the human tissue kallikrein gene.(2005) Passaglio, Kátia Tomagnini; Baltatu, Ovidiu; Machado, Raquel do Pilar; Reis, Adelina Martha dos; Pesquero, João Bosco; Bader, Michael; Santos, Robson Augusto Souza dosThe renal response to acute volume expansion was investigated in transgenic (TGR) rats harboring the human tissue kallikrein gene. After a primer injection of 0.9% NaCl (3 ml/100 g, i.v), Sprague–Dawley (SD) or TGR rats received a continuous infusion of 0.9% NaCl (15 Al/ 100 g/min, i.a.) through a catheter placed into the carotid artery. Acute volume expansion was produced by a second injection of 0.9% NaCl (2 ml/100 g, i.v.) 65 min after the first injection. Plasma vasopressin (AVP) and atrial natriuretic peptide (ANP) concentration was measured before and within 10 min of volume expansion. TGR animals presented a blunted response to acute volume expansion evidenced by an attenuated increase in total and fractional water and sodium excretion. Before or after volume expansion, plasma AVP and ANP did not differ between SD and TGR. Pre-treatment with the BK-B2 antagonist HOE-140 (7.5 Ag/100 g. i.a) partially improved the renal response of TGRs and severely blunted the response in SD rats. These data show that TGR (hKLK1) rats have an impaired renal response to acute volume expansion that can not be accounted for by changes in the release of AVP or ANP.Item An orally active angiotensin-(1–7) inclusion compound and exercisetraining produce similar cardiovascular effects in spontaneouslyhypertensive rats.(2014) Bertagnolli, Mariane; Casali, Karina Rabello; Sousa, Frederico Barros de; Rigatto, Katya; Oliveira, Lenice Kappes Becker; Santos, Sergio Henrique Sousa; Dias, Lucinara Dadda; Pinto, Graziela; Dartora, Daniela Ravizzoni; Schaan, Beatriz D'Agord; Milan, Ruben Dario Sinisterra; Irigoyen, Maria Claudia; Santos, Robson Augusto Souza dosLow angiotensin-(1–7) (Ang-(1–7)) concentration is observed in some cardiovascular diseases and exer-cise training seems to restore its concentration in the heart. Recently, a novel formulation of an orallyactive Ang-(1–7) included in hydroxy-propyl-beta-cyclodextrin (HPB-CD) was developed and chronicallyadministered in experimental models of cardiovascular diseases. The present study examined whetherchronic administration of HPB-CD/Ang-(1–7) produces beneficial cardiovascular effects in spontaneouslyhypertensive rats (SHR), as well as to compare the results obtained with those produced by exercisetraining. Male SHR (15-week old) were divided in control (tap water) or treated with HPB-CD/Ang-(1–7)(corresponding to 30 _g kg−1day−1of Ang-(1–7)) by gavage, concomitantly or not to exercise training(treadmill, 10 weeks). After chronic treatment, hemodynamic, morphometric and molecular analysis inthe heart were performed. Chronic HPB-CD/Ang-(1–7) decreased arterial blood pressure (BP) and heartrate in SHR. The inclusion compound significantly improved left ventricular (LV) end-diastolic pressure,restored the maximum and minimum derivatives (dP/dT) and decreased cardiac hypertrophy index inSHR. Chronic treatment improved autonomic control by attenuating sympathetic modulation on heartand vessels and the SAP variability, as well as increasing parasympathetic modulation and HR variability.Overall results were similar to those obtained with exercise training. These results show that chronictreatment with the HPB-CD/Ang-(1–7) inclusion compound produced beneficial effects in SHR resem-bling the ones produced by exercise training. This observation reinforces the potential cardiovasculartherapeutic effect of this novel peptide formulation.Item Angiotensin-(1-7) antagonist, A-779, microinjection into the caudal ventrolateral medulla of renovascular hypertensive rats restores baroreflex bradycardia.(2009) Cangussu, Luiza Michelle; Castro, Uberdan Guilherme Mendes de; Machado, Raquel do Pilar; Silva, Marcelo Eustáquio; Ferreira, Patrícia Maria; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dos; Alzamora, Andréia CarvalhoIn the present study we evaluated the effect of caudal ventrolateral medulla (CVLM) microinjection of the main angiotensin (Ang) peptides, Ang II and Ang-(1-7), and their selective antagonists on baseline arterial pressure (AP) and on baroreceptor-mediated bradycardia in renovascular hypertensive rats (2K1C). Microinjection of Ang II and Ang-(1-7) into the CVLM of 2K1C rats produced similar decrease in AP as observed in Sham rats. In both Sham and 2K1C, the hypotensive effect of Ang II and Ang-(1-7) at the CVLM was blocked, for up to 30 min, by previous CVLM microinjection of the Ang II AT 1 receptor antagonist, Losartan, and Ang-(1-7) Mas antagonist, A-779, respectively. As expected, the baroreflex bradycardia was lower in 2K1C in comparison to Sham rats. CVLM microinjection of A-779 improved the sensitivity of baroreflex bradycardia in 2K1C hypertensive rats. In contrast, Losartan had no effect on the baroreflex bradycardia in either 2K1C or Sham rats. These results suggest that Ang-(1-7) at the CVLM may contribute to the low sensitivity of the baroreflex control of heart rate in renovascular hypertensive ratsItem Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.(2003) Santos, Robson Augusto Souza dos; Silva, Ana Cristina Simões e; Maric, Christine; Rabelo, Denise Maria Rover da Silva; Machado, Raquel do Pilar; Buhr, Insa de; Walther, Silvia Heringer; Pinheiro, Sérgio Veloso Brant; Lopes, Miriam Teresa Paz; Bader, Michael; Mendes, Elizabeth Pereira; Lemos, Virgina Soares; Santos, Maria José Campagnole dos; Schultheiss, Heinz-Peter; Speth, Robert; Walther, ThomasThe renin–angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2–8)], Ang IV [Ang-(3–8)], and Ang-(1–7) may also have important biological activities. Ang-(1–7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1–7) antagonist indicated the existence of a distinct Ang-(1–7) receptor. We demonstrate that genetic deletion of the G proteincoupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1–7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1–7) after an acute water load. Ang-(1–7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1–7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1–7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.Item Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart.(2012) Gava, Elisandra; Castro, Carlos Henrique de; Ferreira, Anderson José; Colleta, Heloísa; Melo, Marcos Barrouin; Alenina, Natalia; Bader, Michael; Oliveira, Laser Antônio Machado de; Santos, Robson Augusto Souza dosIn this study we investigated the effects of genetic deletion of the Angiotensin-(1-7) receptor Mas or the Angiotensin II receptor AT2 on the expression of specific extracellular matrix (ECM) proteins in atria, right ventricles and atrioventricular (AV) valves of neonatal and adult mice. Quantification of collagen types I, III and VI and fibronectin was performed using immunofluorescence-labeling and confocal microscopy. Picrosirius red staining was used for the histological assessment of the overall collagen distribution pattern. ECM proteins, metalloproteinases (MMP), ERK1/2 and p38 levels were quantified by western blot analysis. Gelatin zymography was used to evaluate the activity ofMMP-2 andMMP-9. We observed that the relative levels of collagen types I and III and fibronectin are significantly higher in both the right ventricle and AV valves of neonatal Mas−/− mouse hearts (e.g., collagen type I: 85.28±6.66 vs 43.50±4.41 arbitrary units in the right ventricles of Mas+/+ mice). Conversely, the level of collagen type VI was lower in the right ventricle and AV valves of Mas−/− mice. Adult Mas−/− mouse hearts presented similar patterns as observed in neonates. No significant differences in ECMprotein level were detected in atria. Likewise, no changes in ECM levels were observed in AT2 knockout mouse hearts. Although deletion of Mas induced a significant reduction in the level of the active form of MMP-2 in neonate hearts and a reduction of both MMP-2 and MMP-9 in adult Mas−/− mice, no significant differences were observed inMMP enzymatic activities when compared to controls. The levels of the active, phosphorylated forms of ERK1/2 and p38 were higher in hearts of both neonatal and adult Mas−/− mice. These observations suggest that Mas is involved in the selective expression of specific ECMproteins within both the ventricular myocardium and AV valves. The changes in the ECM profile may alter the connective tissue framework and contribute to the decreased cardiac performance observed in Mas−/− mice.Item Angiotensin-(1–7) oral formulation improves physical performance in mountain bike athletes : a double‐blinded crossover study.(2021) Moura, Samara Silva de; Mendes, Adália Táci Pereira; Martins Junior, Francisco de Assis Dias; Totou, Nádia Lúcia; Coelho, Daniel Barbosa; Oliveira, Emerson Cruz de; Santos, Daisy Motta; Santos, Robson Augusto Souza dos; Oliveira, Lenice Kappes BeckerBackground: The ECA2/Ang-(1–7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPβ-CD-Ang-(1–7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPβ-CD-Ang-(1–7) on the performance of mountain bike (MTB) practitioners. Methods: Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPβ-CD-Ang-(1–7) (1.75 mg) and HPβCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPβ-CD-Ang-(1–7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO2), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer. Results: There were no significant differences in terms of HR or BP at rest and maximum effort between the HPβ-CD-Ang- (1–7) and placebo groups. The VO2max showed significant differences (p = 0.04). It was higher in the Ang-(1–7)condition (66.15 mlO2.kg− 1 .min− 1 ) compared to the placebo (60.72 mlO2.kg− 1 .min− 1 ). This was also observed for TET (Ang-(1–7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1–7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1–7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate. Conclusions: These results suggest that HPβ-CD-Ang-(1–7) improves the physical performance of MTB recreational athletes and could be a promising supplement. Trial registration: RBR-2 × 56pw8, registered January 15th, 2021. The study was prospectively registered.Item Antioxidant effects of oral Ang-(1-7) restore insulin pathway and RAS components ameliorating cardiometabolic disturbances in rats.(2019) Figueiredo, Vivian Paulino; Barbosa, Maria Andréa; Castro, Uberdan Guilherme Mendes de; Zacarias, Aline Cruz; Bezerra, Frank Silva; Cota, Renata Guerra de Sá; Lima, Wanderson Geraldo de; Santos, Robson Augusto Souza dos; Alzamora, Andréia CarvalhoIn prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPβCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPβCD) or HPβCD/Ang-(1-7) in the last 6 weeks. FATHPβCD/ empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPβCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression. in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPβCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.Item AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection.(2012) Gonçalves, Andrey Christian da Costa; Silva, Rodrigo Araújo Fraga da; Leite, Romulo; Santos, Robson Augusto Souza dosThe renin–angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1–7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetizedWistar rats, measured as the ratio between corpus cavernosum pressure andmean arterial pressure, upon electrical stimulation of themajor pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991.We demonstrated that AVE 0991 potentiates the penile erectile response throughMas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.Item Baroreflex modulation by angiotensins at the rat rostral and caudal ventrolateral medulla.(2006) Alzamora, Andréia Carvalho; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dosBaroreflex modulation by angiotensins at the rat rostral and caudal ventrolateral medulla. Am J Physiol Regul Integr Comp Physiol 290: R1027–R1034, 2006. First published November 23, 2005; doi:10.1152/ajpregu.00852.2004.—We determined the effect of microinjection of ANG-(1–7) and ANG II into two key regions of the medulla that control the circulation [rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively)] on baroreflex control of heart rate (HR) in anesthetized rats. Reflex bradycardia and tachycardia were induced by increases and decreases in mean arterial pressure produced by intravenous phenylephrine and sodium nitroprusside, respectively. The pressor effects of ANG-(1–7) and ANG II (25 pmol) after RVLM microinjection (11 0.8 and 10 2 mmHg, respectively) were not accompanied by consistent changes in HR. In addition, RVLM microinjection of these angiotensin peptides did not alter the bradycardic or tachycardic component of the baroreflex. CVLM microinjections of ANG-(1–7) and ANG II produced hypotension ( 11 1.5 and 11 1.9 mmHg, respectively) that was similarly not accompanied by significant changes in HR. However, CVLM microinjections of angiotensins induced differential changes in the baroreflex control of HR. ANG-(1–7) attenuated the baroreflex bradycardia (0.26 0.06 ms/mmHg vs. 0.42 0.08 ms/mmHg before treatment) and facilitated the baroreflex tachycardia (0.86 0.19 ms/mmHg vs. 0.42 0.10 ms/mmHg before treatment); ANG II produced the opposite effect, attenuating baroreflex tachycardia (0.09 0.06 ms/mmHg vs. 0.31 0.07 ms/mmHg before treatment) and facilitating the baroreflex bradycardia (0.67 0.16 ms/mmHg vs. 0.41 0.05 ms/mmHg before treatment). The modulatory effect of ANG II and ANG-(1–7) on baroreflex sensitivity was completely abolished by peripheral administration of methylatropine. These results suggest that ANG II and ANG-(1–7) at the CVLM produce a differential modulation of the baroreflex control of HR, probably through distinct effects on the parasympathetic drive to the heart.Item Bj-PRO-5a and Bj-PRO 10c found at c-type natriuretic peptide precursor of bothrops jararaca change renal function of hypertensive rats.(2017) Custódio, Carlos Henrique Xavier; Miranda, José Rodolfo Rubini; Yamaguchi, Juliana; Silveira, Kátia Daniela da; Teixeira, Mauro Martins; Chianca Júnior, Deoclécio Alves; Silva, Ana Cristina Simões e; Santos, Robson Augusto Souza dos; Camargo, Antônio Carlos Martins de; Ianzer, Danielle AlvesProline-rich oligopeptides from Bothrops jararaca (Bj-PROs) produce potent and long-lasting antihypertensive effect through mechanisms that go beyond ACE inhibition. In this study we evaluated the renal function parameters of spontaneously hypertensive rats (SHR) injected with Bj-PRO-5a and -10c (0.47, 71 or 710 nmol/ kg) found in the CNP-precursor of the snake. At 71 and 710 nmol/kg, Bj-PROs increased urinary flow rate (18.1– 43.5%). At 71 nmol/kg, Bj-PRO 5a and 10c elevated sodium excretion (68.1 and 40.9%, respectively) and Bj- PRO-5a also increased urinary sodium/creatinine ratio (56.5%). At 0.47 nmol/kg, Bj-PROs did not change renal function. All doses of Bj-PROs reduced blood pressure (Δ = −13 to −24mmHg). We conclude that Bj-PROs reduce blood pressure and improve renal functiItem Cardiac and renal effects induced by different exercise workloads in renovascular hypertensive rats.(2011) Soares, Everton Rocha; Lima, Wanderson Geraldo de; Machado, Raquel do Pilar; Carneiro, Cláudia Martins; Silva, Marcelo Eustáquio; Rodrigues, Míriam Carmo; Castro, Uberdan Guilherme Mendes de; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dos; Alzamora, Andréia CarvalhoWe examined the effect of exercise training (Ex) without (Ex 0%) or with a 3% workload (Ex 3%) on different cardiac and renal parameters in renovascular hypertensive (2K1C) male Fisher rats weighing 150-200 g. Ex was performed for 5 weeks, 1 h/day, 5 days/week. Ex 0% or Ex 3% induced similar attenuation of baseline mean arterial pressure (MAP, 119 ± 5 mmHg in 2K1C Ex 0%, N = 6, and 118 ± 5 mmHg in 2K1C Ex 3%, N = 11, vs 99 ± 4 mmHg in sham sedentary (Sham Sed) controls, N = 10) and heart rate (HR, bpm) (383 ± 13 in 2K1C Ex 0%, N = 6, and 390 ± 14 in 2K1C Ex 3%, N = 11 vs 371 ± 11 in Sham Sed, N = 10). Ex 0%, but not Ex 3%, improved baroreflex bradycardia (0.26 ± 0.06 ms/mmHg, N = 6, vs 0.09 ± 0.03 ms/mmHg in 2K1C Sed, N = 11). Morphometric evaluation suggested concentric left ventricle hypertrophy in sedentary 2K1C rats. Ex 0% prevented concentric cardiac hypertrophy, increased cardiomyocyte diameter and decreased cardiac vasculature thickness in 2K1C rats. In contrast, in 2K1C, Ex 3% reduced the concentric remodeling and prevented the increase in cardiac vasculature wall thickness, decreased the cardiomyocyte diameter and increased collagen deposition. Renal morphometric analysis showed that Ex 3% induced an increase in vasculature wall thickness and collagen deposition in the left kidney of 2K1C rats. These data suggest that Ex 0% has more beneficial effects than Ex 3% in renovascular hypertensive rats.Item Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats.(2020) Sousa, Graziele Galdino de; Barbosa, Maria Andréa; Barbosa, Claudiane Maria; Lima, Taynara Carolina; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dos; Alzamora, Andréia CarvalhoHypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1− 7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1− 7), L-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1− 7) effect was increased by L-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1− 7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1− 7) contributes to renovascular hypertension.Item Differential control of vasomotion by angiotensins in the rostral ventrolateral medulla of hypertensive rats.(2015) Ferreira, Patrícia Maria; Custódio, Carlos Henrique Xavier; Alzamora, Andréia Carvalho; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dosThe central and peripheral renin–angiotensin systems are known for playing a key role in cardiovascular control. In the present study,we evaluated the hemodynamic effects produced by nanoinjections of angiotensin II (Ang II) or angiotensin-(1–7) [Ang-(1–7)] into the rostral ventrolateral medulla (RVLM) of adult male normotensive (Wistar—WT) and spontaneously hypertensive rats (SHR). Animals were anesthetized (urethane 1.2 g/kg) and instrumented for recording blood pressure (BP), heart rate (HR) and blood flow (BF) in the femoral, renal or mesenteric arteries. Afterwards, rats were positioned in a stereotaxic and prepared for nanoinjections (100 nl) of saline (NaCl 0.9%), Ang-(1–7) (40 ng) or Ang II (40 ng) into the RVLM. The vascular resistance (VR)was calculated by ΔMAP/ΔBF ratio. In WT, Ang-(1–7) or Ang II caused equipotent pressor effects that were not accompanied by changes in vascular resistance. However, MAP changes were greater in SHR. This strain also showed a concomitant increase in relative vascular resistance (ΔVR/VRbaseline) of renal (0.31 ± 0.07 and 0.3 ± 0.07 vs. 0.02 ± 0.01; Ang-(1–7), Ang II and Saline, respectively) and mesenteric beds (0.3 ± 0.06 and 0.33 ± 0.04 vs. 0.05 ± 0.02; Ang-(1–7), Ang II and saline, respectively). We conclude that Ang II and Ang-(1–7) at the RVLM control the vascular resistance of renal and mesenteric beds during hypertension.Item Discovery and characterization of Alamandine : a novel component of the Renin-Angiotensin system.(2013) Lautner, Roberto Queiroga; Villela, Daniel Campos; Silva, Rodrigo Araújo Fraga da; Silva, Neiva Caldeira; Braga, Thiago Verano; Fraga, Fabiana Costa; Jankowski, Joachim; Jankowski, Vera; Sousa, Frederico Barros de; Alzamora, Andréia Carvalho; Soares, Everton Rocha; Barbosa, Claudiane Maria; Kjeldsen, Frank; Oliveira, Aline Cristina; Braga, Janaina Félix; Savergnini, Silvia Silveira Quintão; Etelvino, Gisele Maia; Peluso, Antonio Augusto Bastos; Silva, Danielle Gomes Passos; Ferreira, Anderson José; Alves, Fabiana; Martins, Almir de Sousa; Raizada, Mohan K.; Paula, Renata Dutra de; Santos, Daisy Motta; Klempin, Friederike; Pimenta, Adriano Monteiro de Castro; Alenina, Natalia; Sinisterra Millán, Ruben Dario; Bader, Michael; Santos, Maria José Campagnole dos; Santos, Robson Augusto Souza dosThe renin–angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1–7). To characterize a novel component of the RAS, alamandine. Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1–7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1–7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein–coupled receptor, member D. Binding of alamandine to Mas-related G-protein–coupled receptor, member D is blocked by D-Pro7-angiotensin-(1–7), the Mas-related G-protein–coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.Item Eccentric overload muscle damage is attenuated by a novel angiotensin- (1-7) treatment.(2018) Oliveira, Lenice Kappes Becker; Totou, Nádia Lúcia; Moura, Samara Silva de; Kangussu, Lucas Miranda; Sinisterra Millán, Ruben Dario; Santos, Maria Jose Campagnole dos; Coelho, Daniel Barbosa; Santos, Daisy Motta; Santos, Robson Augusto Souza dosThe development of new strategies to attenuate exercise-induced muscle damage may be helpful for training regimens. The aim of this study was to determine whether a oral formulation of angiotensin Ang-(1-7)[HPβCD/Ang-(1-7)] is effective to reduce pain, and muscle damage markers after eccentric-overload exercise. HPβCD (Placebo) and HPβCD/Ang-(1-7) (Ang-(1-7) group were treated for 7 days (one capsule/day). The pain was measured by visual analogue scale, maximal strength (MS) using force platform. Blood samples were collected for cytokines and creatine kinase (CK) analysis. The Ang-(1-7)-treated group reported less pain immediately (3.46± 0.64 vs. placebo 3.80± 0.77 cm) and 24h after exercise (3.07±0.71 vs. 3.73±0.58cm placebo) and higher MS at 24h (24±12N) and 48h (30±15N) vs. placebo (-8 ± 9 N and -10 ± 9 N). The CK for Ang-(1-7) (0.5 ± 0.1 and 0.9±0.2 U/L) were lower at 48 and 72h vs. placebo (fold changes of 1.7±0.5 and 1.5±0.3 U/L). The TNF-α level was lower in the treated group post-exercise (38 ± 2.5 pg/ml) vs. placebo (45 ± 2.9 pg/ml) but no significant changes were observed for IL-6 and IL-10. Our data indicate that treatment with Ang-(1-7) may attenuate pain, some of the muscle damage markers and improves performance following eccentric exercise.Item Evidence for a role of AT 2 receptors at the CVLM in the cardiovascular changes induced by low-intensity physical activity in renovascular hypertensive rats.(2007) Rodrigues, Míriam Carmo; Santos, Maria José Campagnole dos; Machado, Raquel do Pilar; Silva, Marcelo Eustáquio; Rocha, José Luiz Marques; Ferreira, Patrícia Maria; Santos, Robson Augusto Souza dos; Alzamora, Andréia CarvalhoIn the present study, we evaluated the involvement of the rennin–angiotensin system (RAS) in the control of the blood pressure (BP), baroreceptor-mediated bradycardia and the reactivity of caudal ventrolateral medulla (CVLM) neurons to Ang II and to AT2 receptor antagonist in sedentary or trained renovascularhypertensive rats. Physical activity did not significantly change the baseline mean arterial pressure (MAP), heart rate (HR) or the sensitivity of the baroreflex bradycardia in normotensive Sham rats. However, in 2K1C hypertensive rats, physical activity induced a significant fall in baseline MAP and HR and produced an improvement of the baroreflex function (bradycardic component). The microinjections of Ang II into the CVLM produced similar decreases in MAP in all groups, Sham and 2K1C, sedentary and trained rats. The hypotensive effect of Ang II at the CVLM was blocked by previous microinjection of the AT2 receptors antagonist, PD123319, in all groups of rats. Unexpectedly, microinjection of PD123319 at the CVLM produced a depres-sor effect in 2K1C sedentary that was attenuated in 2K1C trained rats. No significant changes in MAP were observed after PD123319 i n Sham rats, sedentary or trained. These data showed that low-intensity physical activity is effective in lowering blood pressure and restoring the sensitivity of t he baroreflex bradycardia, however these cardiovascular effects are not accompanied by changes i n the responsiveness to Ang II at CVLM in normotensive or hypertensive, 2K1C rats. In ad dition, the blood pressure changes observed after AT 2 blockade in 2K1C rats suggest that hypertension may trigger an imbalance of AT1 /AT 2 receptors at the CVLM that may be restored, at least in part, by low-intensity physical activityItem Hemodynamic effect produced by microinjection of angiotensins at the caudal ventrolateral medulla of spontaneously hypertensive rats.(2008) Ferreira, Patrícia Maria; Alzamora, Andréia Carvalho; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dosIn the present study, the effect of caudal ventro-lateral medulla (CVLM) microinjection of angiotensin-(1-7) (Ang-(1-7)) and angiotensin II (Ang II) on mean arterial pres-sure (MAP), heart rate (HR) and pulsatile vascular blood flow (VBF; Transonic System) of the femoral, renal or mesenteric arteries was evaluated in male Wistar and spontaneously hypertensive rats (SHR) anesthetized with urethane. The vas-cular resistance (VR) was calculated by the ratio between the changes in MAP and VBF. Ang-(1-7) (40 ng) and Ang II (40 ng) microinjection into the CVLM caused similar depressor ef-fects in Wistar rats and SHR. The hypotensive effect pro-duced by Ang-(1-7) into the CVLM of Wistar rats was accom-panied by a decrease in femoral ( VR/VRbaseline 0.12 0.04 vs. 0.001 0.03; after saline) and renal ( VR/VRbase-line 0.10 0.02 vs. 0.003 0.02; after saline) vascular re-sistance. On the other hand, the Ang II hypotensive effect in Wistar rats produced only changes in renal vascular resis-tance ( VR/VRbaseline 0.16 0.02 vs. 0.003 0.02; after saline). In SHR, the hypotensive effect produced by Ang-(1-7) and Ang II caused decrease in renal vascular resistance ( VR/VRbaseline 0.18 0.03 and 0.13 0.01, respectively, as compared with saline, VR/VRbaseline 0.06 0.02), but did not alter the femoral or mesenteric vascular resistance. These data show that Ang II and Ang-(1-7) hypotensive effect at the CVLM involves the participation of different vascular beds. Further, the lack of involvement of the femoral vascular bed in SHR suggests that hypertension may induce alteration in the neural control of the different vascular beds, at least at the CVLM.Item Hypotensive effect induced by microinjection of Alamandine, a derivative of angiotensin-(1–7), into caudal ventrolateral medulla of 2K1C hypertensive rats.(2017) Soares, Everton Rocha; Barbosa, Claudiane Maria; Santos, Maria José Campagnole dos; Santos, Robson Augusto Souza dos; Alzamora, Andréia CarvalhoIn the present study we evaluated the cardiovascular effects produced by microinjection of the new component of the renin-angiotensin system, alamandine, into caudal ventrolateral medulla of urethane-anesthetized normotensive and hypertensive 2K1C rats. The participation of different angiotensin receptors in the effects of alamandine was also evaluated. Microinjection of angiotensin-(1–7) was used for comparison. The microinjection of 4, 40 and 140 pmol of alamandine or angiotensin-(1–7) into caudal ventrolateral medulla induced similar hypotensive effects in Sham-operated rats. However, contrasting with angiotensin-(1–7), in 2K1C rats the MAP response to the highest dose of alamandine was similar to that observed with saline. The microinjection of A- 779, a selective Mas receptor antagonist, blunted the angiotensin-(1–7) effects but did not block the hypotensive effect of alamandine in Sham or in 2K1C rats. However, microinjection of D-Pro7-angiotensin-(1–7), a Mas/MrgD receptor antagonist, blocked the hypotensive effect induced by both peptides. Furthermore, microinjection of PD123319, a putative AT2 receptor antagonist blocked the hypotensive effect of alamandine, but not of angiotensin-( 1–7), in Sham and 2K1C rats. Microinjection of the AT1 receptor antagonist, losartan, did not alter the hypotensive effect of angiotensin-(1–7) or alamandine in both groups. These results provide new insights about the differential mechanisms participating in the central cardiovascular effects of alamandine and angiotensin- (1–7) in normotensive and 2K1C hypertensive rats.Item Hypotensive effect of Ang II and Ang-(1-7) at the caudal ventrolateral medulla involves different mechanisms.(2002) Alzamora, Andréia Carvalho; Santos, Robson Augusto Souza dos; Santos, Maria José Campagnole dosHypotensive effect of ANG II and ANG-(1–7) at the caudal ventrolateral medulla involves different mechanisms. Am J Physiol Regul Integr Comp Physiol 283: R1187–R1195, 2002. First published July 18, 2002; 10.1152/ ajpregu.00580.2001.—The objective of the present study was to determine the contribution of the autonomic nervous system and nitric oxide to the depressor effect produced by unilateral microinjection of ANG-(1–7) and ANG II into the caudal ventrolateral medulla (CVLM). Unilateral microinjection of ANG-(1–7), ANG II (40 pmol), or saline (100 nl) was made into the CVLM of male Wistar rats anesthetized with urethane before and after intravenous injection of 1) methylatropine, 2.5 mg/kg; 2) prazosin, 25 g/kg; 3) the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), 5 mg/kg; or 4) the specific inhibitor of neuronal NOS, 7-nitroindazole (7-NI), 45 mg/kg. Arterial pressure and heart rate (HR) were continuously monitored. Microinjection of ANG-(1–7) or ANG II into the CVLM produced a significant decrease in mean arterial pressure (MAP; 11 1 mmHg, n 12 and 10 1 mmHg, n 10, respectively) that was not accompanied by consistent changes in HR or in cardiac output. The effect of ANG-(1–7) was abolished after treatment with methyl-atropine ( 3 0.6 mmHg, n 9) or L-NAME ( 2.3 0.5 mmHg, n 8) or 7-NI ( 2.8 0.6 mmHg, n 5). In contrast, these treatments did not significantly interfere with the ANG II effect ( 10 2.6 mmHg, n 8; 8 1.5 mmHg, n 8; and 12 3.6 mmHg, n 6; respectively). Peripheral treatment with prazosin abolished the hypotensive effect of ANG-(1–7) and ANG II. Microinjection of saline did not produce any significant change in MAP or in HR. These results suggest that the hypotensive effect produced by ANG II at the CVLM depends on changes in adrenergic vascular tonus and, more importantly, the hypotensive effect produced by ANG-(1–7) also involves a nitric oxide-related mechanism.