RESUMEN
Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.
Asunto(s)
Apoptosis , Enalapril , Dinámicas Mitocondriales , Infarto del Miocardio , Disfunción Ventricular Izquierda , Animales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/fisiopatología , Ratas , Enalapril/farmacología , Enalapril/uso terapéutico , Apoptosis/efectos de los fármacos , Ratas Sprague-Dawley , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Modelos Animales de Enfermedad , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patologíaRESUMEN
Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos , Levodopa , Oxidopamina , Animales , Masculino , Ratones , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antiparkinsonianos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Captopril/farmacología , Captopril/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/prevención & control , Enalapril/farmacología , Enalapril/uso terapéutico , Levodopa/toxicidad , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Perindopril/farmacología , Perindopril/uso terapéuticoRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Enalapril , Ratones Endogámicos C57BL , Músculo Esquelético , Obesidad , Condicionamiento Físico Animal , Animales , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Obesidad/metabolismo , Obesidad/fisiopatología , Condicionamiento Físico Animal/fisiología , Ratones , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/farmacología , Dieta Alta en Grasa/efectos adversos , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiologíaRESUMEN
BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).
Asunto(s)
Ácido Fólico , Genotipo , Homocisteína , Metilenotetrahidrofolato Reductasa (NADPH2) , Humanos , Ácido Fólico/administración & dosificación , Ácido Fólico/sangre , Homocisteína/sangre , Femenino , Masculino , Método Doble Ciego , Persona de Mediana Edad , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Hipertensión/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Anciano , Enalapril/administración & dosificación , Enalapril/farmacología , Adulto , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/sangreRESUMEN
OBJECTIVE: Enalapril has shown satisfactory potential in controlling increased and sustained blood pressure (BP). However, multiple dysregulated mechanisms that interact with each other and are involved in the pathophysiology of arterial hypertension may not be affected, contributing to the remaining cardiovascular risk. Using an exercise training protocol, we investigated whether adding both approaches to arterial hypertension management could promote higher modulation of regulatory mechanisms of BP in postmenopausal rats. METHODS: Spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with enalapril maleate (OSE) and trained treated with enalapril maleate (OTE). Both the pharmacological and exercise training protocols lasted for 8âweeks. The BP was directly recorded. Inflammation and oxidative stress were evaluated in the cardiac tissue. RESULTS: Although BP reduction was similar between OSE and OTE, trained group showed lower vasopressor systems outflow after sympathetic ganglion blocking by hexamethonium (mean BP) (OTE: -53.7â±â9.86 vs. OS: -75.7â±â19.2âmmHg). Bradycardic and tachycardic response were increased in OTE group (-1.4â±â0.4 and -2.6â±â0.4 vs. OS: -0.6â±â0.3 and -1.3â±â0.4âbpm/mmHg, respectively), as well as BP variability. In addition, the combination of approaches induced an increase in interleukin 10, antioxidant defense (catalase and glutathione peroxidase) and nitrite levels compared with the OS group. CONCLUSION: Despite similar BP, the inclusion of exercise training in antihypertensive drug treatment exacerbates the positive adaptations induced by enalapril alone on autonomic, inflammatory and oxidative stress profiles, probably affecting end-organ damage and remaining risk.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Hipertensión , Ratas , Animales , Presión Sanguínea , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/farmacología , Ratas Endogámicas SHRRESUMEN
BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). OBJECTIVE: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. RESULTS: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. CONCLUSION: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.
Asunto(s)
Disfunción Cognitiva , Enalapril , Dinámicas Mitocondriales , Infarto del Miocardio , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Estrés Oxidativo/efectos de los fármacos , Ratas , Enalapril/farmacología , Quinazolinonas/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacologíaRESUMEN
OBJECTIVE: In this study, we aimed to investigate the effects of the concurrent exercise training (CET) associated with the enalapril maleate on blood pressure variability (BPV) and renal profile in an experimental model of arterial hypertension (AH) and postmenopause. METHODS: Female ovariectomized spontaneously hypertensive rats (SHR) were distributed into 4 groups (n = 8/group): sedentary (SO), sedentary + enalapril (SOE), trained (TO) and trained + enalapril (TOE). Both enalapril (3mg/kg) and CET (3 days/week) were conducted during 8 weeks. Blood pressure (BP) was directly recorded for BPV analyses. Renal function, morphology, inflammation and oxidative stress were assessed. RESULTS: The SOE, TO e TOE groups presented decreased systolic BP compared with SO. Both trained groups (TO and TOE) presented lower BPV and increased baroreflex sensitivity (TO: 0.76 ± 0.20 and TOE: 1.02 ± 0.40 vs. SO: 0.40 ± 0.07 ms/mmHg) compared with SO group, with additional improvements in TOE group. Creatinine and IL-6 levels were reduced in SOE, TO and TOE compared with SO group, while IL-10 was increased only in TOE group (vs. SO). Enalapril combined with CET promote reduction in lipoperoxidation (TOE: 1.37 ± 0.26 vs. SO: 2.08 ± 0.48 and SOE: 1.84 ± 0.35 µmol/mg protein) and hydrogen peroxide (TOE: 1.89 ± 0.40 vs. SO: 3.70 ± 0.19 and SOE: 2.73 ± 0.70 µM), as well as increase in catalase activity (vs. sedentary groups). The tubulointerstitial injury was lower in interventions groups (SOE, TO and TOE vs. SO), with potentialized benefits in the trained groups. CONCLUSIONS: Enalapril combined with CET attenuated BPV and baroreflex dysfunctions, probably impacting on end-organ damage, as demonstrated by attenuation in the AH-induced renal inflammations, oxidative stress and morphofunctional impairments in postmenopausal rats.
Asunto(s)
Hipertensión , Nefritis , Insuficiencia Renal , Femenino , Animales , Ratas , Presión Sanguínea , Posmenopausia , Enalapril/farmacología , Hipertensión/tratamiento farmacológico , Ratas Endogámicas SHR , Modelos TeóricosRESUMEN
BACKGROUND: Although a growing number of observational studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) intake may be a risk factor for psoriasis, evidence is still insufficient to draw definitive conclusions. RESEARCH DESIGN AND METHODS: Drug-targeted Mendelian randomization (DTMR) was used to analyze the causality between genetic proxied ACEIs and psoriasis. Furthermore, we performed a disproportionality analysis based on the FDA adverse event reporting system (FAERS) database to identify more suspicious subclasses of ACEIs. RESULTS: Using two kinds of genetic proxy instruments, the present DTMR research identified genetic proxied ACEIs as risk factors for psoriasis. Furthermore, our disproportionality analysis revealed that ramipril, trandolapril, perindopril, lisinopril, and enalapril were associated with the risk of psoriasis, which validates and refines the findings of the DTMR. CONCLUSIONS: Our integrative study verified that ACEIs, especially ramipril, trandolapril, perindopril, lisinopril, and enalapril, tended to increase the risk of psoriasis statistically.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Psoriasis , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Ramipril/efectos adversos , Lisinopril/farmacología , Perindopril/efectos adversos , Farmacovigilancia , Análisis de la Aleatorización Mendeliana , Enalapril/farmacología , Psoriasis/tratamiento farmacológico , Psoriasis/genéticaRESUMEN
The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hipersensibilidad , Hipertensión , Humanos , Antihipertensivos/uso terapéutico , Lisinopril/uso terapéutico , Tos/inducido químicamente , Tos/tratamiento farmacológico , Presión Sanguínea , Tetrazoles/uso terapéutico , Valina/farmacología , Valina/uso terapéutico , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Amlodipino/uso terapéutico , Valsartán/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Enalapril/farmacología , Edema , Cefalosporinas/farmacología , Amoxicilina/farmacología , Amoxicilina/uso terapéutico , beta-Lactamas/farmacología , beta-Lactamas/uso terapéutico , Antiinflamatorios/uso terapéutico , Atención a la Salud , Quimioterapia CombinadaRESUMEN
BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.
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Enfermedades de los Perros , Prolapso de la Válvula Mitral , Perros , Animales , Furosemida/farmacología , Furosemida/uso terapéutico , Enalapril/farmacología , Enalapril/uso terapéutico , Frecuencia Cardíaca , Válvula Mitral , Cardiotónicos/farmacología , Prolapso de la Válvula Mitral/veterinaria , Diuréticos , Enfermedades de los Perros/tratamiento farmacológicoRESUMEN
This study analyzes sex-based differences in renal structure and the response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Eight weeks old ApoE-/- mice received enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. Each group consisted of six males and six females. Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells, and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in the female group), and hypertrophy of the PECs in males. This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.
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Aterosclerosis , Enfermedades Renales , Femenino , Masculino , Animales , Ratones , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Caracteres Sexuales , Enalapril/farmacología , Aterosclerosis/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Apolipoproteínas E/genética , Antivirales , Modelos Animales de EnfermedadRESUMEN
INTRODUCTION: Differences in class or molecule-specific effects between renin-angiotensin-aldosterone system (RAAS) inhibitors have not been conclusively demonstrated. This study used South African data to assess clinical and cost outcomes of antihypertensive therapy with the three most common RAAS inhibitors: perindopril, losartan and enalapril. METHODS: Using a large, South African private health insurance claims database, we identified patients with a hypertension diagnosis in January 2015 receiving standard doses of perindopril, enalapril or losartan, alone or in combination with other agents. From claims over the subsequent 5 years, we calculated the risk-adjusted rate of the composite primary outcome of myocardial infarction, ischaemic heart disease, heart failure or stroke; rate of all-cause mortality; and costs per life per month (PLPM), with adjustments based on demographic characteristics, healthcare plan and comorbidity. RESULTS: Overall, 32,857 individuals received perindopril, 16,693 losartan and 13,939 enalapril. Perindopril-based regimens were associated with a significantly lower primary outcome rate (205 per 1000 patients over 5 years) versus losartan (221; P < 0.0001) or enalapril (223; P < 0.0001). The risk-adjusted all-cause mortality rate was lower with perindopril than enalapril (100 vs. 139 deaths per 1000 patients over 5 years; P = 0.007), but not losartan (100 vs. 94; P = 0.650). Mean (95% confidence interval) overall risk-adjusted cost PLPM was Rands (ZAR) 1342 (87-8973) for perindopril, ZAR 1466 (104-9365) for losartan (P = 0.0044) and ZAR 1540 (77-10,546) for enalapril (P = 0.0003). CONCLUSION: In South African individuals with private health insurance, a perindopril-based antihypertensive regimen provided better clinical and cost outcomes compared with other regimens.
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Hipertensión , Losartán , Humanos , Losartán/uso terapéutico , Losartán/farmacología , Antihipertensivos/uso terapéutico , Enalapril/uso terapéutico , Enalapril/farmacología , Perindopril/uso terapéutico , Sudáfrica/epidemiología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Hipertensión/complicaciones , Presión SanguíneaRESUMEN
We previously reported that apoptosis is responsible for cognitive impairment in rats with myocardial infarction (MI). Acute administration of an apoptosis inhibitor (Z-vad) effectively reduced brain inflammation in rats with cardiac ischemia/reperfusion injury. However, the beneficial effects of Z-vad on cognitive function, brain inflammation, mitochondrial function, cell death pathways, and neurogenesis in MI rats have not been investigated. Male rats were divided into sham or MI groups (left anterior descending coronary ligation). A successful MI was determined by a reduction of ejection fraction <50 %. Then, MI rats were allocated to receive vehicle, enalapril (10 mg/kg, a positive control), and Z-vad (1 mg/kg) for 4 weeks. Cardiac function, cognitive function, and molecular analysis were investigated. MI rats exhibited cardiac dysfunction, cognitive impairment, blood brain barrier (BBB) breakdown, dendritic spine loss, which were accompanied by an upregulation of oxidative stress, mitochondrial dysfunction, and apoptosis. Chronic treatment with Z-vad attenuated cardiac dysfunction following MI to the same extent as enalapril. Z-vad successfully improved cognitive function and restored dendritic spine density in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction similar to enalapril. Moreover, Z-vad provided greater efficacy than enalapril in enhancing mitophagy, neurogenesis, synaptic proteins and reducing apoptosis in hippocampus of MI rats. Nevertheless, neither Z-vad nor enalapril increased BBB tight junction protein. In conclusion, treatment with an apoptosis inhibitor reduced cognitive impairment in MI rats via reducing oxidative stress, mitochondrial dysfunction, apoptosis, and restoring dendritic spine density, together with enhancing mitophagy and neurogenesis.
Asunto(s)
Disfunción Cognitiva , Encefalitis , Infarto del Miocardio , Ratas , Masculino , Animales , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Enalapril/farmacología , Apoptosis , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicacionesRESUMEN
OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-ß (TGF-ß) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-ß and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-ß/Smad 2/3.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Enalapril , Animales , Humanos , Ratas , Diabetes Mellitus Experimental/complicaciones , Cardiomiopatías Diabéticas/tratamiento farmacológico , Enalapril/farmacología , Enalapril/uso terapéutico , Fibrosis , Hidrolasas Diéster Fosfóricas/metabolismo , Hidrolasas Diéster Fosfóricas/farmacología , Hidrolasas Diéster Fosfóricas/uso terapéutico , Transducción de Señal , Factor de Crecimiento Transformador betaRESUMEN
Enalapril with documented anti-inflammatory potential was evaluated in current investigation to explore its anti-arthritic efficacy. For anti-arthritic evaluation of enalapril, CFA-instigated arthritic model was employed after which various parameters comprising paw volume, body weight, arthritic index, hematological and biochemical parameters, radiographic analysis and level of various cytokines were estimated. Enalapril demonstrated significant (pË0.001) anti-arthritic activity by suppressing paw volume, arthritic index while preserved CFA instigated weight loss. Likewise, enalapril also normalized the hematological and biochemical alterations, suppressed the level of proinflammatory cytokines with elevation of anti-inflammatory cytokines. Radiographic and histopathological analysis also further validates the anti-arthritic attribute of enalapril where enalapril preserved the normal architecture of arthritis induced joints. Outcomes of the study pointed out a notable anti-arthritic activity of enalapril. However detailed mechanistic studies are still required to point out the exact mechanism of action.
Asunto(s)
Artritis Experimental , Citocinas , Animales , Humanos , Citocinas/uso terapéutico , Extractos Vegetales/farmacología , Enalapril/farmacología , Enalapril/uso terapéutico , Artritis Experimental/patología , Antiinflamatorios/efectos adversosRESUMEN
BACKGROUND: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides. METHODS: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death. RESULTS: Compared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01035255.
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Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamente , Péptido Natriurético Encefálico , Guanosina Monofosfato/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Tetrazoles/efectos adversos , Resultado del Tratamiento , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/farmacología , Valsartán/uso terapéutico , Valsartán/farmacología , Enalapril/uso terapéutico , Enalapril/farmacología , Aminobutiratos/efectos adversos , Compuestos de Bifenilo/farmacología , Combinación de Medicamentos , Volumen SistólicoRESUMEN
BACKGROUND: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children. METHODS: We conducted a systematic literature search to identify studies on PRA levels in healthy children and in children with heart failure. In addition, we analysed PRA data measured before (n = 35, aged 25 days-2.1 years), 4 hours after (n = 34) and within the first 8 days of enalapril treatment (n = 29) in children with heart failure from the European project Labeling of Enalapril from Neonates up to Adolescents (LENA). RESULTS: Age has a profound effect on PRA levels in healthy children, as PRA levels in the literature are up to about 7 times higher in neonates than in older children. Children with heart failure younger than 6 months showed 3-4 times higher PRA levels than healthy peers in both the literature and the LENA studies. In the LENA studies, the ACEi enalapril significantly increased median predose PRA by a factor of 4.5 in children with heart failure after 4.7 ± 1.6 days of treatment (n = 29, p < 0.01). Prior to treatment with enalapril, LENA subjects with symptomatic heart failure (Ross score ≥3) had a significantly higher PRA than LENA subjects with asymptomatic heart failure of comparable age (Ross score ≤2, p < 0.05). CONCLUSIONS: Age, heart failure and ACEi treatment have a notable influence on PRA and must be considered when assessing PRA as a clinically meaningful parameter. CLINICAL TRIAL REGISTRATION: The trials are registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu). TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18.
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Inhibidores de la Enzima Convertidora de Angiotensina , Insuficiencia Cardíaca , Humanos , Recién Nacido , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/uso terapéutico , Enalapril/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Renina/metabolismo , Sistema Renina-Angiotensina , Lactante , PreescolarRESUMEN
Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the Kp of metformin but reduced renal slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered.
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Diabetes Mellitus Tipo 2 , Metformina , Ratas , Animales , Metformina/farmacocinética , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Enalapril/farmacología , Enalapril/metabolismo , Ratas Wistar , Antiportadores/metabolismo , Riñón/metabolismoRESUMEN
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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Enalapril , Estrés del Retículo Endoplásmico , Animales , Ratones , Biomarcadores/metabolismo , Dieta , Enalapril/farmacología , Ratones Endogámicos C57BLRESUMEN
Both lisinopril and enalapril are angiotensin-converting enzyme (ACE) drugs and widely used in the treatment of hypertension. Enalapril does not cross the blood-brain barrier, but lisinopril is centrally active. Our goal was to find out if there was a link between the actual concentration of ACE inhibitors and cognition and if there was a detectable difference between the two types of ACE inhibitors. Asymptomatic, non-treated patients were diagnosed by screening and the hypertension was confirmed by ambulatory blood pressure monitoring (ABPM). A battery of cognitive tests was used to assess the impact of randomly assigning participants to receive either lisinopril or enalapril. All neurocognitive functions were measured, especially the most affected by conditions of compromised perfusion pressures, such as hypertension, which are attention and executive functions. The lisinopril concentration showed a significant inverse correlation with mosaic test (coeff. = -0.5779) and seemed to have a significant negative effect on perceptual motor skills (coeff. = -0.5779), complex attention (coeff. = -0.5104) and learning (coeff. = -0.5202). Compared with enalapril, lisinopril is less successful in improving the components of cognitive functions.