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Introduction: We tested the feasibility of adding a potassium binder to enable increased renin angiotensin aldosterone system inhibition (RAASi) and reduce albuminuria in patients with chronic kidney disease (CKD). In a controlled trial design, a potassium binder was introduced exclusively in patients developing hyperkalemia after intensified RAASi, thereby mirroring clinical decision-making. Methods: We planned to include 140 patients aged 18 to 80 years with estimated glomerular filtration rate (eGFR) 25 to 60 ml/min per 1.73 m2, albuminuria, and a history of hyperkalemia to an open-label, randomized trial comparing treatment with or without patiromer alongside maximally tolerated RAASi. Patients were randomized only if developing a documented P-potassium >5.5 mmol/l during run-in with intensified RAASi (losartan/spironolactone). The primary end point was change in urine albumin-creatinine ratio (UACR). Results: Screening among 800,000 individuals with available laboratory results yielded just 317 candidates meeting major selection criteria during 18â months, with 75 ultimately included. Among them, only 23 developed P-potassium >5.5 mmol/l, qualifying for randomization. Consequently, only 20 participants completed the study, falling short of the planned 98, precluding a significant effect on the primary outcome. Inclusion and randomization challenges stemmed from a limited pool of eligible patients for intensified RAASi at risk of hyperkalemia, along with a lower than expected incidence of hyperkalemia during run-in. Conclusion: Despite extensive screening efforts, few eligible patients were identified, and fewer developed hyperkalemia during run-in. Hence, a trial design limited to CKD patients at high hyperkalemia risk and including a run-in phase appears unlikely to provide evidence for a potential renal benefit from additional use of potassium binders.
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Officials have marked the end of the CoVid-19 pandemic, yet we continue to learn more about the SARS-CoV2 virus itself and its lasting multidimensional effects after acute infection. Long COVID, or the post-acute CoViD-19 syndrome (PACS), manifests as a wide range of prolonged physical, mental, and emotional symptoms over at least 1 to 12 months after SARS-CoV2 infection. Here, we describe certain pervasive clinical consequences of PACS on the cardiovascular system, and insight on the potentially improved prognoses in heart failure patients.
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Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.
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The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na+ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na+ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation.
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The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.
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Ventrículos do Coração , Hipertensão , Sistema Renina-Angiotensina , Animais , Hipertensão/metabolismo , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Ratos , Proto-Oncogene Mas , Pressão Sanguínea , Masculino , Camundongos , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Sarcolema/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , Trocador de Sódio e Cálcio/metabolismo , Trocador de Sódio e Cálcio/genética , Camundongos TransgênicosRESUMO
Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.
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Aprotinina , Tratamento Farmacológico da COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Aprotinina/farmacologia , Aprotinina/uso terapêutico , Aprotinina/metabolismo , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , COVID-19/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Peptídeo Hidrolases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Serina Endopeptidases/metabolismoRESUMO
Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.
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Antivirais , Aprotinina , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Aprotinina/uso terapêutico , Aprotinina/farmacologia , Aprotinina/química , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , Antivirais/administração & dosagem , Administração por Inalação , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Animais , Reposicionamento de Medicamentos/métodos , Inibidores de Serina Proteinase/uso terapêutico , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/administração & dosagemRESUMO
The cardiovascular continuum describes how several cardiovascular risk factors contribute to the development of atherothrombosis, ischemic heart disease, and peripheral arteriopathy, leading to cardiac and renal failure and ultimately death. Due to its multiple valences, the renin-angiotensin-aldosterone system plays an important role in all stages of the cardiovascular continuum, starting from a cluster of cardiovascular risk factors, and continuing with the development of atherosclerosis thorough various mechanisms, and culminating with heart failure. Therefore, this article aims to analyze how certain components of the renin-angiotensin-aldosterone system (converting enzymes, angiotensin, angiotensin receptors, and aldosterone) are involved in the underlying pathophysiology of the cardiovascular continuum and the possible arrest of its progression.
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Immune cell dysregulation is increasingly recognized as a pivotal pathological factor in cardiovascular disease. Over the past decade, a surge of research has focused on the role of immune cells such as dendritic cells (DCs), T cells, macrophages, and neutrophils in cardiovascular diseases, findings that are frequently featured in leading cardiology journals. This review provides a comprehensive synthesis of the roles that DCs play in common and potentially fatal arterial diseases, including hypertension, coronary artery atherosclerosis, acute coronary syndrome, pulmonary arterial hypertension, aortic aneurysm, aortic dissection, and vasculitis. Combining with bibliometric analysis, this review delves into the critical mechanisms by which DCs contribute to these diseases and reveals the shared mechanisms across diverse diseases. This review also offers new advances in clinical treatment strategies involving DCs.
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Bibliometria , Doenças Cardiovasculares , Células Dendríticas , Humanos , Células Dendríticas/imunologia , Doenças Cardiovasculares/imunologia , AnimaisRESUMO
This dataset demonstrates the use of computational fragmentation-based and machine learning-aided drug discovery to generate new lead molecules for the treatment of hypertension. Specifically, the focus is on agents targeting the renin-angiotensin-aldosterone system (RAAS), commonly classified as Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs). The preliminary dataset was a target-specific, user-generated fragment library of 63 molecular fragments of the 26 approved ACEI and ARB molecules obtained from the ChEMBL and DrugBank molecular databases. This fragment library provided the primary input dataset to generate the new lead molecules presented in the dataset. The newly generated molecules were screened to check whether they met the criteria for oral drugs and comprised the ACEI or ARB core functional group criterion. Using unsupervised machine learning, the molecules that met the criterion were divided into clusters of drug classes based on their functional group allocation. This process led to three final output datasets, one containing the new ACEI molecules, another for the new ARB molecules, and the last for the new unassigned class molecules. This data can aid in the timely and efficient design of novel antihypertensive drugs. It can also be used in precision hypertension medicine for patients with treatment resistance, non-response or co-morbidities. Although this dataset is specific to antihypertensive agents, the model can be reused with minimal changes to produce new lead molecules for other health conditions.
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Introduction: The classical axis of the renin-angiotensin system (RAS) makes an important contribution to blood pressure regulation under general anesthesia via the vasopressor angiotensin II (Ang II). As part of the alternative RAS, angiotensin-converting enzyme 2 (ACE2) modulates the pro-inflammatory and fibrotic effects of Ang II by processing it into the organ-protective Ang 1-7, which is cleaved to Ang 1-5 by ACE. Although the levels of ACE2 may be associated with postoperative complications, alternative RAS metabolites have never been studied perioperatively. This study was designed to investigate the perioperative kinetics and balance of both RAS axes around major abdominal surgery. Methods: In this observational cohort study, 35 patients undergoing elective major abdominal surgery were included. Blood sampling was performed before and after induction of anesthesia, at 1 h after skin incision, at the end of surgery, and on postoperative days (POD) 1, 3, and 7. The equilibrium concentrations of Ang I-IV, Ang 1-7, and Ang 1-5 in plasma were quantified using mass spectrometry. The plasma protein levels of ACE and ACE2 were measured with ELISA. Results: Surgery caused a rapid, transient, and primarily renin-dependent activation of both RAS axes that returned to baseline on POD 1, followed by suppression. After induction, the Ang II/Ang I ratio persistently decreased, while the ACE levels started to increase on POD 1 (all p < 0.01 versus before anesthesia). Conversely, the ACE2 levels increased on POD 3 and 7 (both p < 0.001 versus before anesthesia), when the median Ang 1-7 concentrations were unquantifiably low. Discussion: The postoperative elevation of ACE2 may prolong the decrease of the Ang II/Ang I ratio through the increased processing of Ang II. Further clarification of the intraoperative factors leading to relative Ang II deficiency and the sources of postoperatively elevated ACE2 is warranted.
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Abdome , Angiotensina II , Enzima de Conversão de Angiotensina 2 , Procedimentos Cirúrgicos Eletivos , Complicações Pós-Operatórias , Sistema Renina-Angiotensina , Humanos , Angiotensina II/sangue , Feminino , Masculino , Sistema Renina-Angiotensina/fisiologia , Pessoa de Meia-Idade , Abdome/cirurgia , Idoso , Enzima de Conversão de Angiotensina 2/metabolismo , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/sangue , Peptidil Dipeptidase A/sangue , Estudos de Coortes , Período Pós-Operatório , Angiotensina I/sangueRESUMO
Heart failure (HF) remains a huge medical burden worldwide, with aging representing a major risk factor. Here, we report the effects of sacubitril/valsartan, an approved drug for HF with reduced EF, in an experimental model of aging-related HF with preserved ejection fraction (HFpEF). Eighteen-month-old female Fisher 344 rats were treated for 12 weeks with sacubitril/valsartan (60 mg/kg/day) or with valsartan (30 mg/kg/day). Three-month-old rats were used as control. No differential action of sacubitril/valsartan versus valsartan alone, either positive or negative, was observed. The positive effects of both sacubitril/valsartan and valsartan on cardiac hypertrophy was evidenced by a significant reduction of wall thickness and myocyte cross-sectional area. Contrarily, myocardial fibrosis in aging heart was not reduced by any treatment. Doppler echocardiography and left ventricular catheterization evidenced diastolic dysfunction in untreated and treated old rats. In aging rats, both classical and non-classical renin-angiotensin-aldosterone system (RAAS) were modulated. In particular, with respect to untreated animals, both sacubitril/valsartan and valsartan showed a partial restoration of cardioprotective non-classical RAAS. In conclusion, this study evidenced the favorable effects, by both treatments, on age-related cardiac hypertrophy. The attenuation of cardiomyocyte size and hypertrophic response may be linked to a shift towards cardioprotective RAAS signaling. However, diastolic dysfunction and cardiac fibrosis persisted despite of treatment and were accompanied by myocardial inflammation, endothelial activation, and oxidative stress.
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Envelhecimento , Aminobutiratos , Compostos de Bifenilo , Combinação de Medicamentos , Insuficiência Cardíaca , Ratos Endogâmicos F344 , Tetrazóis , Valsartana , Animais , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Compostos de Bifenilo/farmacologia , Valsartana/farmacologia , Valsartana/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Feminino , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fibrose , Estresse Oxidativo/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Modelos Animais de Doenças , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologiaRESUMO
BACKGROUND: Chronic kidney disease (CKD) is a significant risk factor for pulmonary hypertension (PH), a complication that adversely affects patient prognosis. However, the mechanisms underlying this association remain poorly understood. A major obstacle to progress in this field is the lack of a reliable animal model replicating CKD-PH. METHODS: This study aimed to establish a stable rat model of CKD-PH. We employed a combined approach, inducing CKD through a 5/6 nephrectomy and concurrently exposing the rats to a high-salt diet. The model's hemodynamics were evaluated dynamically, alongside a comprehensive assessment of pathological changes in multiple organs. Lung tissues and serum samples were collected from the CKD-PH rats to analyze the expression of angiotensin-converting enzyme 2 (ACE2), evaluate the activity of key vascular components within the renin-angiotensin-aldosterone system (RAAS), and characterize alterations in the serum metabolic profile. RESULTS: At 14 weeks post-surgery, the CKD-PH rats displayed significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension. Additionally, right ventricular hypertrophy was observed. Notably, no evidence of pulmonary vascular remodeling was found. Further analysis revealed RAAS dysregulation and downregulated ACE2 expression within the pulmonary vascular endothelium of CKD-PH rats. Moreover, the serum metabolic profile of these animals differed markedly from the sham surgery group. CONCLUSIONS: Our findings suggest that the development of pulmonary arterial hypertension in CKD-PH rats is likely a consequence of a combined effect: RAAS dysregulation, decreased ACE2 expression in pulmonary vascular endothelial cells, and metabolic disturbances.
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Angiotensina II , Hipertensão Pulmonar , Nefrectomia , Cloreto de Sódio na Dieta , Animais , Masculino , Ratos , Angiotensina II/sangue , Enzima de Conversão de Angiotensina 2/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/induzido quimicamente , Rim/metabolismo , Rim/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Sistema Renina-Angiotensina/fisiologia , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
Background: Persistent left ventricular hypertrophy after transcatheter aortic valve replacement (TAVR) has been associated with poor outcomes. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), due to their favorable effects on ventricular remodeling, have been hypothesized to improve outcomes post-TAVR, yet there are no recommendations regarding their use. Objectives: This study aimed to compare the outcomes of patients receiving ACEIs/ARBs with those not receiving ACEIs/ARBs after TAVR. Methods: We performed a literature search on PubMed and Cochrane Library until June 14, 2023, and included all studies comparing clinical outcomes between patients given ACEIs/ARBs and those not given ACEIs/ARBs after TAVR. All-cause mortality was the primary outcome. We used a random effects model with appropriate corrections to calculate relative risk (RR) and CIs, with all analyses carried out using R v4.0.3. Results: We included ten studies on the use of ACEIs/ARBs post-TAVR. Patients on ACEIs/ARBs had lower risk of all-cause mortality (RR: 0.74, 95% CI: 0.65-0.86, I2 = 62%, chi-square P < 0.01), cardiovascular mortality (RR: 0.70, 95% CI: 0.56-0.88, I2 = 0%, chi-square P = 0.54), and new-onset atrial fibrillation (RR: 0.71, 95% CI: 0.52-0.96, I2 = 0%, chi-square P = 0.59). Patients on ACEIs/ARBs had a similar risk of myocardial infarction, heart failure, stroke, new permanent pacemaker implantation, acute kidney injury, major bleeding, vascular complications, aortic regurgitation, and mitral regurgitation. Conclusions: We found that patients receiving ACEIs/ARBs had a lower risk of all-cause mortality, cardiovascular mortality, and new-onset atrial fibrillation. Risk of other outcomes was similar to patients not receiving ACEIs/ARBs. Randomized clinical trials are needed to explore the benefits of ACEIs/ARBs post-TAVR, so that definitive guidelines can be developed.
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BACKGROUND: Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons. RESULT: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes. CONCLUSION: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Astrócitos , AVC Isquêmico , Microglia , Neurônios , Ratos Wistar , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Telmisartan , Animais , Ratos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais Recém-Nascidos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Benzimidazóis/farmacologia , Comunicação Celular/fisiologia , Comunicação Celular/efeitos dos fármacos , Células Cultivadas , Imidazóis/farmacologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Piridinas/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Telmisartan/farmacologiaRESUMO
Recent years have seen a resurgence of interest for the renin-angiotensin-aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II-angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin-angiotensin-aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin-angiotensin-aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin-angiotensin-aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions.
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Angiotensina II , Hipotensão , Humanos , Hipotensão/tratamento farmacológico , Angiotensina II/administração & dosagem , Relação Dose-Resposta a Droga , Vasoconstritores/administração & dosagem , Vasoconstritores/uso terapêutico , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Masculino , FemininoRESUMO
Background: This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods: Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results: The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92-3.41; P < .0001). Conclusions: In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment.
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As a regulator in renin-angiotensin-aldosterone system, angiotensin-converting enzyme 2 (ACE2) closely correlated with tumor progression of pancreatic cancer, meantime, was easily affected by a variety of factors. [99mTc]Tc-cyc-DX600 SPECT was established as an ACE2-specific imaging protocol to figure out the ACE2 status in pancreatic tumor. BALB/C-NU mice were used to prepare the subcutaneous cell derived xenograft (CDX) models with HEK-293T or HEK-293T/hACE2 cells to validate ACE2 specificity of [99mTc]Tc-cyc-DX600 SPECT and establish SPECT imaging protocol. On the basis of [99mTc]Tc-cyc-DX600 SPECT and [18F]F-FDG PET/CT, ACE2-dependence on tumor size and tumor metabolism were further verified on orthotopic pancreatic cancer model with KPC cells. Immunohistochemical analysis was used to demonstrate the findings on ACE2 SPECT. [99mTc]Tc-cyc-DX600 was of superior tumor uptake in HEK-293T/hACE2 CDX than wild type (6.74 ± 0.31 %ID/mL vs 1.83 ± 0.26 %ID/mL at 1.5 h post injection (p.i.); 3.14 ± 0.31 %ID/mL vs 1.16 ± 0.15 %ID/mL at 4.5 h p.i.). For the CDX models with PANC-1 cells, a significant negative correlation between the slope of tumor volume and tumor uptake was observed (r = -0.382 for the 1-4th day; r = -0.146 for the 1-5th day; r = -0.114 for the 1-6th day; r = -0.152 for the 1-7th day; but P > 0.05 for all). For orthotopic pancreatic cancer model, the linear correlation between FDG PET and ACE2 SPECT of the pancreatic lesions was negative (r = -0.878), the quantitative values of ACE2 SPCET was positively correlated with the volume of primary lesions (r = 0.752) and also positively correlated with the quantitative values of ACE2 immunohistochemical analysis (r = 0.991). Conclusively, [99mTc]Tc-cyc-DX600 SPECT is an ACE2-specific imaging protocol with clinical translational potential, adding multidimensional information on the disease progression of pancreatic cancer.
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The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.