ABSTRACT
The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.
Subject(s)
Annexin A1/metabolism , Electroacupuncture/methods , Hyperalgesia/therapy , Nociceptive Pain/therapy , Receptors, Formyl Peptide/metabolism , Receptors, Opioid/metabolism , Animals , Freund's Adjuvant/toxicity , Heptanoic Acids/pharmacology , Hyperalgesia/etiology , Hyperalgesia/metabolism , Male , Mice , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Nociception/drug effects , Nociceptive Pain/etiology , Nociceptive Pain/metabolism , Receptors, Formyl Peptide/antagonists & inhibitors , Receptors, Opioid/therapeutic useABSTRACT
Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1ß, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
Subject(s)
Dermatitis/prevention & control , Heptanoic Acids/administration & dosage , Radiation-Protective Agents/administration & dosage , Receptors, Lipoxin/antagonists & inhibitors , Animals , CD59 Antigens/metabolism , Dermatitis/etiology , Dermatitis/metabolism , Disease Models, Animal , Docosahexaenoic Acids/metabolism , Dose-Response Relationship, Drug , Heptanoic Acids/pharmacology , Lipoxins/metabolism , Mice , Mice, Hairless , Radiation-Protective Agents/pharmacology , Ultraviolet Rays/adverse effectsABSTRACT
PURPOSE: N-myc downstream-regulated gene 2 (NDRG2) is down-regulated in grade-III meningioma [anaplastic meningioma (AM)] and associated with clinically aggressive behavior. Current therapies in the treatment of high-grade meningioma are lacking with limited success. This study aims to validate the effect of NDRG2-targeted therapy using structurally related bioactive triterpene compounds derived from the edible mushroom Ganoderma lucidum (ganoderic acid A:GA-A/ganoderic acid DM:GA-DM) in human AM in relevant pre-clinical models. METHODS: Tissue samples from the AM tumor regions of three human patients and control non-tumor samples were used to analyze the expression pattern of NDRG2. In vitro cell culture and in vivo cell-line-derived orthotopic xenograft animal models of AM were utilized to assess efficacy of treatment with GA-A/DM. RESULTS: Downregulation of NDRG2 expression was observed in surgically resected high-grade meningiomas compared to normal brain. These results prompt us to use NDRG2-targeting agents GA-A/DM. In vitro results showed that 72-h treatments of 25 µM GA-A/DM induced AM cell death, upregulate NDRG2 protein expression, downregulate NDRG2 promoter methylation in meningioma cells as compared to azacitidine and decitabine, the most commonly used demethylating agents. Our results also demonstrated that GA-A/DM does not have any detrimental effect on normal human neurons and arachnoid cells. GA-A/DM promoted apoptotic factors (Bax) while suppressing MMP-9, p-P13K, p-AKT, p-mTOR, and Wnt-2 protein expression. RNAi-mediated knockdown of NDRG2 protein expression increased tumor proliferation, while forced expression of wt-NDRG2 decreased proliferation in an in vitro model. Magnetic resonance (MR) imaging and Hematoxylin (H&E) staining demonstrated gross reduction of tumor volume in GA-A/DM treated mice at 5 weeks when compared with saline-treated orthotopic AM xenografted controls. There was an overall decrease in tumor cell proliferation with increased survival in GA-A/DM-treated animals. Enzyme assays showed that GA-A/DM did not negatively impact hepatic function. CONCLUSION: GA-A/DM may be a promising natural therapeutic reagent in the treatment of AM by suppressing growth via NDRG2 modulation and altering of intracellular signal pathways. We have shown it could potentially be an effective treatment for AM with decreased cellular proliferation in vitro, decreased tumor volume and increased survival in vivo.
Subject(s)
Heptanoic Acids/pharmacology , Lanosterol/analogs & derivatives , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Triterpenes/pharmacology , Tumor Suppressor Proteins/drug effects , Aged , Anaplasia , Animals , Antimetabolites, Antineoplastic/pharmacology , Apoptosis/drug effects , Azacitidine/pharmacology , Cell Death/drug effects , DNA Methylation/drug effects , Decitabine/pharmacology , Down-Regulation , Gene Knockdown Techniques , Humans , In Vitro Techniques , Lanosterol/pharmacology , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Meningeal Neoplasms/pathology , Meningioma/pathology , Mice , Mice, SCID , Middle Aged , Molecular Targeted Therapy , Neoplasm Grading , Phosphatidylinositol 3-Kinases/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Promoter Regions, Genetic , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/drug effects , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolism , Wnt2 Protein/drug effects , Wnt2 Protein/metabolism , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/drug effects , bcl-2-Associated X Protein/metabolismABSTRACT
BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.
Subject(s)
Diabetes Complications/drug therapy , Diabetic Nephropathies/drug therapy , Fluorobenzenes/therapeutic use , Heptanoic Acids/therapeutic use , Kidney/drug effects , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Sulfonamides/therapeutic use , Adult , Analysis of Variance , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Atorvastatin , Creatinine/urine , Dose-Response Relationship, Drug , Double-Blind Method , Europe , Fluorobenzenes/pharmacology , Heptanoic Acids/pharmacology , Humans , Lipids/blood , North America , Proteinuria , Pyrimidines/pharmacology , Pyrroles/pharmacology , Rosuvastatin Calcium , South America , Sulfonamides/pharmacologyABSTRACT
OBJECTIVES: to evaluate the Nosocomial Infection Control Programs in hospital institutions regarding structure and process indicators. METHOD: this is a descriptive, exploratory and quantitative study conducted in 2013. The study population comprised 13 Nosocomial Infection Control Programs of health services in a Brazilian city of the state of São Paulo. Public domain instruments available in the Manual of Evaluation Indicators of Nosocomial Infection Control Practices were used. RESULTS: The indicators with the highest average compliance were "Evaluation of the Structure of the Nosocomial Infection Control Programs" (75%) and "Evaluation of the Epidemiological Surveillance System of Nosocomial Infection" (82%) and those with the lowest mean compliance scores were "Evaluation of Operational Guidelines" (58.97%) and "Evaluation of Activities of Control and Prevention of Nosocomial Infection" (60.29%). CONCLUSION: The use of indicators identified that, despite having produced knowledge about prevention and control of nosocomial infections, there is still a large gap between the practice and the recommendations. .
OBJETIVOS: avaliar os Programas de Controle de Infecção Hospitalar nas instituições hospitalares, quanto aos indicadores de estrutura e processo. MÉTODO: trata-se de um estudo descritivo, exploratório e quantitativo, realizado em 2013. A população foi composta por 13 Programas de Controle de Infecção Hospitalar de serviços de saúde, de uma cidade brasileira do interior paulista. Foram utilizados instrumentos de domínio público, disponibilizados no Manual de Indicadores de Avaliação de Práticas de Controle de Infecção Hospitalar. RESULTADOS: os indicadores com maior média de conformidade foram "Avaliação da Estrutura dos Programas de Controle de Infecção Hospitalar" (75%) e "Avaliação do Sistema de Vigilância Epidemiológica de Infecção Hospitalar" (82%) e os com menores médias foram "Avaliação das Diretrizes Operacionais" (58,97%) e "Avaliação das Atividades de Controle e Prevenção de Infecção Hospitalar" (60,29%). CONCLUSÃO: o uso de indicadores identificou que, apesar do conhecimento produzido sobre ações de prevenção e controle de infecções hospitalares, ainda existe um grande hiato entre prática e recomendações. .
OBJETIVOS: evaluar los Programas de Control de Infección Hospitalaria en las instituciones hospitalarias respecto a los indicadores de estructura y proceso. MÉTODO: se trata de un estudio descriptivo, exploratorio y cuantitativo, desarrollado en 2013. La población fue compuesta por 13 Programas de Control de Infección Hospitalaria de servicios de salud de una ciudad brasileña del interior paulista. Fueron utilizados instrumentos de dominio público, disponibles en el Manual de Indicadores de Evaluación de Prácticas de Control de Infección Hospitalaria. RESULTADOS: los indicadores con mayor promedio de conformidad fueron "Evaluación de la Estructura de los Programas de Control de Infección Hospitalaria" (75%) y "Evaluación del Sistema de Vigilancia Epidemiológica de Infección Hospitalaria" (82%) y aquellos con menores promedios "Evaluación de las Directivas Operacionales" (58,97%) y "Evaluación de las Actividades de Control y Prevención de Infección Hospitalaria" (60,29%). CONCLUSIÓN: el uso de indicadores posibilitó identificar que, a pesar del conocimiento producido sobre acciones de prevención y control de infecciones hospitalarias, todavía existe un gran hiato entre la práctica y las recomendaciones. .
Subject(s)
Humans , Male , Female , Aged , Amlodipine/therapeutic use , Antihypertensive Agents/therapeutic use , Blood Pressure , Heptanoic Acids/therapeutic use , Hypertension/drug therapy , Kidney/physiopathology , Pyrroles/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Amlodipine/pharmacology , Antihypertensive Agents/pharmacology , Biomarkers/metabolism , Blood Pressure/drug effects , Capsules , Drug Therapy, Combination , Glucose/metabolism , Heptanoic Acids/pharmacology , Hypertension/complications , Hypertension/physiopathology , Inflammation/pathology , Kidney Function Tests , Kidney/drug effects , Lipid Metabolism/drug effects , Multivariate Analysis , Oxidative Stress/drug effects , Pyrroles/pharmacology , Regression Analysis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/physiopathologyABSTRACT
BACKGROUND: Nitric oxide (NO) has been largely associated with cardiovascular protection through improvement of endothelial function. Recently, new evidence about modulation of NO release by microRNAs (miRs) has been reported, which could be involved with statin-dependent pleiotropic effects, including anti-inflammatory properties related to vascular endothelium function. OBJECTIVE: To evaluate the effects of cholesterol-lowering drugs including the inhibitors of cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs potentially involved in NO bioavailability. METHODS: Human umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin, simvastatin or ezetimibe (0 to 5.0 µM). Cells were submitted to total RNA extraction and relative quantification of NOS3 mRNA and miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by ozone-chemiluminescence. RESULTS: Both statins increased NO levels and NOS3 mRNA expression but no influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced only after the atorvastatin treatment. The magnitude of the reduction of miR-221 and miR-222 after treatment with statins correlated with the increment in NOS3 mRNA levels. No influence was observed on the miR-1303 expression after treatments. CONCLUSION: NO release in endothelial cells is increased by statins but not by the inhibitor of cholesterol absorption, ezetimibe. Our results provide new evidence about the participation of regulatory miRs 221/222 on NO release induction mediated by statins. Although ezetimibe did not modulate NO levels, the down-regulation of miR-221 could involve potential effects on endothelial function.
Subject(s)
Anticholesteremic Agents/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , MicroRNAs/metabolism , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/metabolism , Analysis of Variance , Atorvastatin , Azetidines/pharmacology , Cell Survival/drug effects , Cells, Cultured , Down-Regulation , Endothelium, Vascular/drug effects , Ezetimibe , Heptanoic Acids/pharmacology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Luminescence , Pyrroles/pharmacology , Real-Time Polymerase Chain Reaction , Simvastatin/pharmacologyABSTRACT
Oxidative stress [increased bioavailability of reactive oxygen species (ROS)] plays a role in the endothelial dysfunction and vascular inflammation, which underlie vascular damage in diabetes. Statins are cholesterol-lowering drugs that are vasoprotective in diabetes through unknown mechanisms. We tested the hypothesis that atorvastatin decreases NADPH oxidase (Nox)-derived ROS generation and associated vascular injury in diabetes. Lepr(db)/Lepr(db) (db/db) mice, a model of Type 2 diabetes and control Lepr(db)/Lepr(+) (db/+) mice were administered atorvastatin (10 mg/kg per day, 2 weeks). Atorvastatin improved glucose tolerance in db/db mice. Systemic and vascular oxidative stress in db/db mice, characterized by increased plasma TBARS (thiobarbituric acid-reactive substances) levels and exaggerated vascular Nox-derived ROS generation respectively, were inhibited by atorvastatin. Cytosol-to-membrane translocation of the Nox regulatory subunit p47(phox) and the small GTPase Rac1/2 was increased in vessels from db/db mice compared with db/+ mice, an effect blunted by atorvastatin. The increase in vascular Nox1/2/4 expression and increased phosphorylation of redox-sensitive mitogen-activated protein kinases (MAPKs) was abrogated by atorvastatin in db/db mice. Pro-inflammatory signalling (decreased IκB-α and increased NF-κB p50 expression, increased NF-κB p65 phosphorylation) and associated vascular inflammation [vascular cell adhesion molecule-1 (VCAM-1) expression and vascular monocyte adhesion], which were increased in aortas of db/db mice, were blunted by atorvastatin. Impaired acetylcholine (Ach)- and insulin (INS)-induced vasorelaxation in db/db mice was normalized by atorvastatin. Our results demonstrate that, in diabetic mice, atorvastatin decreases vascular oxidative stress and inflammation and ameliorates vascular injury through processes involving decreased activation of Rac1/2 and Nox. These findings elucidate redox-sensitive and Rac1/2-dependent mechanisms whereby statins protect against vascular injury in diabetes.
Subject(s)
Arteries/drug effects , Heptanoic Acids/pharmacology , NADPH Oxidases/metabolism , Pyrroles/pharmacology , rac GTP-Binding Proteins/metabolism , rac1 GTP-Binding Protein/metabolism , Acetylcholine/pharmacology , Animals , Arteries/metabolism , Arteries/physiopathology , Atorvastatin , Blotting, Western , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Insulin/pharmacology , Lipids/blood , Male , Mice, Mutant Strains , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Thiobarbituric Acid Reactive Substances/metabolism , Vasodilation/drug effects , Vasodilator Agents/pharmacology , RAC2 GTP-Binding ProteinABSTRACT
The aim of this study was to investigate the influence of atorvastatin on the opening of the mitochondrial permeability transition pore (MPTP) and the expression of cytochrome C (Cyt C) in Sprague-Dawley rats with cerebral ischemia-reperfusion (I/R). The rat model of cerebral artery ischemia was established by the suture-occluded method with ischemia for 2 h and reperfusion for 72 h. Thirty-four male rats were randomly divided into four groups: the normal group and the sham-operation group without any treatment, the I/R group with only intragastric administration of normal saline, and the intervention group, which received intragastric administration of 10 mg/kg atorvastatin at different times. All rats were sacrificed at 72 h. Compared with the I/R group, the morphology of nerve cells in the intervention group was reduced, the number of TUNEL-positive cells decreased, the expression of cortical cytoplasm Cyt C decreased, and the mitochondrial absorbance value increased. All of these differences were statistically significant. Atorvastatin could inhibit neuronal apoptosis and alleviate the cerebral I/R injury. The mechanism may be related to the blocking of the MPTP opening and the subsequent reduction of Cyt C release.
Subject(s)
Anticholesteremic Agents/pharmacology , Brain Ischemia/prevention & control , Heptanoic Acids/pharmacology , Infarction, Middle Cerebral Artery/prevention & control , Mitochondrial Membrane Transport Proteins/drug effects , Pyrroles/pharmacology , Reperfusion Injury/prevention & control , Animals , Apoptosis/drug effects , Atorvastatin , Brain Ischemia/metabolism , Cytochromes c/metabolism , Disease Models, Animal , Infarction, Middle Cerebral Artery/metabolism , Male , Mitochondrial Permeability Transition Pore , Rats, Sprague-Dawley , Reperfusion Injury/metabolismABSTRACT
Statins have a beneficial effect after myocardial infarction, but the relationship between glucose transporters and their use before the event has not yet been studied. We assessed the effects of atorvastatin treatment pre- and post-myocardial infarction on cardiovascular function and glucose transporter 4 (GLUT4) in the heart. Wistar-Kyoto rats were treated with 20 mg/kg atorvastatin or vehicle for 14 days before coronary artery occlusion surgery (myocardial infarction) or sham surgery. Echocardiographic evaluations were carried out 48 h after myocardial infarction (protocol A) and after 7 days (protocol B), when atorvastatin was also administered. Plasma inflammatory markers and GLUT4 in the heart were also evaluated. Animals were divided into the following groups: sham-operated and vehicle (C), myocardial infarction and vehicle (I), sham-operated and atorvastatin (CAt) and myocardial infarction and atorvastatin (IAt). After 48 h, myocardial infarction induced higher left ventricular fractional shortening in IAt versus I (~ 60%, P = 0.036), and the ejection fraction was lower (protocol A ~ 37%; protocol B ~ 30%). Myocardial infarction was associated with a rise in plasma membrane GLUT4 after 48 h (~ 40%, P < 0.001), and a reduction in GLUT4 after 7 days (I 25%; IAt 49%, P < 0.001). Atorvastatin treatment for 48 h after the infarction did not change GLUT4 expression, and after 7 days it had an additional negative effect on GLUT4 content (~ 39%, P = 0.030). In conclusion, atorvastatin treatment pre- and post-myocardial infarction improved myocardial contractility after 48 h, but not after 7 days, and was not associated with an increase in GLUT4 expression.
Subject(s)
Heart Ventricles/drug effects , Heptanoic Acids/pharmacology , Muscle Contraction/drug effects , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Pyrroles/pharmacology , Animals , Atorvastatin , Echocardiography/methods , Glucose Transporter Type 4/metabolism , Heart Ventricles/metabolism , Male , Myocardium/metabolism , Rats , Rats, Inbred WKY , Ventricular Remodeling/drug effectsABSTRACT
BACKGROUND: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. OBJECTIVE: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. METHODS: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. RESULTS: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). CONCLUSIONS: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.
Subject(s)
Anticholesteremic Agents/pharmacology , Heptanoic Acids/pharmacology , Hypercholesterolemia/drug therapy , Hypolipidemic Agents/pharmacology , Pyrroles/pharmacology , Sex Factors , Simvastatin/pharmacology , Adult , Aged , Aged, 80 and over , Anticholesteremic Agents/adverse effects , Atorvastatin , Brazil , Cholesterol/blood , Creatine Kinase/drug effects , Female , Heptanoic Acids/adverse effects , Humans , Hypercholesterolemia/blood , Hypolipidemic Agents/adverse effects , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Male , Middle Aged , Myalgia/etiology , Prospective Studies , Pyrroles/adverse effects , Simvastatin/adverse effectsABSTRACT
Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .
Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Anticholesteremic Agents/pharmacology , Heptanoic Acids/pharmacology , Hypercholesterolemia/drug therapy , Hypolipidemic Agents/pharmacology , Pyrroles/pharmacology , Sex Factors , Simvastatin/pharmacology , Anticholesteremic Agents/adverse effects , Brazil , Cholesterol/blood , Creatine Kinase/drug effects , Heptanoic Acids/adverse effects , Hypercholesterolemia/blood , Hypolipidemic Agents/adverse effects , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Myalgia/etiology , Prospective Studies , Pyrroles/adverse effects , Simvastatin/adverse effectsABSTRACT
INTRODUCTION: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. OBJECTIVE: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. MATERIALS AND METHODS: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. RESULTS: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. CONCLUSION: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.
Subject(s)
Corpus Striatum/drug effects , Dopaminergic Neurons/drug effects , GABAergic Neurons/drug effects , Heptanoic Acids/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Ischemic Attack, Transient/drug therapy , Neuroprotective Agents/therapeutic use , Pyrroles/therapeutic use , Substantia Nigra/drug effects , Animals , Atorvastatin , Behavior, Animal , Corpus Striatum/blood supply , Corpus Striatum/pathology , Dopaminergic Neurons/enzymology , Dopaminergic Neurons/pathology , Drug Evaluation, Preclinical , Enzyme Induction/drug effects , GABAergic Neurons/enzymology , GABAergic Neurons/pathology , Glutamate Decarboxylase/biosynthesis , Glutamate Decarboxylase/genetics , Heptanoic Acids/pharmacology , Infarction, Middle Cerebral Artery/pathology , Ischemic Attack, Transient/pathology , Male , Movement Disorders/etiology , Movement Disorders/prevention & control , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuroprotective Agents/pharmacology , Pyrroles/pharmacology , Rats , Rats, Wistar , Recovery of Function , Sensation Disorders/etiology , Sensation Disorders/prevention & control , Specific Pathogen-Free Organisms , Substantia Nigra/blood supply , Substantia Nigra/pathology , Tyrosine 3-Monooxygenase/biosynthesis , Tyrosine 3-Monooxygenase/geneticsABSTRACT
Statins are potent cholesterol biosynthesis inhibitors that exert protective effects in humans and in experimental models of stroke. The mechanisms involved in these protective actions are not completely understood. This study evaluates whether atorvastatin (ATV) treatment affects the GluN1 and GluN2B subunits of the N-methyl-D-aspartic acid receptor in the somatosensory cerebral cortex at short and long periods following ischemia. Sham and ischemic male Wistar rats received 10 mg/kg of ATV or placebo by gavage every 24 hr for 3 consecutive days. The first dose was administered 6 hr after ischemia-reperfusion or the sham operation. ATV treatment resulted in faster recovery of neurological scores than placebo, prevented the appearance of pyknotic neurons, and restored microtubule-associated protein 2 and neuronal nuclei staining to control values in the somatosensory cerebral cortex and the hippocampus at 72 hr and 15 days postischemia. Furthermore, ATV prevented spatial learning and memory deficits caused by cerebral ischemia. Cerebral ischemia reduced the number of GluN1/PSD-95 and GluN2B/PSD-95 colocalization clusters in cortical pyramidal neurons and reduced the levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. These effects of the ischemic insult were prevented by ATV, which also induced GluN2B/PSD-95 colocalization in neuronal processes and an association of GluN2B with TrkB. The GluN2B pharmacological inhibitor ifenprodil prevented the increase in BDNF levels and the motor and cognitive function recovery caused by ATV in ischemic rats. These findings indicate that GluN2B is involved in the neuroprotective mechanism elicited by ATV to promote motor and cognitive recovery after focal cerebral ischemia.
Subject(s)
Anticholesteremic Agents/therapeutic use , Brain Ischemia/drug therapy , Heptanoic Acids/therapeutic use , Pyrroles/therapeutic use , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Anticholesteremic Agents/pharmacology , Atorvastatin , Brain Ischemia/complications , Brain Ischemia/pathology , Cells, Cultured , Cerebral Cortex/cytology , Disease Models, Animal , Embryo, Mammalian , Heptanoic Acids/pharmacology , Male , Maze Learning , Nerve Tissue Proteins/metabolism , Nervous System Diseases/drug therapy , Nervous System Diseases/etiology , Piperidines/pharmacology , Piperidines/therapeutic use , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Pyrroles/pharmacology , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/genetics , Recovery of Function/drug effects , Somatosensory Cortex/drug effects , Time FactorsABSTRACT
Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.
Introducción. La isquemia cerebral es la tercera causa de muerte y la primera de discapacidad permanente en el mundo. La atorvastatina es un fármaco neuroprotector prometedor para el tratamiento de la apoplejía; sin embargo, su acción sobre las poblaciones neuronales del sistema nigroestriatal después de la isquemia aún se desconoce. Objetivo. Evaluar el efecto de la atorvastatina sobre poblaciones gabérgicas y dopaminérgicas en regiones exofocales en un modelo de oclusión transitoria de la arteria cerebral media. Materiales y métodos. Se utilizaron 28 ratas Wistar macho de ocho semanas de edad. Los ejemplares con isquemia simulada y los ejemplares sometidos a isquemia fueron tratados con atorvastatina (10 mg/kg) y carboximetilcelulosa (placebo) administrados por medio de sonda a las 6, 24, 48 y 72 horas después de la reperfusión. Se analizó la inmunorreacción de la descarboxilasa del ácido glutámico y de la tirosina hidroxilasa en el globo pálido, el putamen caudado y la sustancia negra. Resultados. Los datos confirmaron el daño neurológico y la pérdida celular en el putamen caudado. Se incrementó la inmunorreacción de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata , disminuyendo la inmunorreacción de la descarboxilasa del ácido glutámico en el globo pálido lateral de los animales isquémicos tratados con placebo; sin embargo, el tratamiento con atorvastatina pudo revertirla, lo que logró una disminución significativa de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata y aumentando los niveles de descarboxilasa del ácido glutámico en el globo pálido lateral. Conclusión. Nuestros datos sugieren que la atorvastatina en el tratamiento posterior a la isquemia ejerce neuroprotección en las zonas exofocales, modulando las poblaciones neuronales gabérgicas y dopaminérgicas del sistema nigroestriatal, lo que podría prevenir trastornos neurológicos.
Subject(s)
Animals , Male , Rats , Corpus Striatum/drug effects , Dopaminergic Neurons/drug effects , GABAergic Neurons/drug effects , Heptanoic Acids/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Ischemic Attack, Transient/drug therapy , Neuroprotective Agents/therapeutic use , Pyrroles/therapeutic use , Substantia Nigra/drug effects , Behavior, Animal , Corpus Striatum/blood supply , Corpus Striatum/pathology , Drug Evaluation, Preclinical , Dopaminergic Neurons/enzymology , Dopaminergic Neurons/pathology , Enzyme Induction/drug effects , GABAergic Neurons/enzymology , GABAergic Neurons/pathology , Glutamate Decarboxylase/biosynthesis , Glutamate Decarboxylase/genetics , Heptanoic Acids/pharmacology , Infarction, Middle Cerebral Artery/pathology , Ischemic Attack, Transient/pathology , Movement Disorders/etiology , Movement Disorders/prevention & control , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuroprotective Agents/pharmacology , Pyrroles/pharmacology , Rats, Wistar , Recovery of Function , Specific Pathogen-Free Organisms , Sensation Disorders/etiology , Sensation Disorders/prevention & control , Substantia Nigra/blood supply , Substantia Nigra/pathology , /biosynthesis , /geneticsABSTRACT
Imbalance on endothelial turnover can predict cardiovascular outcomes. We aimed at evaluating the effects of lipid-modifying therapies on circulating endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and platelet microparticles (PMPs) in high cardiovascular risk subjects with elevated C-reactive protein (CRP). Sixty-three individuals with coronary heart disease (CHD) or CHD risk equivalent on stable statin therapy, with LDL-cholesterol <100 mg/dL and CRP ≥ 2.0 mg/L were selected. After a 4-week run-in period with atorvastatin 10 mg, those with persistent CRP ≥ 2.0 mg/L were randomized to another 4-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or atorvastatin 40 mg/ezetimibe 10 mg. EPC (CD34(+)/CD133(+)/KDR(+)), EMP (CD51(+)), and PMP (CD42(+)/CD31(+)) were quantified by flow cytometry. Atorvastatin 40 mg and atorvastatin 40 mg/ezetimibe 10 mg reduced LDL-cholesterol (P < 0.001, paired T test, vs. baseline). Combined therapy, but not ezetimibe reduced CRP. CD34(+)/KDR(+) EPC were reduced after ezetimibe alone (P = 0.011 vs. baseline, Wilcoxon test) or combined with atorvastatin (P = 0.016 vs. baseline, Wilcoxon test). In addition, ezetimibe increased CD51(+) EMP (P = 0.017 vs. baseline, Wilcoxon test). No correlations between these markers and LDL-cholesterol or CRP were observed. These results contribute to understand the link between inflammation and vascular homeostasis and highlight the broader benefit of statins decreasing inflammation and preventing microparticles release, an effect not observed with ezetimibe alone.
Subject(s)
Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Cell-Derived Microparticles/drug effects , Endothelial Progenitor Cells/drug effects , Aged , Atorvastatin , Biomarkers/blood , Blood Platelets/cytology , C-Reactive Protein/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Cell-Derived Microparticles/metabolism , Cholesterol, LDL/blood , Drug Interactions , Endothelial Progenitor Cells/metabolism , Ezetimibe , Heptanoic Acids/pharmacology , Humans , Middle Aged , Pyrroles/pharmacology , RiskABSTRACT
The objective of this study was to evaluate whether levels of high mobility group box 1 (HMGB1) in granulomatosis with polyangiitis (GPA) patients are associated with carotid atherosclerosis, related to levels of soluble receptor for advanced glycation end-products (sRAGE) and influenced by immunosuppressive or lipid-lowering therapy. Twenty-three GPA patients and 20 controls were evaluated for HMGB1- and sRAGE levels and for carotid atherosclerosis using ultrasound to determine intima-media thickness (IMT). In vitro the effect of atorvastatin on the production of HMGB1 by lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVEC) was assessed. Serum HMGB1 and sRAGE levels did not differ between patients and controls. A negative correlation was found between sRAGE and maximum IMT but HMGB1 and carotid IMT were not related. HMGB1 levels were reduced in GPA patients on statins and prednisolone. In vitro, atorvastatin reduced HMGB1 levels in supernatants of activated HUVEC. In conclusion, carotid IMT is inversely correlated with sRAGE levels but not with HMGB1 levels. Statins and prednisolone are associated with reduced serum HMGB1 levels and atorvastatin decreases HMGB1 release by activated HUVEC in vitro, indicating an additional anti-inflammatory effect of statins.
Subject(s)
Atherosclerosis/blood , Atherosclerosis/complications , Granulomatosis with Polyangiitis/complications , HMGB1 Protein/blood , Receptors, Immunologic/blood , Receptors, Immunologic/chemistry , Atherosclerosis/drug therapy , Atorvastatin , Female , Heptanoic Acids/pharmacology , Heptanoic Acids/therapeutic use , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Prednisolone/pharmacology , Prednisolone/therapeutic use , Pyrroles/pharmacology , Pyrroles/therapeutic use , Receptor for Advanced Glycation End Products , SolubilityABSTRACT
Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake inhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in the hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5-HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation.
Subject(s)
Antidepressive Agents/therapeutic use , Brain/metabolism , Depression/drug therapy , Depression/metabolism , Heptanoic Acids/therapeutic use , Pyrroles/therapeutic use , Serotonin/metabolism , Animals , Antidepressive Agents/pharmacology , Atorvastatin , Brain/drug effects , Heptanoic Acids/pharmacology , Male , Mice , Pyrroles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Treatment OutcomeABSTRACT
Our aim was to investigate the effects of four different statins on acute lung inflammation induced by cigarette smoke (CS). C57BL/6 male mice were divided into a control group (sham-smoked) and mice exposed to CS from 12 cigarettes/day for 5 days. Mice exposed to CS were grouped and treated with vehicle (i.p.), atorvastatin (10 mg/kg), pravastatin (10 mg/kg), rosuvastatin (5 mg/kg), or simvastatin (20 mg/kg). Treatment with statins differentially improved the pulmonary response when compared to the CS group. Atorvastatin and pravastatin demonstrated slightly effects on inflammation and oxidative stress. Rosuvastatin demonstrated the best anti-inflammatory effect, whereas simvastatin demonstrated the best antioxidant response.
Subject(s)
Fluorobenzenes/pharmacology , Heptanoic Acids/pharmacology , Lung/metabolism , Oxidative Stress/physiology , Pravastatin/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Simvastatin/pharmacology , Smoking/metabolism , Sulfonamides/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Atorvastatin , Fluorobenzenes/therapeutic use , Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Inhalation Exposure/adverse effects , Lung/drug effects , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Pravastatin/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Rosuvastatin Calcium , Simvastatin/therapeutic use , Smoking/drug therapy , Smoking/pathology , Sulfonamides/therapeutic useABSTRACT
Nitric oxide (NO)-derived metabolites including the anion nitrite can recycle back to NO and thus complement NO formation independent of NO synthases. While nitrite is as a major vascular storage pool and source of NO, little is known about drugs that increase tissue nitrite concentrations. This study examined the effects of atorvastatin or sildenafil, or the combination, on vascular nitrite concentrations and on endothelial dysfunction in the 2 kidney-1 clip (2K1C) hypertension model. Sham-operated or 2K1C hypertensive rats were treated with vehicle, atorvastatin (50 mg/Kg), sildenafil (45 mg/Kg), or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Nitrite concentrations were assessed in the aortas and in plasma samples by ozone-based reductive chemiluminescence assay. Aortic rings were isolated to assess endothelium-dependent and independent relaxation. Aortic NADPH activity and ROS production were evaluated by luminescence and dihydroethidium, respectively, and plasma TBARS levels were measured. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. Atorvastatin and sildenafil, alone or combined, significantly lowered SBP by approximately 40 mmHg. Atorvastatin significantly increased vascular nitrite levels by 70% in hypertensive rats, whereas sildenafil had no effects. Both drugs significantly improved the vascular function, and decreased vascular NADPH activity, ROS, and nitrotyrosine levels. Lower plasma TBARS concentrations were found with both treatments. The combination of drugs showed no improved responses compared to each drug alone. These findings show evidence that atorvastatin, but not sildenafil, increases vascular NO stores, although both drugs exert antioxidant effects, improve endothelial function, and lower blood pressure in 2K1C hypertension.
Subject(s)
Heptanoic Acids/administration & dosage , Hypertension, Renovascular/drug therapy , Hypertension, Renovascular/pathology , Nitric Oxide/blood , Piperazines/administration & dosage , Pyrroles/administration & dosage , Sulfonamides/administration & dosage , Animals , Aorta/metabolism , Aorta/pathology , Atorvastatin , Blood Pressure/drug effects , Body Weight/drug effects , Disease Models, Animal , Drug Therapy, Combination , Heptanoic Acids/pharmacology , Male , Nitric Oxide/metabolism , Piperazines/pharmacology , Purines/administration & dosage , Purines/pharmacology , Pyrroles/pharmacology , Rats , Rats, Wistar , Sildenafil Citrate , Sulfonamides/pharmacologyABSTRACT
The studies on hormone replacement therapy (HRT) in females with estrogen deficiency are not conclusive. Thus, non-estrogen therapies, such as atorvastatin (ATO), could be new strategies to substitute or complement HRT. This study evaluated the effects of ATO on mesenteric vascular bed (MVB) function from ovariectomized (OVX) female rats. Female rats were divided into control SHAM, OVX, and OVX treated with 17ß-estradiol (EST) or ATO groups. The MVB reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine staining, and the expression of target proteins by western blot. The reduction in acetylcholine-induced relaxation in OVX rats was restored by ATO or EST treatment. The endothelium-dependent nitric oxide (NO) component was reduced in OVX rats, whereas the endothelium-derived hyperpolarizing factor (EDHF) component or prostanoids were not altered in the MVBs. Endothelial dysfunction in OVX rats was associated with oxidative stress, an up-regulation of iNOS and NADPH oxidase expression and a down-regulation of eNOS expression. Treatment with ATO or EST improved the NO component of the relaxation and normalized oxidative stress and the expression of those signaling pathways enzymes. Thus, the protective effect of ATO on endothelial dysfunction caused by estrogen deficiency highlights a significant therapeutic benefit for statins independent of its effects on cholesterol, thus providing evidence that non-estrogen therapy could be used for cardiovascular benefit in an estrogen-deficient state, such as menopause.