Mas Receptor Pathway Research Articles

Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice

Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1–7), which in turn acts on MAS receptors (ACE2/Ang (1–7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1–7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1–7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1–7)/MAS receptor pathway and resulting in antidepressant-like effects.

Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway.

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.

Angiotensin-(1-7)/Mas receptor modulates anti-inflammatory effects of exercise training in a model of chronic allergic lung inflammation

AimsExercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. Material and methodsBALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 μg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. Key findingsBlocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. SignificanceOur results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.

The Pathophysiology, Diagnosis and Treatment of Corona Virus Disease 2019 (COVID-19).

Since the beginning of this century, beta coronaviruses (CoV) have caused three zoonotic outbreaks. However, little is currently known about the biology of the newly emerged SARS-CoV-2 in late 2019. There is a spectrum of clinical features from mild to severe life threatening disease with major complications like severe pneumonia, acute respiratory distress syndrome, acute cardiac injury and septic shock. The genome of SARS-CoV-2 encodes polyproteins, four structural proteins and six accessory proteins. SARS-CoV-2 tends to utilize Angiotensin-converting enzyme 2 (ACE2) of various mammals. The imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang(1–7)/Mas receptor pathway in the renin-angiotensin system leads to multi-system inflammation. The early symptoms of COVID-19 pneumonia are low to midgrade fever, dry cough and fatigue. Vigilant screening is important. The diagnosis of COVID-19 should be based on imaging findings along with epidemiological history and nucleic acid detection. Isolation and quarantine of suspected cases is recommended. Management is primarily supportive, with newer antiviral drugs/vaccines under investigation.

Blood flow restriction exercise stimulates mobilization of hematopoietic stem/progenitor cells and increases the circulating ACE2 levels in healthy adults.

Adult CD34+ hematopoietic stem/progenitor cells (HSPC) in the systemic circulation are bone marrow-derived and have the propensity of maintaining cardiovascular health. Activation of angiotensin-converting enzyme-2 (ACE2)-angiotensin-(1-7)-Mas receptor pathway, the vascular protective axis of the renin-angiotensin system (RAS), stimulates vasculogenic functions of HSPCs. In a previous study, exposure to hypoxia increased the expressions of ACE2 and Mas, and stimulated ACE2 shedding. The current study tested if blood flow restriction exercise (BFR)-induced regional hypoxia recapitulates the in vitro observations in healthy adults. Hypoxia was induced by 80% limb occlusion pressure (LOP) via inflation cuff. Muscle oxygen saturation was determined using near-infrared spectroscopy. Peripheral blood was collected 30 min after quiet sitting (control) or after BFR. Lin-CD45lowCD34+ HSPCs were enumerated by flow cytometry, and ACE and ACE2 activities were determined in plasma and cell lysates and supernatants. Regional hypoxia resulted in muscle oxygen saturation of 17.5% compared with 49.7% in the control condition (P < 0.0001, n = 9). Circulating HSPCs were increased following BFR (834.8 ± 62.1/mL) compared with control (365 ± 59, P < 0.001, n = 7), which was associated with increased stromal-derived factor 1α and vascular endothelial growth factor receptor levels by four- and threefold, respectively (P < 0.001). ACE2 activity was increased in the whole cell lysates of HSPCs, resulting in an ACE2-to-ACE ratio of 11.7 ± 0.5 in BFR vs 9.1 ± 0.9 in control (P < 0.05). Cell supernatants have threefold increase in the ACE2-to-ACE ratio following BFR compared with control (P < 0.001). Collectively, these findings provide strong evidence for the upregulation of ACE2 by acute regional hypoxia in vivo. Hypoxic exercise regimens appear to be promising means of enhancing vascular regenerative capacity.NEW & NOTEWORTHY Although many studies have explored the mechanisms of skeletal muscle growth and adaptation with hypoxia exercise interventions, less attention has been given to the potential for vascular adaptation and regenerative capacity. This study shows for the first time an acute upregulation of the angiotensin-converting enzyme 2 and increase in CD34+ vasculogenic cells following an acute bout of blood flow restriction with low-intensity exercise. These rapid changes collectively promote skeletal muscle angiogenesis. Therefore, this study supports the potential of hypoxic exercise interventions with low intensity for vascular and muscle health.

Targeting Angiotensin-Converting Enzyme-2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases.

Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.

Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia

The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.

Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia

The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.

Liraglutide Enhances the Activity of the ACE-2/Ang(1-7)/Mas Receptor Pathway in Lungs of Male Pups from Food-Restricted Mothers and Prevents the Reduction of SP-A.

In utero growth restriction and being born small for gestational age are risk factors for respiratory morbidity. IUGR (in utero growth retardation) is associated to overall reduction in lung weight, surfactant content and activity, impaired maturation of the alveolar type II cells, and decreased alveolar formation. The renin-angiotensin system (RAS) may be a key target underlying pathophysiological lung alterations. GLP-1 and agonists of its receptor modulate the expression levels of different components of RAS and also are very important for lung maturation and the production of surfactant proteins. The aim of this study was to elucidate the effects of IUGR induced by perinatal food restriction of the mother in the lung function of pups at early stages of life (PD21) and to determine if liraglutide had any effect during gestational period. Sprague-Dawley pregnant rats were randomly assigned to 50% food restriction (MPFR) or ad libitum control (CT) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant MPFR and CT rats were treated with liraglutide or vehicle. At postnatal day 21 and before weaning, 20 CT and 20 FR male pups were sacrificed and lungs were analyzed by RT-PCR. Liraglutide restored surfactant protein A (SP-A) mRNA expression in pup lungs from food-restricted mothers. Surfactant protein B (SP-B) mRNA expression is not affected by neither IUGR nor liraglutide treatment. Moreover, liraglutide modulated different elements of RAS, increasing angiotensin-converting enzyme 2 (ACE2) and MasR mRNA expression only in pups from food-restricted mothers (MPFR), despite food restriction had not any direct effect at this early stage. Liraglutide also increased endothelial nitric oxide synthase (eNOS) expression in MPFR lungs, reflecting the activation of MasR by angiotensin 1–7. In conclusion, liraglutide prevented the alteration in lung function induced by IUGR and promoted the positive effects of ACE2-Ang(1–7)-MasR in restoring lung function.

Recent Advances in Angiotensin Research

The complexity of the renin–angiotensin system (RAS) has increased considerably in the past 2 decades. From a hormonal system occurring exclusively in the circulation, it moved into the direction of a local system existing in virtually every organ of the body. In both cases, the active end product still was angiotensin (Ang) II, acting via its classical type 1 (AT1) receptor. Next, multiple novel angiotensin metabolites and receptors were discovered, all having effects of their own and often opposing those of the Ang II–AT1 receptor pathway, for instance the Ang III–Ang II type 2 (AT2) pathway and the Ang (1–7)–Mas receptor pathway. As a consequence, RAS stimulation and RAS blockade may have wide-ranging effects, depending on what angiotensin metabolites/receptors are up- or downregulated and often occurring in a disease- and tissue-specific manner. This review critically addresses angiotensin-related work published in Hypertension over the past 2 years, focusing on the brain, pregnancy, sex-related aspects, and the kidney. All major angiotensin receptors (AT1, AT2, and Mas) are expressed in the brain. An important question is what angiotensin these receptors actually see: blood derived or locally synthesized Ang II, Ang III, and Ang-(1–7)? And in case of local synthesis, does a so-called brain RAS, acting independently of the circulating RAS, truly exist? An independent brain RAS would require the presence of renin, angiotensinogen, and angiotensin-converting enzyme (ACE) at levels that allow a meaningful interaction, that is, that results in angiotensin concentrations that are sufficiently high to stimulate these receptors. For instance, at the reported angiotensinogen levels in cerebrospinal fluid, corresponding with only 10% to 15% of the plasma levels,1 one would require brain renin levels that are roughly 10-fold those in plasma to at least yield the same levels of angiotensins as in blood plasma. …

Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.

The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma.

Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: Role of the angiotensin-(1–7)/Mas receptor axis

The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1–7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1–7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent.

Clinical relevance of local Renin Angiotensin systems.

The concept of a “local” renin angiotensin system (RAS) can mean different things to different people. Its main purpose is to differentiate the “local” RAS operating in tissues from the classical “circulating” RAS, but it is difficult to differentiate between the two systems because of their extensive overlap. The circulating RAS comprises kidney-derived renin acting on liver-derived angiotensinogen to generate angiotensin (Ang) I that is converted to Ang II by angiotensin converting enzyme (ACE). However, tissues are the main site of production of angiotensin peptides by the circulating RAS, whereby plasma-derived renin acts on plasma-derived angiotensinogen to generate Ang I, which is converted to Ang II by endothelial ACE (1–4). Local RAS refers to tissue-based mechanisms of Ang peptide formation that operate separately from the circulating RAS. Although many different concepts of local RAS have been described, a key feature is the local synthesis of RAS components including angiotensinogen and enzymes such as renin that cleave angiotensinogen to produce Ang peptides independently of the circulating RAS. ACE and Ang II type 1 (AT1) and type 2 (AT2) receptors are invariably locally synthesized, but these are also components of the circulating RAS. Many other potential components of local RAS have been described that may contribute to tissue-specific mechanisms of Ang peptide formation, and that may either participate in disease processes or contribute to mechanisms that protect from tissue injury. These include the (pro)renin receptor (5), renin-independent mechanisms of Ang peptide generation from Ang- (1-12) (6), intracellular (or intracrine) RAS that may contribute to cardiovascular disease (7, 8), and AT2 receptors (7) and the ACE2/Ang-(1-7)/Mas receptor pathway (6–8) that may mediate therapeutic benefit in cardiovascular disease. In addition, novel Ang peptides with novel pharmacology, including Ang IV, Ang A, alamandine, and angioprotectin (6, 8), have the potential to contribute to disease or to protective mechanisms. Moreover, the brain RAS, including the ACE2/Ang-(1-7)/Mas receptor and the Ang IV/insulin regulated aminopeptidase pathways may play a role in Alzheimer’s and Parkinson’s diseases (9). Local production of aldosterone may have a pathogenic role (7, 10), ACE, AT2 receptors, Ang-(1-7) and acetyl-Ser-Asp-Lys-Pro may have a role in hematopoiesis (11), and the ACE2/Ang-(1-7)/Mas receptor pathway may contribute to fetal programing, reproduction, and cancer (6, 12). This short opinion piece discusses the potential clinical relevance of local RAS. The challenge in demonstrating the independence of local from circulating RAS, and the potential interaction of ACE inhibitor and AT1 receptor blocker (ARB) therapies with local RAS are discussed. Attempts to define local RAS that are independent of the circulating RAS have been primarily based on animal models and the clinical relevance of local RAS is uncertain. However, this area of research continues to evolve, and today’s opinions may change as we gain better understanding of how these novel components and mechanisms impact on clinical medicine.

Angiotensin Converting Enzyme 2/Ang‐(1–7)/Mas Axis Protects Brain from Ischemic Injury with a Tendency of Age‐dependence

The angiotensin (Ang) converting enzyme 2 (ACE2)/Ang-(1-7)/Mas receptor pathway is an important component of the renin-angiotensin system and has been suggested to exert beneficial effects in ischemic stroke. This study explored whether the ACE2/Ang-(1-7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age. We used three-month and eight-month transgenic mice with neural over-expression of ACE2 (SA) and their age-matched nontransgenic (NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation (OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1-7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species (ROS) production and cell death were measured. (1) Middle cerebral artery occlusion -induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight-month animals; (2) OGD-induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight-month mice; (3) Ang-(1-7) and A779 had opposite effects on OGD-induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production. Angiotensin converting enzyme 2/Ang-(1-7)/Mas axis protects brain from ischemic injury via the Nox/ROS signaling pathway, with a greater effect in older animals.

Pathophysiological role of the renin–angiotensin system on erectile dysfunction

The renin-angiotensin system (RAS) has been shown to play an active role within the erectile tissues. The aim of this narrative review is to summarize the literature addressing the pathophysiological role of RAS on erectile function. Additionally, we update evidence on recent findings on the role of the Ang-(1-7) and Mas receptor on the erectile function and its therapeutic potential for treating erectile dysfunction (ED). This narrative review is based on the material searched and obtained via MEDLINE and PubMed up to November 2012. The search terms we used are 'angiotensin, erectile dysfunction, renin, Mas receptor' in combination with 'pathophysiology, fibrosis, pathways'. The levels of angiotensin (Ang) II, the main component of this system, are increased in the corpus cavernosum as compared to those found in the systemic circulation. Moreover, emerging evidence indicates that an increased activity of Ang II via AT1 receptor might contribute to the development of ED, whereas the pharmacological blockage of Ang II/AT1 actions has beneficial effects on the erection. On the other hand, the heptapeptide Ang-(1-7), known as a major endogenous counter-regulator of Ang II actions, favours penile erection via the activation of Mas receptor. Ang-(1-7) and Mas receptor pathway might be considered as a promising therapeutic target for the treatment of ED.

Angiotensin (1‐7) into rostral ventrolateral medulla is enhanced in spontaneously hypertensive rats

BackgroundAngiotensin‐(1‐7) (Ang‐(1‐7)) is recognized as an important mediator of renin angiotensin system. Ang‐(1‐7) is a peptide of ligand for Ang‐(1‐7)‐Mas receptor, and has opposite actions of angiotensin II in the vasculature. In the central nervous system, however, it has been shown that microinjection of Ang‐(1‐7) into rostral ventrolateral medulla (RVLM), one of vasomotor centers of brainstem increased blood pressure in normotensive rats. The aim of the present study was to determine the possible involvement of Ang‐(1‐7) in the RVLM in hypertension.Methods and ResultsIn anesthetized Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we microinjected Ang‐(1‐7) (100 pmol) and a Mas receptor antagonist (A‐779: 100 pmol) into the RVLM. Microinjection of Ang‐(1‐7) increased blood pressure in both strains. The changes were, however, significantly greater in SHR than WKY rats (13.3 ± 1.3 mmHg, n=7 vs. 6.6 ± 0.8 mmHg, n=5; p&lt;0.05). In contrast, microinjection of a Mas receptor antagonist (A‐779) deceased blood pressure significantly greater in SHR than WKY rats (‐26.4 ± 1.7 mmHg, n=5 vs. ‐13.7 ± 0.8 mmHg, n=5; p&lt;0.05).ConclusionBoth exogenous and endogenous Ang‐(1‐7) in the RVLM are enhanced in spontaneously hypertensive rats. The Ang‐(1‐7)‐Mas receptor pathway in RVLM may contribute to the mechanisms of blood pressure elevation in spontaneously hypertensive rats.