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1.
Environ Health ; 19(1): 102, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958007

RESUMO

BACKGROUND: Residents in a large area of North-Eastern Italy were exposed to perfluoroalkyl substances (PFAS) via drinking water. Studies on the association between PFAS and blood pressure levels are limited, and results are inconsistent. Using cross-sectional data from the Regional health surveillance program, we aimed to quantify the associations between PFAS serum concentrations and blood pressure and hypertension prevalence. METHODS: The study comprised 16,224 individuals aged 20-39 years. Pregnant women (n = 327), or individuals with missing information on the selected covariates (n = 111) were excluded, leaving 15,786 subjects for the analyses. Hypertension was defined as any self-reported diagnosis, use of antihypertensive drugs, or elevated systolic blood pressure (SBP ≥ 140 mmHg)/diastolic blood pressure (DBP ≥ 90 mmHg). Generalized additive models were used to investigate the relation between perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)) natural log (ln) transformed and by decile, and SBP, DBP, hypertension, adjusted for potential confounders. RESULTS: Both SBP and DBP increased significantly with an increase in the ln-transformed serum PFAS concentrations in a monotonic way. The predicted increase in SBP and DBP were 1.54 mmHg (95%CI 0.61-2.47), 1.60 mmHg (95%CI 0.92-2.27) from lowest to highest decile of PFOA. The associations were stronger for SBP in men and for DBP in women. One unit increase in each In-transformed PFAS was positively associated with an increased odd of hypertension in men: PFOA OR = 1.06 (1.01-1.11), PFOS OR = 1.13 (1.03-1.23), PFHxS OR = 1.08 (1.02-1.15), PFNA OR = 1.20 (1.02-1.40). CONCLUSIONS: Our findings suggest that serum PFAS concentrations were associated with increased systolic and diastolic blood pressure in a large highly exposed young adult population. Although the magnitude of the observed effect was relatively small, if confirmed it would be of public health relevance since even small increases in blood pressure levels at the population level may be associated to a raised risk of adverse outcomes such as cardiovascular disease and target organ damage.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Poluentes Ambientais/sangue , Fluorcarbonetos/sangue , Hipertensão/epidemiologia , Adulto , Estudos Transversais , Água Potável/química , Feminino , Humanos , Hipertensão/induzido quimicamente , Itália/epidemiologia , Masculino , Prevalência , Adulto Jovem
2.
Ecotoxicol Environ Saf ; 203: 111044, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888613

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.


Assuntos
Poluentes Atmosféricos/toxicidade , Angiotensina I/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Material Particulado/toxicidade , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Acetilglucosaminidase/urina , Angiotensina I/sangue , Animais , Biomarcadores/sangue , Biomarcadores/urina , Hipertensão/urina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , beta-Galactosidase/urina
4.
Am J Physiol Renal Physiol ; 319(4): F647-F653, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799674

RESUMO

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.


Assuntos
Pressão Sanguínea , Ciclo-Oxigenase 2/metabolismo , Acetato de Desoxicorticosterona , Hipertensão/enzimologia , Rim/enzimologia , Receptores de Superfície Celular/metabolismo , Cloreto de Sódio na Dieta , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/enzimologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Proteinúria/induzido quimicamente , Proteinúria/enzimologia , Proteinúria/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais
5.
Toxicol Lett ; 333: 80-89, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738273

RESUMO

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin-angiotensin system and COX2 pathway activation.


Assuntos
Cloreto de Cádmio/toxicidade , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hipertensão/induzido quimicamente , NADPH Oxidases/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Cádmio/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Poluentes Ambientais/sangue , Hipertensão/enzimologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Injeções Intraperitoneais , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos
6.
N Engl J Med ; 383(9): 813-824, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32846060

RESUMO

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão/induzido quimicamente , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-ret/análise , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Transaminases/sangue , Resultado do Tratamento , Adulto Jovem
7.
J Cardiovasc Magn Reson ; 22(1): 57, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32758255

RESUMO

BACKGROUND: Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure. METHODS: We performed a longitudinal study with serial cardiovascular magnetic resonance (CMR) imaging every 2 weeks in mice (n = 31) subjected to angiotensin II-induced hypertension for 6 weeks and investigated reverse remodelling following normalisation of afterload beyond 6 weeks (n = 9). Left ventricular (LV) volumes, mass, and function as well as myocardial fibrosis were measured using cine CMR and the extracellular volume fraction (ECV) s. RESULTS: Increased blood pressure (65 ± 12 vs 85 ± 9 mmHg; p < 0.001) resulted in higher indices of LV hypertrophy (0.09 [0.08, 0.10] vs 0.12 [0.11, 0.14] g; p < 0.001) and myocardial fibrosis (ECV: 0.24 ± 0.03 vs 0.30 ± 0.02; p < 0.001) whilst LV ejection fraction fell (LVEF, 59.3 [57.6, 59.9] vs 46.9 [38.5, 49.6] %; p < 0.001). We found a strong correlation between ECV and histological myocardial fibrosis (r = 0.89, p < 0.001). Following cessation of angiotensin II and normalisation of blood pressure (69 ± 5 vs baseline 65 ± 12 mmHg; p = 0.42), LV mass (0.11 [0.10, 0.12] vs 0.09 [0.08, 0.11] g), ECV (0.30 ± 0.02 vs 0.27 ± 0.02) and LVEF (51.1 [42.9, 52.8] vs 59.3 [57.6, 59.9] %) improved but remained impaired compared to baseline (p < 0.05 for all). There was a strong inverse correlation between LVEF and %ECV during both systemic hypertension (r = - 0.88, p < 0.001) and the increases in ECV observed in the first two weeks of increased blood pressure predicted the reduction in LVEF after 6 weeks (r = - 0.77, p < 0.001). CONCLUSIONS: We have established and characterized angiotensin II infusion and repeated CMR imaging as a model of LV hypertrophy and reverse remodelling in response to systemic hypertension. Changes in myocardial fibrosis and alterations in cardiac function are only partially reversible following relief of hypertension.


Assuntos
Pressão Sanguínea , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Angiotensina II , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo
8.
N Engl J Med ; 383(9): 825-835, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32846061

RESUMO

BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).


Assuntos
Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão/induzido quimicamente , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-ret/análise , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Transaminases/sangue , Resultado do Tratamento , Adulto Jovem
9.
Arch Gynecol Obstet ; 302(4): 829-836, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32588134

RESUMO

OBJECTIVE: To investigate the efficacy and safety of prophylactic infusion of norepinephrine (NE) versus normal saline in patients undergoing cesarean section. METHODS: Patients (n = 97) were randomized to receive a bolus of NE (6 µg) immediately following spinal anesthesia with maintenance NE (0.05 µg/kg/min IV) or normal saline (n = 98). The primary endpoint was the incidence of postspinal anesthesia hypotension [systolic blood pressure (SBP) < 80% of baseline] at 1-20 min following spinal anesthesia. Secondary outcomes were the overall stability of SBP control versus baseline, inferior vena cava collapsibility index (IVC-CI), other adverse events (bradycardia, nausea, vomiting, and hypertension), and neonatal outcomes (blood gas values and Apgar scores). RESULTS: The rates of postspinal anesthesia hypotension and severe postspinal anesthesia hypotension (SBP < 60% of the baseline) were significantly lower in the NE group (17.5% vs. 62.2%, p < 0.001; 7.2% vs. 17.4%, p = 0.031). In the NE group, SBP remained more stable and closer to baseline (p < 0.001), and IVC-CI values were lower 5 min after spinal anesthesia and 5 min after fetal delivery (p = 0.045; p < 0.001, respectively). Other adverse effects and neonatal outcomes were not different between the two groups. CONCLUSION: Prophylactic NE infusion effectively lowers the incidence of postspinal anesthesia hypotension and does not increase other adverse events in patients or neonates.


Assuntos
Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Cesárea/efeitos adversos , Hipotensão/prevenção & controle , Infusões Parenterais/efeitos adversos , Norepinefrina/administração & dosagem , Profilaxia Pré-Exposição/métodos , Vasoconstritores/administração & dosagem , Adulto , Anestesia Obstétrica/métodos , Raquianestesia/métodos , Pressão Sanguínea , Bradicardia/induzido quimicamente , Bradicardia/epidemiologia , Cesárea/métodos , China/epidemiologia , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/complicações , Hipotensão/epidemiologia , Recém-Nascido , Infusões Parenterais/métodos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/epidemiologia , Norepinefrina/efeitos adversos , Gravidez , Resultado do Tratamento , Vasoconstritores/efeitos adversos , Vômito/induzido quimicamente , Vômito/epidemiologia , Adulto Jovem
10.
Cardiovasc Drugs Ther ; 34(5): 605-618, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32564303

RESUMO

OBJECTIVE: We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. METHODS: Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. RESULTS: In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. CONCLUSIONS: Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.


Assuntos
Compostos Alílicos/farmacologia , Hipertensão/tratamento farmacológico , Mitocôndrias Musculares/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Sulfetos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Angiotensina II , Animais , Movimento Celular/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Fenótipo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo
11.
Kardiologiia ; 60(5): 1069, 2020 Jun 02.
Artigo em Russo | MEDLINE | ID: mdl-32515702

RESUMO

Aim To evaluate dynamics of biomarkers for endothelial dysfunction (ED), including endothelin-1 (ET-1) and von Willebrand factor (VWF) in patients with stomach cancer (adenocarcinoma) before and after polychemotherapy (PCT); to compare these results with respective values in healthy volunteers and patients with cardiovascular diseases (CVD); to study correlations of the ED biomarkers with indexes of instrumental evaluation of endothelial dysfunction.Material and methods The study included 75 participants, including 25 healthy volunteers (control group), 25 patients with documented CVDs (arterial hypertension + ischemic heart disease), and 25 patients of the main group with histologically documented stage II-IV stomach cancer (adenocarcinoma) who received different courses of PCT with platinum-based agents (oxaliplatin, cisplatin) and fluoropyrimidines (5 fluorouracil, capecitabin). Laboratory measurement of ED biomarkers, computerized nailfold video capillaroscopy (CNVC), and finger laser photoplethysmography (PPG) (methods for noninvasive evaluation of vascular wall and ED), electrocardiography, 24-h ECG Holter monitoring, and echocardiography (EchoCG) were performed for all patients of the main group prior to PCT and within one months after the last course completion. This evaluation was performed once for healthy volunteers and patients of the CVD group upon inclusion into the study.Results In the main group, ET-1 levels were non-significantly lower than normal and did not change during the courses of antitumor treatment (0.95 [0.6; 1.4] and 0.94 [0.7; 1.4] pg /ml (р<0.9) before and after PCT, respectively). Statistically significant differences were found between the control group and oncological patients after the treatment (р<0.04). Levels of VWF remained within the normal range in all examined participants and did not significantly differ between study groups, including oncological patients before and after the specific treatment (р>0.05 for all comparisons). The correlation analysis detected significant correlations of ET-1 levels with functional disorders of microcirculation, ET-1 with the occlusion index (rs=0.56; p=0.005), ЕТ-1 with percentage of capillary restoration (PCR, rs= -0.72; p=0.018) and with the incidence rate of supraventricular extrasystole (rs=0.48; p=0.032).Conclusion The dynamics of ED biomarkers was studied for the first time in patients with stomach cancer receiving a specific antitumor therapy. Although no significant changes in ЕТ-1 and VWF were observed during the PCT (probably due to exhaustion of the endothelial system and a small patient sample), these indexes can be considered as early vasculotoxicity markers due to the presence of significant correlations with indexes of impaired endothelial function according to the results of instrumental evaluation.


Assuntos
Hipertensão , Neoplasias Gástricas , Biomarcadores , Ecocardiografia , Humanos , Hipertensão/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico
12.
CMAJ ; 192(12): E295-E301, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32392512

RESUMO

BACKGROUND: Only a few population-based studies have examined the association between glucocorticoids and hypertension, with inconsistent results. We aimed to investigate the effect of oral glucocorticoids on incidence of hypertension in adults with chronic inflammatory diseases. METHODS: We analyzed electronic health records from 389 practices in England during 1998-2017 of adults diagnosed with any of 6 chronic inflammatory diseases but with no previous diagnosis of hypertension. We used glucocorticoid prescription data to construct time-variant daily and cumulative variables of prednisolone-equivalent dose (cumulated from 1 year before the start of follow-up) and estimated incidence rates and adjusted hazard ratios (HRs) for hypertension using Cox regression analysis. RESULTS: Among 71 642 patients in the cohort, 24 896 (34.8%) developed hypertension during a median follow-up of 6.6 years. The incidence rate of hypertension was 46.7 (95% confidence interval [CI] 46.0-47.3) per 1000 person-years. Incidence rates increased with higher cumulative glucocorticoid prednisolone-equivalent dose, from 44.4 per 1000 person-years in periods of nonuse to 45.3 per 1000 person-years for periods with between > 0.0 and 959.9 mg (HR 1.14, 95% CI 1.09-1.19), to 49.3 per 1000 person-years for periods with 960-3054.9 mg (HR 1.20, 95% CI 1.14-1.27), and to 55.6 per 1000 person-years for periods with ≥ 3055 mg (HR 1.30, 95% CI 1.25-1.35). Cumulative effects were seen for the 6 diseases studied, but dose-response effects were not found for daily dose. INTERPRETATION: Cumulative dose of oral glucocorticoids was associated with increased incidence of hypertension, suggesting that blood pressure should be monitored closely in patients routinely treated with these drugs. Given that glucocorticoids are widely prescribed, the associated health burden could be high. Trial registration: ClinicalTrials. gov, no. NCT03760562.


Assuntos
Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Hipertensão/epidemiologia , Inflamação/tratamento farmacológico , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Administração Oral , Esquema de Medicação , Registros Eletrônicos de Saúde , Inglaterra/epidemiologia , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hipertensão/induzido quimicamente , Incidência , Masculino , Pessoa de Meia-Idade , Vigilância da População , Prednisolona/administração & dosagem , Estudos Retrospectivos
13.
Clin Exp Hypertens ; 42(6): 571-579, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32423257

RESUMO

PURPOSE:  Vehicle exhaust emissions primarily comprise of nitrogen, oxygen, water, CO2, NO2, CO, hydrocarbons and particulate matter. While adverse effects of hydrocarbon and particulate matter on cardiovascular functions are known, the effect of pro-oxidants CO2, NO2 and CO are not clear. METHODS:  Here, using an animal model of a simulated mixture of pro-oxidants (0.04% CO2, 0.9 ppm NO2 and 3 ppm CO with air as a base), we examined the effect of simulated vehicle exhaust exposure (SVEE) on various cardiovascular parameters. Male Sprague-Dawley rats were exposed to SVEE or ambient air (Control: CON) for 30 min/day for 2 weeks. Thereafter, systolic and diastolic blood pressure, heart rate and glomerular filtration rate were measured. Later, rats were sacrificed, blood plasma and kidneys were collected. RESULTS:  The systolic and diastolic blood pressure, heart rate and glomerular filtration rate remained unchanged. Plasma corticosterone increased in SVEE rats when compared to CON group. Plasma 8-isoprostane, a systemic marker of oxidative stress, increased while total antioxidant capacity decreased in SVEE but not in CON. Kidney cortical tissue homogenates exhibited increase in superoxide, hydrogen peroxide and protein carbonylation in SVEE but not CON, all indicative of heightened oxidative stress. Renal cortical mitochondrial SOD activity was significantly reduced in SVEE than CON. CONCLUSION:  Significant decline in mitochondrial respiration and oxygen consumption was observed, in addition to low ATP, reduced ATP synthase and cytochrome C oxidase levels, as well as accelerated mitochondrial fission, and reduced fusion processes, were observed in SVEE than CON rats, all indicative of renal mitochondrial impairment.


Assuntos
Hipertensão , Mitocôndrias , Dinâmica Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/efeitos adversos , Emissões de Veículos/toxicidade , Animais , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Exposição por Inalação/efeitos adversos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico Sintase/análise , Estresse Oxidativo , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxidos/análise
14.
J Cardiovasc Transl Res ; 13(3): 463-477, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32430701

RESUMO

Angiogenesis inhibitors, also known as vascular endothelial growth factor (VEGF) or vascular signaling pathway (VSP) inhibitors, have improved care of neoplastic diseases over the past decade. However, cardiovascular toxicities associated with these agents, such as hypertension and less commonly left ventricular systolic dysfunction and heart failure, have often been a limiting factor for continued use. Balancing the benefits of these agents with the associated toxicities is critical to ensure these therapies do not negatively impact oncological outcomes. The care of cancer patients with cardiovascular risks is challenging due to the heterogeneity of cardiovascular complications, paucity of evidence-based guidelines, and lack of channels for collaboration among healthcare providers. Herein, we provide a team-based approach for treatment of angiogenesis inhibitor-induced hypertension along with recommendations on monitoring and appropriate selection of anti-hypertensive agents.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sobreviventes de Câncer , Hipertensão/tratamento farmacológico , Neoplasias/tratamento farmacológico , Equipe de Assistência ao Paciente , Anti-Hipertensivos/efeitos adversos , Tomada de Decisão Clínica , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Seleção de Pacientes , Resultado do Tratamento
15.
J Ayub Med Coll Abbottabad ; 32(1): 152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468778

RESUMO

Eleven months old female patient presented to paediatric out patient with parents concerned about her facial swelling. Upon examination child's weight and height for age were normal on her percentiles, she had a cushingoid facies with plethoric cheeks (Figure-1,2) though generalized oedema was absent and there was centripetal obesity with some muscle wasting (Figure-3,4). Systemic examination was normal excluding blood pressure which was high for her age. Electrolytes and cortisol levels were normal. On further inquiry it was revealed that she had been using a nappy rash cream containing a potent steroid, i.e., fluticasone for 2 months and this was identified as a cause for her cushingoid features.


Assuntos
Síndrome de Cushing/induzido quimicamente , Hipertensão/induzido quimicamente , Creme para a Pele/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Dermatite das Fraldas/tratamento farmacológico , Feminino , Fluticasona/efeitos adversos , Fluticasona/uso terapêutico , Humanos , Doença Iatrogênica , Lactente , Pomadas/efeitos adversos , Pomadas/química , Pomadas/uso terapêutico , Creme para a Pele/química , Creme para a Pele/uso terapêutico
16.
Am J Physiol Renal Physiol ; 318(6): F1400-F1408, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308022

RESUMO

In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT1Rs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2X1R and P2X7R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT1R influence. To evaluate the interactions between P2XRs and AT1Rs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2X1Ri (NF4490; 1 µM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2X1Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT1Ri (SML1394; 1 µM) increased AAD by 10 ± 7%. In contrast, treatment with P2X1Ri increased AAD by 21 ± 14%; combination with P2X1Ri plus P2X7Ri (A438079; 1 µM) increased AAD further by 25 ± 8%. The results indicate that P2X1R, P2X7R, and AT1R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT1Rs on AAR in ANG II-dependent hypertension.


Assuntos
Arteríolas/metabolismo , Pressão Sanguínea , Hipertensão/metabolismo , Rim/irrigação sanguínea , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Purinérgicos P2X1/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Angiotensina II , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores Purinérgicos P2X1/efeitos dos fármacos , Receptores Purinérgicos P2X7/efeitos dos fármacos , Transdução de Sinais
17.
PLoS One ; 15(4): e0231472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298299

RESUMO

Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.


Assuntos
Acetofenonas/farmacocinética , Lesão Renal Aguda/induzido quimicamente , Catalase/farmacologia , Ciclosporina/toxicidade , Hipertensão/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Animais , Hemodinâmica/efeitos dos fármacos , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , NADPH Oxidase 4/metabolismo , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos WKY
18.
Medicine (Baltimore) ; 99(15): e19781, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282741

RESUMO

INTRODUCTION: Surgical stress and pain are potential provoking factors for postoperative myasthenic crisis (POMC). We report the occurrence of early POMC and late deep vein thrombosis (DVT) in a man with myasthenia gravis (MG) undergoing thymectomy, addressing possible link between reversal of opioid overdose with naloxone and the triggering of POMC. PATIENT CONCERNS: A 71-year-old man with impaired renal function (ie, estimated glomerular filtration rate [egfr]: 49.1 mL/min/1.73 m) with diagnosis of MG made 2 months ago was scheduled for thymectomy. After uncomplicated surgery, he experienced opioid overdose that was treated with naloxone. Hyperlactatemia then developed with a concomitant episode of hypertension. Three hours after reversal, he suffered from myasthenic crisis presenting with respiratory failure and difficult weaning from mechanical ventilation. DIAGNOSIS: Stress-induced hyperlactatemia and subsequent myasthenic crisis INTERVENTIONS:: Pyridostigmine and immunosuppressive therapy with prednisolone were initiated. Hyperlactatemia subsided on postoperative day (POD) 5. Tracheal extubation was performed successfully on POD 6. OUTCOMES: During the course of hospitalization, his eGFR (ie, 88.9 mL/min/1.73 m) was found to improve postoperatively. After discharge from hospital, he developed DVT in the left femoral and popliteal veins on POD 24 when he was readmitted for immediate treatment with low-molecular-weight heparin. He was discharged without sequelae on POD 31. There was no recurrence of myasthenic crisis or DVT at 3-month follow-up. CONCLUSIONS: Following naloxone administration, hyperlactatemia may be an indicator of pain-related stress response, which is a potential provoking factor for myasthenic crisis. Additionally, patients with MG may have an increased risk of DVT possibly attributable to immune-mediated inflammation. These findings highlight the importance of perioperative avoidance of provoking factors including monitoring of stress-induced elevations in serum lactate concentration, close postoperative surveying for myasthenic crisis, and early recognition of possible thromboembolic complications in this patient population.


Assuntos
Miastenia Gravis/complicações , Timectomia/efeitos adversos , Trombose Venosa/etiologia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/uso terapêutico , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Hiperlactatemia/induzido quimicamente , Hiperlactatemia/diagnóstico , Hiperlactatemia/tratamento farmacológico , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Miastenia Gravis/diagnóstico , Miastenia Gravis/cirurgia , Naloxona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Readmissão do Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Brometo de Piridostigmina/administração & dosagem , Brometo de Piridostigmina/uso terapêutico , Respiração Artificial/métodos , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Resultado do Tratamento
19.
Eur J Cancer ; 129: 107-116, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32146304

RESUMO

INTRODUCTION: Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC. METHODS: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review. RESULTS: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%). CONCLUSIONS: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02489695.


Assuntos
Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Hipertensão/epidemiologia , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hipertensão/induzido quimicamente , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Indução de Remissão/métodos
20.
Clin Exp Hypertens ; 42(7): 581-589, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32202168

RESUMO

PURPOSE: The present work aimed to study the effect of aqueous extract of large cardamom (AELC) to prevent vascular remodeling and oxidative stress in Nω-Nitro-L-arginine methyl ester (L-NAME)-induced hypertension. METHOD: Male Wistar rats were administered with L-NAME 40 mg/kg/day for 28 days by oral gavage. The treatments included captopril (20 mg/kg/day) or AELC (100, 200 and 400 mg/kg/day) along with L-NAME administration. RESULTS: L-NAME treated rats showed high systolic, diastolic and mean arterial pressure, decreased nitric oxide level, increased level of malondialdehyde in plasma, heart, aorta and kidney, hypertrophy of the vascular wall and reduced vascular response to acetylcholine in phenylephrine-precontracted aorta. Treatment with AELC markedly reduced the blood pressure, restored the nitric oxide level, reduced the malondialdehyde level, alleviated the hypertrophy in L-NAME-induced hypertensive rats. Additionally, it also improved the vascular response to acetylcholine in phenylephrine pre-contracted aorta. CONCLUSION: In conclusion, our results demonstrate the preventive effect of AELC in L-NAME-induced hypertensive model, which is possibly related to antioxidant activities and restoration of nitric oxide level.


Assuntos
Elettaria , Hipertensão/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Remodelação Vascular/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Anti-Hipertensivos/uso terapêutico , Antioxidantes/farmacologia , Aorta/metabolismo , Pressão Arterial/efeitos dos fármacos , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Captopril/uso terapêutico , Hipertensão/induzido quimicamente , Hipertensão/complicações , Hipertrofia/etiologia , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , NG-Nitroarginina Metil Éster , Óxido Nítrico/sangue , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
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