Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome.

Objective: Angiotensin (Ang)-(1-7) has preventive effects on metabolic syndrome (MetS). The aim of this study was to evaluate the therapeutic effect of oral Ang-(1-7) on mean arterial pressure (MAP), insulin resistance (IR), inflammatory process, and remodeling of white adipose tissue (WAT) in rats with establishedMetS. Methods: Rats were subjected to control (CT; AIN-93M) or high-fat (HF) diets for 13 wk to induce MetS and treated with Ang-(1-7) or vehicle (V) for the last 6 wk. At the end of 13 wk, MAP, biochemical and histological parameters, and uncoupling protein (UCP) and inflammatory gene expression were determined by quantitative reverse transcription polymerase chain reaction. Results: HF-V rats showed increased visceral fat deposition, inflammatory cytokine expression, hyperplasia, and hypertrophy in retroperitoneal (WAT) and brown adipose tissue (BAT). Additionally, the gastrocnemius muscle reduced UCP-3 and increased the UCP-1 expression in BAT. HF-V also elevated levels of plasma insulin, glucose, homeostatic model assessment (HOMA) of IR and HOMA-b, and increased body mass, adiposity, and MAP. Ang-(1-7) treatment in rats with MetS [HF-Ang-(1-7)] reduced WAT area, number of adipocytes, and expression of proinflammatory adipokines in WAT and BAT and increased UCP-3 in gastrocnemius muscle and UCP-1 expression in BAT compared with the HF-V group. These events prevented body mass gain, reduced adiposity, and normalized fasting plasma glucose, insulin levels, HOMA-IR, HOMA-b, and MAP. Conclusion: Data from the present study demonstrated that oral Ang-(1-7) treatment is effective in restoring biochemical parameters and hypertension in established MetS by improving hypertrophy and hyperplasia in WAT and inflammation in adipose tissue, and regulating metabolic processes in the gastrocnemius muscle and BAT

Age-dependent effect of high-fructose and high-fat diets on lipid metabolism and lipid accumulation in liver and kidney of rats.

Background: 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

Antioxidant effects of oral Ang-(1-7) restore insulin pathway and RAS components ameliorating cardiometabolic disturbances in rats.

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HP?CD/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 (HP?CD) or HP?CD/Ang-(1-7) in the last 6 weeks. FATHP?CD/ 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 HP?CD/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, HP?CD/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

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan

Hypotensive effect of Ang II and Ang-(1-7) at the caudal ventrolateral medulla involves different mechanisms.

Hypotensive 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

Maternal high-fat diet triggers metabolic syndrome disorders that are transferred to first and second offspring generations.

A high-fat (H) diet increases metabolic disorders in offspring. However, there is great variability in the literature regarding the time of exposure, composition of the H diets offered to the genitors and/or offspring and parameters evaluated. Here, we investigated the effect of a H diet subjected to the genitors on different cardio-metabolic parameters on first (F1)- and second (F2)-generation offspring. Female Fischer rats, during mating, gestation and breast-feeding, were subjected to the H diet (G0HF) or control (G0CF) diets. Part of F1 offspring becomes G1 genitors for generating the F2 offspring. After weaning, F1 and F2 rats consumed only the C diet. Nutritional, biometric, biochemical and haemodynamic parameters were evaluated. G0HF genitors had a reduction in food intake but energy intake was similar to the control group. Compared with the control group, the F1H and F2H offspring presented increased plasma leptin, insulin and fasting glucose levels, dietary intake, energy intake, adiposity index, mean arterial pressure, sympathetic drive evidenced by the hexamethonium and insulin resistance. Our data showed that only during mating, gestation and breast-feeding, maternal H diet induced cardio-metabolic disorders characteristic of human metabolic syndrome that were transferred to both females and males of F1 and F2 offspring, even if they were fed control diet after weaning. This process probably occurs due to the disturbance in mechanisms related to leptin that increases energy intake in F1H and F2H offspring. The present data reinforce the importance of balanced diet during pregnancy and breast-feeding for the health of the F1 and F2 offspring

Baroreflex modulation by angiotensins at the rat rostral and caudal ventrolateral medulla.

Baroreflex 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

Hemodynamic effect produced by microinjection of angiotensins at the caudal ventrolateral medulla of spontaneously hypertensive rats.

In 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

Hypotensive effect induced by microinjection of Alamandine, a derivative of angiotensin-(1?7), into caudal ventrolateral medulla of 2K1C hypertensive rats.

In 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

Cardiopulmonary reflex and blood pressure response after swimming and treadmill exercise in hypertensive rats.

Cardiopulmonary sensitivity was evaluated after exercise training through swimming and running in spontaneously hypertensive rats (SHR) that were divided into three groups: (a) run exercise; (b) swim exercise; and (c) sedentary. For 8 wks, the run exercise was performed on a treadmill while the swim exercise was performed by swimming. Cardiopulmonary reflex was evaluated by chemical and mechanical pathways through the injections of phenylbiguanide (PBG) (5.0 mg?kg-1) and volume expansion with isotonic saline (0.75% of body weight), respectively. Both types of exercise training decreased systolic blood pressure (SBP) compared to the sedentary group. The swim trained group reduced SBP faster than the run trained group. The sensitivity of the chemically activated endings of the cardiopulmonary reflex was increased in both exercise-trained groups for hypotensive response. The exercise training groups had higher levels of urine output after acute volume expansion. The production of urine showed that swimming and treadmill training were more efficient than the sedentary group. These results indicate that: (a) exercise improved cardiopulmonary reflex sensitivity; and (b) swim training led to a faster SBP reduction and a more sensitive reflex response to pressure stimuli