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There are multiple challenges for neuropharmacology in the future. Undoubtedly, one of the greatest challenges is the development of strategies for pharmacological targeting of specific brain regions for treatment of diseases. GABA is the main inhibitory neurotransmitter in the central nervous system, and dysfunction of GABAergic mechanisms is associated with different neurological conditions. Liposomes are lipid vesicles that are able to encapsulate chemical compounds and are used for chronic drug delivery. This short review reports our experience with the development of liposomes for encapsulation and chronic delivery of GABA to sites within the brain. Directions for future research regarding the efficacy and practical use of GABA-containing liposomes for extended periods of time as well as understanding and targeting neurological conditions are discussed. [ABSTRACT FROM AUTHOR]

Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion by bilateral common carotid arteries occlusion/reperfusion (BCCAo/R). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed seven days after transient BCCAo/R in transgenic rats (TG-7371) overexpressing Angiotensin-(1-7) and Sprague-Dawley (SD) rats. To assess blood-brain barrier (BBB) permeability Evans blue dye (EB) was intravenously injected. Cytokine levels were quantified in the whole brain through Elisa assay and oxidative stress was measured 7 days after ischemia. The expression of AT 1 and Mas receptors and inducible nitric oxide synthase (iNOS) was evaluated by RT-PCR. Neurological deficits were observed in both SD-BCCAo/R and TG-BCCAo/R, contrasting to sham-operated groups. However, TG-BCCAo/R showed a significant lower neurological score and latency in BAT when compared with SD-BCCAo/R. BBB integrity in TG-BCCAo/R was improved, since these animals showed lower extravasation of EB than SD-BCCAo/R. Interestingly, TG-BCCAo/R presented lower levels of pro-inflammatory cytokines when compared to SD-BCCAo/R. Levels of IL-10 were higher in SD-BCCAo/R than in SD control and even higher in TG-BCCAo/R. TG-BCCAo/R animals presented decreased levels of TBARS and increase in SOD activity and GSH levels when compared to SD sham rats. RT-PCR results showed higher levels of AT 1 receptor and iNOS in SD-BCCAo/R compared to TG-BCCAo/R, but no difference was observed for Mas receptor. The present study shows that lifetime increase in cerebral expression of an Ang-(1-7)-producing fusion protein induces neuroprotection in experimental global cerebral ischemia and reperfusion, reassuring that, pharmacological strategies leading to increase in Ang-(1-7) can be an additional tool for stroke therapy. • Higher levels of Ang-(1-7) causes neuroprotection in rats submitted to BCCAo/R. • TG-7371 showed improved behavior on neurological tests after BCCAo/R. • TG-7371 ameliorated inflammation and oxidative stress in brain after BCCAo/R. • TG-7371 presented decreased AT 1 receptor and iNOS expression in brain after BCCAo. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated the physiological importance of Angiotensin-(1-7) receptor Mas on reflex control of circulation. Experiments were performed in male Mas-knockout (Mas-KO) and Wild Type (WT) conscious mice (12–20wk of age). Baroreceptor reflex was evaluated by the bradycardic response induced by phenylephrine (0.25μg/5μl, i.v.). Bezold–Jarisch reflex was evaluated by phenylbiguanide (0.5μg/5μl, i.v.) and chemoreflex by potassium cyanide (2.5μg/5μl, i.v.). Baseline mean arterial pressure was higher in Mas-KO (n =14) as compared with WT mice (n =18) (118±1mmHg vs. 109±2mmHg); however, heart rate was similar in both strains (615±30bpm vs. 648±13bpm). Baroreflex bradycardia was lower (0.78±0.44ms/mmHg vs. 1.30±0.14ms/mmHg) in Mas-KO compared with WT mice. The depressor (−17±5mmHg vs. −45±6mmHg) and bradycardic (−212±36bpm vs. −391±29bpm) components of the Bezold–Jarisch reflex were also lower in Mas-KO mice. In addition, chemoreflex pressor response (+20±3mmHg vs. +12±0.8mmHg) and bradycardic response (−250±74bpm vs. −52±26bpm) were significantly higher in Mas-KO. These results further advances previous studies by showing that the lack of Mas receptor induced important imbalance in the neural control of blood pressure, altering not only the baroreflex but also the chemo- and Bezold–Jarisch reflexes. [Copyright &y& Elsevier]

Abstract Diabetic cardiomyopathy (DC) describes diabetes-associated changes in the structure and function of myocardium that are not directly linked to other factors such as hypertension. Currently there are some models of DC; however, they take a large time period to mimic key features. In the present study, we investigated the effects of a short-term high-fat/high salt diet (HFHS) treatment on myocardial function and structure, and vascular reactivity in C57BL/6 male mice. After 14 weeks HFHS induced hypertension (MAP = 144.95 ± 16.13 vs 92.90 ± 18.95 mm Hg), low glucose tolerance (AUC = 1049.01 ± 74.79 vs 710.50 ± 52.57 a.u.), decreased insulin sensitivity (AUC = 429.83 ± 35.22 vs 313.67 ± 19.55 a.u.) and increased adiposity (epididymal fat weight 0.96 ± 0.10 vs 0.59 ± 0.06 OW/BW × 102), aspects present in metabolic syndrome. Cardiac evaluation showed diastolic dysfunction (E/A ratio = 1.20 vs 1.90 u.a.) and cardiomyocyte hypertrophy (cardiomyocyte area = 502.82 ± 31.46 vs 385.58 ± 22.11 μm2). Lastly, vascular reactivity was impaired with higher contractile response (136.10 ± 3.49 vs 120.37 ± 5.43%) and lower response to endothelium-dependent vasorelaxation (74.01 ± 4.35 vs 104.84 ± 3.57%). In addition, the diet was able to induce an inward coronary remodeling (vascular total area: SCNS 6185 ± 800.6 vs HFHS 4085 ± 213.7 μm2). Therefore, we conclude that HFHS short-term treatment was able to induce metabolic syndrome-like state, cardiomyopathy and vascular injury working as an important tool to study cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to identify the effects of swimming training on the mRNA expression and protein levels of the calcium handling proteins in the hearts of renovascular hypertensive rats submitted to swimming protocol during 6 weeks. Main methods Fischer rats with renovascular hypertension 2-kidney 1-clip (2K1C) and SHAM groups were divided among sedentary and exercised groups. The exercise protocol lasted for 6 weeks (1 h/day, 5×/week), and the mean arterial pressure, cardiomyocytes hypertrophy parameters, mRNA expression and protein levels of some calcium handling proteins in the left ventricle were evaluated. Key findings Swimming training was able to reduce the levels of mean arterial pressure in the hypertensive group compared to 2K1C SED, and to promote cardiac hypertrophy in SHAM EX and 2K1C EX groups in comparison to the respective control groups. The mRNA levels of B-type natriuretic peptide were reduced in the 2K1C EX when compared to 2K1C SED. The mRNA and protein levels of the sarcoplasmic reticulum Ca 2 + -ATPase increased after the swimming training in SHAM and 2K1C groups. The mRNA and protein levels of phospholamban, displayed an increase in their levels in the exercised SHAM and in hypertensive rats in comparison to their respective controls; while mRNA levels of Na + /Ca 2 + exchanger was reduced in the left ventricle comparing to the sedentary hypertensive rats. Significance Taken altogether, we provide evidence that the aerobic training may lead to cardiac remodeling, and modulate the calcium handling proteins expression in the heart of hypertensive rats. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ang-(1–7) and Resveratrol Ameliorate Diet-Induced Hyperlipidemia. [•] Ang-(1–7) and resveratrol improve glucose metabolism AMPK/FOXO1/PPAR-γ pathway. [•] Cross-talking between renin-angiotensin-system and sirtuins in primary cell culture. [Copyright &y& Elsevier]

Abstract: Aims: The nonpeptide Ang-(1–7) analog, AVE 0991, is recognized as having beneficial cardiovascular effects similar to those induced by Ang-(1–7). In this study, we evaluated the effects of AVE 0991 on cardiovascular functions and on cardiac and renal remodeling in rats with 2K1C renovascular hypertension. Main methods: Fisher rats underwent surgery to induce 2K1C renovascular hypertension and were then treated with AVE 0991 (1 or 3mg/kg) for 28days. At the end of treatment, the blood pressure (BP), heart rate (HR), and baroreflex sensitivity were evaluated, in conscious animals. The rats were then euthanized and the heart and kidneys removed for subsequent histological analysis. Key findings: Treatment with AVE 0991 in 2K1C rats restored the baroreflex sensitivity of both bradycardic and tachycardic components to levels comparable to those of normotensive SHAM rats. At a higher dose (3mg/kg), AVE 0991 was also anti-hypertensive in 2K1C rats. Furthermore, AVE 0991 reduced the heart weight, thickness of myocardial fibers, number of inflammatory cells, and area of collagen deposition in the hearts of 2K1C rats compared to SHAM rats. The inflammatory process and tissue area of collagen deposition were decreased in the clipped kidney of AVE 0091-treated 2K1C rats. Significance: Our data showed that oral treatment with AVE 0991 reduces blood-pressure cardiac remodeling and improves baroreflex sensitivity in 2K1C renovascular hypertensive rats. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: The Mas protooncogene encodes a G protein-coupled receptor that has been described as a functional receptor for the cardioprotective fragment of the renin-angiotensin system (RAS), Angiotensin (Ang)-(1-7). The aim of this current study was to evaluate the responsiveness of Mas expression in hearts during different physiological and pathological conditions in rats. Physical training was considered a physiological condition, while isoproterenol-induced hypertrophy, myocardial infarction and DOCA-salt model of hypertension were used as pathological models of heart injury. The expression of Mas was analyzed by western blotting. Although swim-trained rats presented significant cardiac hypertrophy, our physical training protocol was unable to induce changes in the expression of Mas. On the other hand, cardiac hypertrophy and damage elicited by isoproterenol treatment led to a reduction in Mas expression. Myocardial infarction also significantly decreased the expression of Mas after 21 days of myocardial ischemia. Additionally, Mas expression levels were increased in hearts of DOCA-salt rats. Our present data indicate that Mas expression is responsive to different pathological stimuli, thereby suggesting that Mas receptor is involved in the homeostasis of the heart, as well as in the establishment and progression of cardiac diseases. [Copyright &y& Elsevier]

Abstract: In 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 30min, by previous CVLM microinjection of the Ang II AT1 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 rats. [Copyright &y& Elsevier]

• O 2 – participates in the Ang II effect at CVLM of 2K1C rats. • NO participates in the Ang-(1−7) effect at CVLM of 2K1C rats. • Ang II and Ang-(1−7) at CVLM contribute to hypertension in 2K1C rats. Hypertension 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. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)], a peptide of the renin-angiotensin system, has anti-inflammatory, anti-fibrotic and antiproliferative effects in acute or chronic inflammatory disease of respiratory system. In this study, we evaluated the effect of treatment with Ang-(1-7) on pulmonary tissue damage and behavior of mice submitted to experimental model of elastase-induced pulmonary emphysema (PE). Initially, male C57BL/6 mice were randomly assigned into two main groups: control (CTRL) and PE. In the PE group, the animals received three intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals (0.2 IU in 50 μL of saline). The CTRL group received the same volume of saline solution (50 μL). Twenty-four hours after the last instillation, animals of the PE group were randomly divided into two groups: PE and PE + Ang-(1-7). The PE + Ang-(1-7) group was treated with 60 μg/kg of Ang-(1-7) and 92 μg kg of HPβCD in gavage distilled water, 100 μl. The CTRL and PE groups were treated with vehicle (HPβCD- 92 μg/kg in distilled water per gavage, 100 μl), orally daily for 3 weeks. On the 19th day of treatment, all groups were tested in relation to locomotor activity and exploratory behavior. After 48 h, the animals were euthanized and lungs were collected. The animals of PE group presented rupture of alveolar walls and consequently reduction of alveolar tissue area. Treatment with Ang-(1-7) partially restored the alveolar tissue area. The PE reduced the locomotor activity and the exploratory behavior of the mice in relation to the control group. Treatment with Ang-(1-7) attenuated this change. In addition, it was observed that Ang-(1-7) reduced lung levels of IL-1β and increased levels of IL-10. These results show an anti-inflammatory effect of Ang-(1-7), inducing the return of pulmonary homeostasis and attenuation of the behavioral changes in experimental model of PE by elastase. [ABSTRACT FROM AUTHOR]