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Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

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Los inhibidores de la enzima convertidora de angiotensina son utilizados por más de 40 millones de personas en todo el mundo para el tratamiento de enfermedades cardiovasculares. Son considerados seguros, aunque pueden producir angioedema severo en el 0,1 a 0, 5 % de los pacientes. Se presenta el caso de un paciente del sexo masculino, de 67 años de edad, con diagnóstico de diabetes mellitus e hipertensión arterial, tratado con metformina, hidroclorotiazida y enalapril desde hacía aproximadamente cuatro años, que ingresó en cuerpo de guardia con edema severo del tercio anterior de la lengua, sin compromiso respiratorio. Se indicó hidrocortisona y difenhidramina y evolucionó satisfactoriamente, por lo que fue dado de alta y se prescribió prednisona y difenhidramina por vía oral; se suspendió el enlapril y a las 48 horas se reevaluó y estaba asintomático. El mecanismo por el que estos medicamentos producen angioedema no está claro, pero probablemente sería por la acumulación tisular de bradiquinina y puede presentarse en cualquier momento del tratamiento. La correcta anamnesis, el diagnóstico precoz y el tratamiento inmediato con hidrocortisona por vía endovenosa son aspectos a considerar ante casos similares. El análisis del evento mediante la farmacovigilancia, permitió clasificarlo como severo, probablemente relacionado con el consumo de enalapril. Esto genera alertas para informar al personal de salud y tomar decisiones relacionadas con los medicamentos, que permitan la actuación inmediata con la finalidad de reducir la morbimortalidad.

Angiotensin converting enzyme inhibitors are used by more than 40 million people worldwide for the treatment of cardiovascular diseases. They are considered safe, although they can cause severe angioedema in 0.1 to 0.5% of patients. The case of a 67-years-old male patient diagnosed with diabetes mellitus and arterial hypertension, treated with metformin, hydrochlorothiazide and enalapril for approximately four years, who was admitted to the emergency room with severe edema of the third anterior of the tongue, without respiratory compromise is presented. Hydrocortisone and diphenhydramine were indicated and he evolved satisfactorily, for which he was discharged and prednisone and diphenhydramine were prescribed orally; he discontinued enlapril, 48 hours later he was reassessed and was asymptomatic. The mechanism by which these drugs produce angioedema is not clear, but it would probably be due to the tissue accumulation of bradykinin and can occur at any time during treatment. The correct history, early diagnosis and immediate treatment with intravenous hydrocortisone are aspects to consider in similar cases. Analysis of the event through pharmacovigilance allowed it to be classified as severe, probably related to the enalapril consumption. This generates alerts to inform health staff and make decisions related to medications, which allow immediate action in order to reduce morbidity and mortality.

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INTRODUCTION: Enalapril maleate is an antihypertensive ethyl ester pro-drug with two crystalline forms. A network of hydrogen bonds in both polymorphs plays an important role on solid-state stability, charge transfer process and degradation reactions (when exposed to high humidity, temperature and/or pH changes). COMPUTATIONAL PROCEDURES: Supramolecular arrangement was proposed by Hirshfeld surface using the CrystalExplorer17 software and quantum theory of atoms in molecules. The electronic structure properties were calculated using the functional hybrid M06-2X with 6-311++G** base function employing diffuse and polarization functions to improve the description of hydrogen atoms on intermolecular interactions. Also, the H+ charge transfer between enalapril and maleate molecules was performed using Car-Parrinello molecular dynamics with the Verlet algorithm. In both simulations, the temperature of the ionic system was maintained around 300 K using the Nosé-Hoover thermostat and the electronic system evolved without the use of the thermostat. RESULTS: This work evaluates the effect of maleate on the structural stability of enalapril maleate solid state. The electronic structural analysis points out a partially covalent character for N1-H∙∙∙O7 interaction; and the molecular dynamic showed a decentralized hydrogen on maleate driving a decomposition by charge transfer process while a centered hydrogen driving the stabilization. The charge transfer process and the mobility of the proton (H+) between enalapril and maleate molecules was demonstrated using supramolecular modeling analyses and molecular dynamics calculations.

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BACKGROUND: Hypertension treatment with renin-angiotensin system inhibitors (RASi) presents contradictions about the recovery of damage in cardiovascular autonomic modulation characterized by reduced heart rate variability (HRV) and increased blood pressure variability (BPV). Conversely, the association of RASi with physical training can influence achievements in cardiovascular autonomic modulation. OBJECTIVE: To investigate the effects of aerobic physical training on hemodynamics and cardiovascular autonomic modulation in hypertensive volunteers untreated and treated with RASi. METHODS: A non-randomized controlled trial in which 54 men (≅ 40-60 years old) with a history of hypertension for >2 years were allocated in accordance with their characteristics into three groups: untreated (Control; n=16), treated with type 1 angiotensin II (AT1) receptor blocker (losartan; n=21), and treated with angiotensin-converting enzyme inhibitor (enalapril; n=17). All participants underwent hemodynamic, metabolic, and cardiovascular autonomic evaluation using baroreflex sensitivity (BRS) and spectral analysis of HRV and BPV, before and after 16 weeks of supervised aerobic physical training. RESULTS: The volunteers treated with RASi had lower BPV and HRV, both in the supine position and in the tilt test, with the losartan group having the lowest values. Aerobic physical training increased HRV and BRS in all groups. However, the association of enalapril with physical training appears to be more prominent. CONCLUSION: Long-term treatment with enalapril and losartan may harm the autonomic modulation of HRV and BRS. Aerobic physical training is essential to promote positive adjustments in the autonomic modulation of HRV and BRS in hypertensive patients treated with RASi, especially with enalapril.

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AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.

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The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

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Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B1 and B2 receptors. Moreover, angiotensin I converting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, can enhance pain by blocking the degradation of peptides such as substance P and bradykinin, besides enhancing kinin receptors signalling. We investigated the effect of ACE inhibitors on reserpine-induced fibromyalgia-like pain symptoms and the involvement of kinins in this effect in mice. Nociceptive parameters (mechanical and cold allodynia and overt nociception) were evaluated after ACE inhibitors administration in mice previously treated with reserpine. The role of kinin B1 and B2 receptors was investigated using pharmacological antagonism. Additionally, bradykinin levels, as well as the activity of ACE and kininase I, were measured in the sciatic nerve, spinal cord and cerebral cortex of the mice. The ACE inhibitors enalapril and captopril enhanced reserpine-induced mechanical allodynia, and this increase was prevented by kinin B1 and B2 receptor antagonists. Substance P and bradykinin caused overt nociception and increased mechanical allodynia in animals treated with reserpine. Reserpine plus ACE inhibitors increased bradykinin-related peptide levels and inhibited ACE activity in pain modulation structures. Since hypertension is a frequent comorbidity affecting fibromyalgia patients, hypertension treatment with ACE inhibitors in these patients should be reviewed once this could enhance fibromyalgia-like pain symptoms. Thus, the treatment of hypertensive patients with fibromyalgia could include other classes of antihypertensive drugs, different from ACE inhibitors.

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Obesity is a chronic disease caused multiple associated factors that results in excessive body fat accumulation. The Renin-Angiotensin System (RAS) unbalance is now recognized as a key factor on regulating body energy and metabolism. AIM: The aim of the present study was to evaluate the Enalapril (ACE inhibitor) effects on the metabolic function and hepatic steatosis of obese mice evaluating Angiotensin Converting Enzymes (ACEs) expression. METHODS: The experiment was performed using 32 male Swiss mice (8 weeks old) equally and randomly divided into 4 groups (n = 8): standard diet (ST), standard diet plus Enalapril (ST + ENAL), hyperlipidic diet (HF) and hyperlipidic diet plus Enalapril (HF + ENAL). Weekly measurements of animal weight and feed consumption were performed. At the end of treatment period a glucose tolerance test (GTT) and insulin sensitivity test (IST) were performed. Ultrasonography was used to evaluate hepatic and epididymal fat pad. Liver samples were submitted to HE histology and gene expression analyses were performed using Real-Time PCR. RESULTS: The main results showed a decrease in body weight after treatment with Enalapril, as well as a reduced size of epididymal fat pad (EFP). Hepatic echogenicity and steatosis measurement were lower in the obese groups treated with Enalapril also modulating ACE2/ACE expressions. CONCLUSIONS: Enalapril use improved metabolism reducing hepatic steatosis, decreasing ACE expression and increasing ACE2 expression.

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OBJECTIVES: Evaluate whether the RAS dual blockade would induce additional beneficial effects on cardiovascular remodelling when compared to monotherapy in renal hypertensive two kidneys-one clip (2K-1C) rats. METHODS: Hypertensive 2K-1C and normotensive (2K) rats were treated for 14 days with submaximal doses of losartan (LOS), enalapril (ENA), losartan plus enalapril (LOS + ENA) or vehicle (water). Blood pressure and some parameters of cardiovascular remodelling were evaluated. RESULTS: Systolic blood pressure (SBP) was higher in 2K-1C (209 ± 3 mm Hg, P < .05) than in 2K (113 ± 1 mm Hg) rats. There was an additional effect in 2K-1C treated with LOS + ENA (153 ± 9 mm Hg) on lowering SBP when compared to LOS (184 ± 12 mm Hg) or ENA (177 ± 9 mm Hg). None of the treatments had effect on SBP in 2K rats. In 2K-1C, cardiomyocyte hypertrophy was reduced by all treatments, although the cardiac hypertrophy indexes remained unchanged. 2K-1C aortas presented medial thickening that was partially reduced by the treatments. Intimal hyperplasia observed in 2K-1C (15.56 ± 0.89 µm vs 8.24 ± 0.80 µm) was reversed by ENA (9.52 ± 0.45 µm) or LOS + ENA (8.17 ± 0.53 µm). Collagen deposition was increased in 2K-1C hearts (1.77 ± 0.16 vs 1.28 ± 0.09) and aortas (8.1 ± 0.6 vs 5.2 ± 0.2). Treatment with LOS reduced (1.12 ± 0.14%) and ENA (0.81 ± 0.11%) or LOS + ENA (0.86 ± 0.11%) additionally diminished collagen only in 2K-1C hearts. CONCLUSIONS: Submaximal doses of ACEi and/or ARB have inhibitory actions on cardiac remodelling and vascular hypertrophy not entirely dependent on their effects on blood pressure normalization in renovascular hypertensive rats. Combined therapy produced additional reduction in blood pressure than monotherapy despite a similar inhibition on cardiovascular remodelling.

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Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 µM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 µM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 µM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.