RESUMO
We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg/kg) was administered to rats with PAH (monocrotaline 60 mg/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 ± 0.01 vs. 0.47 ± 0.06 pmoles/mL, allicin and control, respectively) and plasma (0.57 ± 0.05 vs. 0.75 ± 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 ± 1.22 and 51.4 ± 3.45 pmoles/mL), tetrahydrobiopterin (8.43 ± 0.33 and 10.14 ± 0.70 pmoles/mL), cyclic guanosine monophosphate (5.54 ± 0.42 and 5.64 ± 0.73 pmoles/mL), and Ang-(1-7) (0.88 ± 0.23 and 0.83 ± 0.056 pmoles/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 ± 0.3 and 5.64 ± 0.73 pmoles/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1α and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1α and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.
Assuntos
Hipertensão Arterial Pulmonar , Humanos , Animais , Ratos , Remodelação Vascular , Hipertensão Pulmonar Primária Familiar , HipertrofiaRESUMO
Deodorized garlic (DG) may favor the activity of the antioxidant enzymes and promote the synthesis of hydrogen sulfide (H2S). The objective was to test if DG favors an increase in H2S and if it decreases the oxidative stress caused by lipopolysaccharide (LPS) in rat hearts. A total of 24 rats were divided into 4 groups: Group 1 control (C), Group 2 LPS, Group 3 DG, and Group 4 LPS plus DG. The cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and oxidative stress markers, such as total antioxidant capacity (TAC), glutathione (GSH), selenium (Se), lipid peroxidation (LPO), thiols, hydrogen sulfide (H2S), and the activities and expressions of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), cystathionine synthetase (CBS), cystathionine γ-lyase (CTH), iNOS, and eNOS-p, were analyzed in the heart. Infarct zones in the cardiac tissue were present (p = 0.01). The CMP and CVR decreased and increased (p ≤ 0.05), TAC, GSH, H2S, NO, thiols, and GST activity (p ≤ 0.01) decreased, and LPO and iNOS increased (p ≤ 0.05). The activities and expressions of TrxR, GPx, eNOS-p, CTH, and CBS (p ≤ 0.05) decreased with the LPS treatment; however, DG normalized this effect. DG treatment decreases heart damage caused by LPS through the cross-talk between the H2S and NO systems.
Assuntos
Alho , Sulfeto de Hidrogênio , Selênio , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Alho/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Lipopolissacarídeos/farmacologia , Estresse Oxidativo , Selênio/farmacologia , Compostos de Sulfidrila/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo , Transferases/metabolismoRESUMO
The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here, we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the control of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats perfused according to the Langendorff technique were used to study the effects of an agonist of TRPV1, capsaicin (CS), an antagonist, capsazepine (CZ), and their combination CZ+CS. The hearts were subjected to three conditions: (1) control, (2) ischemia and (3) ischemia-reperfusion. We determined cardiac mechanical activity and the levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue after administration of CS, CZ and CZ+CS. Western blots were used to study the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac mechanical activity and elevating the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.
Assuntos
Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Canais de Cátion TRPV/metabolismo , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
BACKGROUND: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood. METHODS: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically. RESULTS: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88â pmol·mL-1 versus 0.19, 0.10-0.37â pmol·mL-1; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL-1 versus 12.9, 9.55-19.9â ng·dL-1; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91â pmol·mL-1 versus 4.07, 2.82-6.73â pmol·mL-1; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2â ng·mL-1 versus 4.53, 1.47-14.3 ng·mL-1; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL-1 versus 5.97, 3.1-17.8 nmol·mL-1; p<0.001). No significant differences were found among the three different aetiological forms of PAH. CONCLUSIONS: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.
Assuntos
Enzima de Conversão de Angiotensina 2 , Hipertensão Arterial Pulmonar , Angiotensina I , Animais , Humanos , Fragmentos de Peptídeos , Peptidil Dipeptidase ARESUMO
ATP-binding cassette membrane transporters (ABC), functions as an outflow facilitator of phospholipids and cellular cholesterol, playing an important role in the development of atherosclerosis and arterial hypertension. ABC's transporters could post-transcriptionally regulated by miRs. Evaluate the association in the transporters ABCA1 and ABCG1 with the expression of miR-33a and miR-144 and the carotid intima media thickness (cIMT) in patients with essential arterial hypertension. The miR-33a-5p, miR-144-3p and mRNA ABCA1 and ABCG1 expression in monocytes from Mexican hypertensive patients were examined by RT-PCR. The miR-33a and miR-144 expression in monocytes and mRNA ABCA1 and ABCG1 from Mexican hypertensive patients were examined by RT-PCR. This study involved 84 subjects (42 normotensive subjects and 42 patients with essential hypertension). Our study revealed that miR-33a expression (p = 0.001) and miR-144 (p = 0.985) were up-regulated, meanwhile, ABCA1 and ABCG1 transporters were down-regulated (p = 0.007 and p = 0.550 respectively) in hypertensive patients compared with the control group. The trend remains for miR33a/ABCA1 in presence of cIMT. Moreover, an inverse correlation was found with the expression levels of ABCA1 and ABCG1 as well as in HDL-C with miR-33a and miR-144. Our results showed an increase in the expression of miR-33a and miR-144 and an inverse correlation in their target ABCA1 and ABCG1; it may be associated with essential arterial hypertension in patients with cIMT and as consequence for atheromatous plaque.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Espessura Intima-Media Carotídea , Regulação da Expressão Gênica , Estudos de Associação Genética , Hipertensão/genética , MicroRNAs/genética , Angiotensinas/metabolismo , Índice de Massa Corporal , Dislipidemias/genética , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a public health problem lacking an approved pharmacological treatment. Omega-3 fatty acids have shown to reverse NAFLD. Chia is a seed rich in α-linolenic acid (ALA), antioxidants, and fiber; therefore, it could be useful to treat NAFLD. METHODS: In a single arm experimental design study, the effect of 25 g/day of milled chia was assessed in 25 patients with NAFLD. After two weeks of dietary stabilization (basal condition) and eight weeks of a chia-supplemented isocaloric diet, liver:spleen attenuation index and visceral abdominal fat (VAF) were measured by computed tomography. Lipids, lipoproteins, free fatty acids (FFA), and ALA plasma concentrations were also determined. RESULTS: Dietary chia supplementation induced an increase in plasma ALA concentration (75%) and dietary fiber (55%) consumption. After chia supplementation, VAF (9%), body weight (1.4%), total cholesterol (2.5%), non-high density lipoprotein cholesterol (3.2%), and circulating FFA (8%) decreased. Furthermore, NAFLD regressed in 52% of the treated patients (P < 0.05 for all). CONCLUSIONS: The results of the present study show that 25 g/day of milled chia ameliorates NAFLD. Chia is an accessible vegetal source of omega-3 fatty acids, antioxidants, and fiber, which could have the potential to prevent metabolic abnormalities in NAFLD patients. Considering that there is no pharmacological treatment approved for NAFLD, the findings of the present study suggest that a chia-supplemented diet could be an innovative alternative to control this disease. RETROSPECTIVELY REGISTERED: https://clinicaltrials.gov/show/NCT03942822.
Assuntos
Colesterol/sangue , Gordura Intra-Abdominal/patologia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Salvia/química , Sementes/química , Adulto , Idoso , Antioxidantes/farmacologia , Fibras na Dieta/farmacologia , Suplementos Nutricionais , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Baço/patologia , Ácido alfa-Linolênico/farmacologiaRESUMO
A worldwide public health problem is chronic kidney disease (CKD) presenting alarming epidemiological data. It currently affects about 10% of the adult population worldwide and has a high mortality rate. It is now known that oxidative stress represents one of the most important mechanisms in its pathophysiology, from the early stages to the terminal phase. Oxidation increases inflammation and reduces the capacity of NO⢠to relax vascular smooth muscle, in part by decreasing bioavailability of tetrahydrobiopterin (BH4), leading to endothelial dysfunction and high blood pressure, and due to the limited effectiveness of existing treatments, new drugs are needed to prevent and/or treat these mechanisms. The aim of this study was to test apocynin in a 5/6 nephrectomy mouse model of CKD to investigate whether its known antioxidant effect can improve the disease outcome. This effect results from the inhibition of NADPH oxidase and consequently a reduced production of the superoxide anion ([Formula: see text]). Animals were divided into five groups: sham, 5/6 nephrectomy only, and 5/6 nephrectomy followed by treatment with captopril, losartan or apocynin. The parameters evaluated were blood pressure and markers of oxidative stress ([Formula: see text]) and endothelial function (BH4). There were significantly lower levels of [Formula: see text] and a greater availability of serum BH4 in the apocynin-treated animals versus the control group and the two other drug treatments. The present findings suggest that apocynin in conjunction with a coadjuvant for modulating blood pressure may be useful for controlling the progression of CRF.
Assuntos
Acetofenonas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Acetofenonas/farmacologia , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Captopril/farmacologia , Captopril/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Losartan/farmacologia , Losartan/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/etiologia , Resultado do TratamentoRESUMO
Deleterious effects of purinergic P2X1 and P2X7 receptors (P2XRs) in ANG II-dependent hypertension include increased renal vascular resistance, and impaired autoregulation and pressure natriuresis. However, their specific effects on the determinants of glomerular hemodynamics remain incompletely delineated. To investigate the P2XR contributions to altered glomerular hemodynamics in hypertension, the effects of acute blockade of P2X1R, P2X7R, and P2X4R with NF449, A438079, and PSB12054, respectively, were evaluated in ANG II-infused rats (435 ng·kg-1·min-1). P2X1R or P2X7R blockade reduced afferent (6.85 ± 1.05 vs. 2.37 ± 0.20 dyn·s-1·cm-5) and efferent (2.85 ± 0.38 vs. 0.99 ± 0.07 dyn·s-1·cm-5) arteriolar resistances, leading to increases in glomerular plasma flow (75.82 ± 5.58 vs. 206.7 ± 16.38 nl/min), ultrafiltration coefficient (0.0198 ± 0.0024 vs. 0.0512 ± 0.0046 nl·min-1·mmHg-1), and single-nephron glomerular filtration rate (22.73 ± 2.02 vs. 51.56 ± 3.87 nl/min) to near normal values. Blockade of P2X4R did not elicit effects in hypertensive rats. In normotensive sham-operated rats, only the P2X1R antagonist caused an increase plasma flow and single-nephron glomerular filtration rate, whereas the P2X4R antagonist induced glomerular vasoconstriction that was consistent with evidence that P2X4R stimulation increases release of nitric oxide from endothelial cells. Mean arterial pressure remained unchanged in both hypertensive and normotensive groups. Western blot analysis showed overexpression of P2X1R, P2X7R, and P2X4R proteins in hypertensive rats. Whereas it has been generally assumed that the altered glomerular vascular resistances in ANG II hypertension are due to AT1 receptor-mediated vasoconstriction, these data indicate a predominant P2X1R and P2X7R control of glomerular hemodynamics in ANG II hypertension.
Assuntos
Angiotensina II , Hemodinâmica , Hipertensão/metabolismo , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/metabolismo , Receptores Purinérgicos P2X1/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Circulação Renal , Animais , Pressão Arterial , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Hemodinâmica/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Glomérulos Renais/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos Wistar , Receptores Purinérgicos P2X1/efeitos dos fármacos , Receptores Purinérgicos P2X4/efeitos dos fármacos , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Fluxo Plasmático Renal , Transdução de Sinais , VasoconstriçãoRESUMO
Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co) and Rosmarinus officinalis (Ro) extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); (c) Ro extract-treated myocardial infarction (MI-Ro); (d) Co extract-treated myocardial infarction (MI-Co); or (e) Ro+Co-treated myocardial infarction (MI-Ro+Co). Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD)-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1), increased vasodilators agents (angiotensin 1-7 and bradikinin) and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Crataegus/química , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Rosmarinus/química , Angiotensinas/farmacologia , Animais , Biomarcadores/metabolismo , Bradicinina/farmacologia , Fármacos Cardiovasculares/farmacologia , Cromatografia Líquida de Alta Pressão , Testes de Função Cardíaca , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Óxido Nítrico Sintase Tipo III/metabolismo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos Wistar , Vasoconstrição/efeitos dos fármacosRESUMO
Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1ß, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.
Assuntos
Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/metabolismo , PPAR alfa/biossíntese , Animais , Clofibrato/farmacologia , Clofibrato/uso terapêutico , Regulação da Expressão Gênica , Masculino , Infarto do Miocárdio/tratamento farmacológico , PPAR alfa/genética , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.
Assuntos
Angiotensina II/metabolismo , Antioxidantes/uso terapêutico , Fenofibrato/uso terapêutico , Resistência à Insulina/fisiologia , Síndrome Metabólica/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Catalase/sangue , Modelos Animais de Doenças , Insulina/sangue , Masculino , NADPH Oxidase 4 , NADPH Oxidases/sangue , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Superóxido Dismutase-1/sangue , Triglicerídeos/sangueRESUMO
The antioxidant properties of aged garlic extract (AGE) on cardiovascular functioning (CF) in metabolic syndrome (MS) remains poorly studied. Here we study the AGE effects on CF in a rat model of MS. Control rats plus saline solution (C + SS), MS rats (30% sucrose in drinking water from weaning) plus saline solution (MS + SS), control rats receiving AGE (C + AGE 125 mg/Kg/12 h) and MS rats with AGE (MS + AGE) were studied. MS + SS had increased triglycerides, systolic blood pressure, insulin, leptin, HOMA index, and advanced glycation end products. AGE returned their levels to control values (p < 0.01). Cholesterol was decreased by AGE (p = 0.05). Glutathion and GPx activity were reduced in MS + SS rats and increased with AGE (p = 0.05). Lipid peroxidation was increased in MS + SS and AGE reduced it (p = 0.001). Vascular functioning was deteriorated by MS (increased vasocontraction and reduced vasodilation) and AGE improved it (p = 0.001). Coronary vascular resistance was increased in MS rats and AGE decreased it (p = 0.001). Cardiac performance was not modified by MS but AGE increased it. NO measured in the perfusate liquid from the heart and serum citrulline, nitrites/nitrates were decreased in MS and AGE increased them (p < 0.01). In conclusion, AGE reduces MS-induced cardiovascular risk, through its anti-oxidant properties.
Assuntos
Antioxidantes/administração & dosagem , Alho/química , Testes de Função Cardíaca/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Colesterol/sangue , Modelos Animais de Doenças , Produtos Finais de Glicação Avançada/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/fisiopatologia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Triglicerídeos/sangueRESUMO
The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2.
Assuntos
Angiotensina II/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Rim/fisiologia , Transdução de Sinais/fisiologia , Angiotensina II/farmacologia , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Ceramidas/fisiologia , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Fosfolipases A2/fisiologia , Ratos , Ratos Wistar , Tromboxano B2/fisiologia , Vasoconstrição/efeitos dos fármacosRESUMO
We have recently demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) stimulation lowers the production of angiotensin II while increasing the production of Ang-(1-7), both in cardiac and plasmatic level. This stimulation improves nitric oxide bioavailability, preserving cardiac histologic features and functioning. Based on these results, we decided to study the effect of PPARα stimulation on renin-angiotensin system components of ischemic myocardium. Male Wistar rats (weighing 300-350 g) were assigned to the following groups: (1) sham, (2) myocardial ischemia vehicle-treated (MI-V), and (3) myocardial ischemia clofibrate-treated. Expression of the angiotensin-converting enzyme increased during ischemia, whereas clofibrate-treated group remained comparable to control. Activation of the PPARα receptor stimulated the expression of angiotensin-converting enzyme-2; while the activity of this enzyme was increased in MI-V, clofibrate inhibited any change. The concentration of bradykinin and phospho-Akt(SER473) in homogenate increased in the animals treated with the drug. Mas receptor expression increased in MI-V rats. In conclusion, stimulation of PPARα by clofibrate prevents an increase in the activity of renin-angiotensin system and promotes the production of vasodilator substances.
Assuntos
Clofibrato/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , PPAR alfa/agonistas , Sistema Renina-Angiotensina/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2 , Animais , Bradicinina/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Masculino , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , PPAR alfa/metabolismo , Peptidil Dipeptidase A/metabolismo , Fosforilação , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismo , Serina , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipertensão Renal/metabolismo , Córtex Renal/metabolismo , Renina/metabolismo , 6-Cetoprostaglandina F1 alfa/sangue , 6-Cetoprostaglandina F1 alfa/metabolismo , Angiotensina I/sangue , Angiotensina I/metabolismo , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Captopril/uso terapêutico , Celecoxib/uso terapêutico , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Renal/sangue , Hipertensão Renal/prevenção & controle , Córtex Renal/efeitos dos fármacos , Córtex Renal/enzimologia , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Wistar , Renina/genéticaRESUMO
Pomegranate (Punica granatum L.) is considered a functional food due to its polyphenol content that benefits the body. The type of processing the fruit undergoes is important, as this also influences the concentrations of these compounds. The pomegranate juice was extracted by two methods: manual extraction using a manual juicer through heat treatment in a water bath (Man-P), and extraction through mechanical pressing using Good Nature X-1 equipment and hyperbaric sanitization (Mech-Hyp). Bromatological analyses showed significant differences (p ≤ 0.05) between the two treatments. When subjected to hyperbaric sanitization, the juice showed higher concentrations of moisture, soluble solids, protein, and carbohydrates. In an antioxidant analysis, the ABTS radical showed no significant difference in the treatments, with 96.99% inhibition. For the DPPH radical, the sample with the highest inhibition was Man-P with 98.48%. The determination of phenols showed that there was a higher concentration in juice that underwent pasteurization (104.566 mg GAE/mL). However, the Mech-Hyp treatment exhibited a minor concentration of phenols with 85.70 mg GAE/mL. FTIR spectra revealed that the functional groups were mainly associated with carbohydrates. Regarding ACE inhibition, it was observed that the Man-P and Mech-Hyp juices showed greater inhibition of enzyme in hypertensive patients compared to normotensive patients. This activity can be attributed to the mechanisms of action of antioxidant compounds. Both extraction methods manual and mechanical pressing resulted in increased antioxidant and antihypertensive activity. The antioxidant compounds accompanied by adequate sanitation were decisive in an antimicrobial analysis, since no pathogenic microorganisms were observed in the juices.
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Prediabetes is defined as a state of moderate hyperglycemia. Here, we used freeze-dried seeds of Stenocereus stellatus (white tunillo) as a possible therapeutic strategy for the treatment of prediabetes. In the aqueous extract of freeze-dried seeds of white tunillo, polyphenols were identified using the Folin-Ciocalteu technique, separated by UPLC and analyzed by infrared spectrophotometry. Five well-defined peaks with good resolution were observed in the chromatogram of the aqueous extract obtained by UPLC. Two of these peaks corresponded to polyphenols with similarity to quercetin and rutin. The subchronic oral administration of freeze-dried seeds of white tunillo for 14 days in a prediabetes model in female Wistar rats reversed hyperglycemia and glucose intolerance. Treatment with the freeze-dried seeds reversed the decrease in the hepatic expression of Akt, eNOS, and p-eNOSSer1177 but did not reverse the decrease in MnSOD, catalase, and GPx1. No changes in the expression of GPx4 and p-AktSer473 were observed in the pathological state or with the treatment but there was an increase in the expression and activity of eNOS. The bioactive compounds present in the freeze-dried seeds of Stenocereus stellatus could provide guidelines for studying the mechanisms of action through which they reverse signs of prediabetes.
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Epidemiological studies imply there is a higher risk of cardiovascular disease in menopausal women. Some explanations suggest a lack of estrogens as the cause, but estrogens do not disappear completely and are just transformed into different products called estrogenic degradation metabolites (EDMs). When estrogens are metabolized, reactive oxygen species (ROS) increase, causing DNA damage and increasing oxidative stress. These conditions are associated to neurodegenerative diseases and different types of cancer. However, their effect on the cardiovascular system remains unknown. This paper compares estrogenic metabolite levels in serum from post-menopausal women with cardiovascular risk (CAC>1) and with establish cardiovascular disease (CVD), against levels in healthy women (Ctrl). Sample sera were obtained from the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Serum levels of eleven estrogenic metabolites were quantified by High performance liquid chromatography (HPLC) and oxidative stress markers such as ROS, lipoperoxidation levels (TBARS), total antioxidant capacity (TAC), super oxide dismutase activity (SOD) and cytokine levels were evaluated. 8-hydroxy-2-deoxyguanosine (8-OHdG) was also determined as a marker of nuclear damage.There were significant differences between serum levels of some EDMs in CAC> 1 and CVD vs. serum levels in Ctrl women. Results also revealed an increase in oxidative stress and a diminished capacity to manage oxidative stress. These findings provide an overview, and suggest that some estrogenic metabolites may be associated with an increased risk of CVD in menopausal women. However, additional studies are needed to evaluate the impact of these EDMs directly on cardiovascular function.
Assuntos
Doenças Cardiovasculares , Cardiopatias , Feminino , Humanos , Estrogênios/metabolismo , Doenças Cardiovasculares/etiologia , Espécies Reativas de Oxigênio , MenopausaRESUMO
Garlic (Allium sativum) possesses healing properties for diseases like systemic arterial hypertension, cancer and diabetes, among others. Its main component, allicin, binds to the Transient Receptor Potential Vanilloid Type 1 (TRPV1). In this study, we investigated TRPV1's involvement in the regulation of various molecules at the systemic and aortic levels in Wistar rats treated with bacterial lipopolysaccharide (LPS) and garlic to activate the receptor. The experimental groups were as follows: 1) Control, 2) LPS, 3) Garlic, and 4) LPS + Garlic. Using Uv-visible spectrophotometry and capillary zone electrophoresis, we measured the levels of nitric oxide (NO), biopterins BH2 and BH4, total antioxidant capacity (TAC) and oxidizing capacity (OXCA). We also analyzed molecules related to vascular homeostasis such as angiotensin Ang 1-7 and Ang II, as well as endothelin ET-1. In addition, we assessed the inflammatory response by determining the levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and galectin-3 (GTN-3). For cell damage assessment, we measured levels of malondialdehyde (MDA), malonate (MTO) and 8-hydroxy-2-deoxyguanosine (8HO2dG). The results showed that LPS influenced the NO pathway at both systemic and aortic levels by increasing OXCA and reducing TAC. It also disrupted vascular homeostasis by increasing Ang-II and ET-1, while decreasing Ang1-7 levels. IL-6, TNFα, GTN-3, as well as MDA, MTO, and 8HO2dG were significantly elevated compared to the control group. The expression of iNOS was increased, but TRPV1 remained unaffected by LPS. However, garlic treatment effectively mitigated the effects of LPS and significantly increased TRPV1 expression. Furthermore, LPS caused a significant decrease in calcitonin gene-related peptide (CGRP) in the aorta, which was counteracted by garlic treatment. Overall, TRPV1 appears to play a crucial role in regulating oxidative stress and the molecules involved in damage and inflammation induced by LPS. Thus, studying TRPV1, CGRP, and allicin may offer a potential strategy for mitigating inflammatory and oxidative stress in sepsis.
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Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-×¥-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1-7) [Ang-(1-7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1-7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1-7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1-7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.