Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.705
Filtrar
2.
J Agric Food Chem ; 67(35): 9805-9811, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407895

RESUMO

Stachydrine (STA) is a constituent of citrus fruits and Leonurus heterophyllus Sweet. In the present study, we established that STA caused acute endothelium-dependent relaxation. The vascular action of STA was mediated by nitric oxide (NO) via cyclic guanosine monophosphate. Mechanistically, STA activated AMP-activated protein kinase (AMPK), protein kinase B/Akt, and endothelial NO synthase (eNOS) in vascular endothelial cells (ECs). AMPK inhibition by compound C blocked STA-induced Akt/eNOS phosphorylation, suggesting that AMPK is the upstream of Akt and eNOS. Inhibition of Akt by MK2206 blocked STA-stimulated eNOS phosphorylation without altering AMPK phosphorylation. Furthermore, we showed that STA activated AMPK via the induction of liver kinase B1 phosphorylation. These results indicated that STA can induce eNOS phosphorylation and vasorelaxation by regulating the interplay between AMPK and Akt pathways in ECs. These findings further highlighted the potential of STA as a nutritional factor in the beneficial effects of fruit intake in preventing the endothelial dysfunction-related metabolic cardiovascular diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aorta Torácica/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Prolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vasodilatadores/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Bovinos , Citrus/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Técnicas In Vitro , Leonurus/química , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação/efeitos dos fármacos , Prolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
3.
Int J Cardiovasc Imaging ; 35(9): 1745-1753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312997

RESUMO

No data exist whether statins have robust anti-inflammatory effects of atherosclerotic plaques primarily during the early treatment period or continuously throughout use. This prospective three time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study of the carotid artery assessed anti-inflammatory effects of statin during the early treatment period (initiation to 3 months) and late treatment period (3 months to 1 year) and their correlation with lipid and inflammatory profile changes during a year of therapy. Nine statin-naïve stable angina patients with inflammatory carotid plaques received 20 mg/day atorvastatin after undergoing initial 18F-FDG PET/CT scanning of carotid arteries and ascending thoracic aorta, and then completed serial 18F-FDG PET/CT imaging at 3 and 12 months whose data were analyzed. The primary outcome was the inter-scan percent change in target-to-background ratio (ΔTBR) within the index vessel. At 3 months of atorvastatin treatment, mean serum low-density lipoprotein cholesterol (LDL-C) level decreased by 36.4% to < 70 mg/dL (p = 0.001) and mean serum high-density lipoprotein cholesterol level increased to > 40 mg/dL (p = 0.041), with both maintained with no further reduction up to 1 year (p = 0.516 and 0.715, respectively) while mean serum high sensitivity C-reactive protein level only numerically decreased (p = 0.093). The index vessel ΔTBR showed continuous plaque inflammation reduction over 1 year, by 4.4% (p = 0.015) from the initiation to 3rd months and 6.2% (p = 0.009) from 3rd months to 1 year, respectively, without correlation with lipid profile changes. The ΔTBR of the bilateral carotid arteries and ascending aorta also continuously decreased from 3 months to 1 year. Three time point 18F-FDG PET/CT imaging demonstrates that statin's anti-inflammatory effect continues throughout its use up to 1 year, even though yielding stable below-target plasma LDL-C levels at 3 months.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/tratamento farmacológico , Fluordesoxiglucose F18/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/patologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
4.
Chem Pharm Bull (Tokyo) ; 67(7): 675-689, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257323

RESUMO

An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.


Assuntos
Produtos Biológicos/química , Cistanche/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Cistanche/metabolismo , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monoterpenos/química , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Caules de Planta/química , Caules de Planta/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Vasodilatadores/química , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia
5.
Life Sci ; 232: 116662, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323271

RESUMO

AIMS: Vascular endothelial cells act as a selective barrier between circulating blood and vessel wall and play an important role in the occurrence and development of cardiovascular diseases. Astragaloside IV (As-IV) has a protective effect on vascular endothelial cells, but its underlying mechanism remains unclear. This study is aimed at investigating the effect of As-IV on endothelial dysfunction (ED). METHODS: Male Sprague-Dawley (SD) were injected intraperitoneally with 65 mg/kg streptozotocin (STZ) to induce diabetes and then administered orally with As-IV (40, 80 mg/kg) for 8 weeks. Vascular function was evaluated by vascular reactivity in vivo and in vitro. The expression of calpain-1 and eNOS in the aorta of diabetic rats was examined by western blot. NO production was measured using nitrate reductase method. Oxidative stress was determined by measuring SOD, GSH-px and ROS. RESULTS: Our results showed that As-IV administration significantly improved diabetes associated ED in vivo, and both NAC (an antioxidant) and MDL-28170 (calpain-1 inhibitor) significantly attenuated hyperglycemia-induced ED in vitro. Meanwhile, pretreatment with the inhibitor l-NAME nearly abolished vasodilation to ACh in all groups of rats. Furthermore, As-IV increased NO production and the expression of eNOS in the thoracic aorta of diabetic rats. In addition, the levels of ROS were significantly increased, and the activity of SOD and GSH-px were decreased in diabetic rats, while As-IV administration reversed this change in a concentration-dependent manner. CONCLUSION: These results suggest that As-IV improves endothelial dysfunction in thoracic aortas from diabetic rats by reducing oxidative stress and calpain-1.


Assuntos
Calpaína/metabolismo , Endotélio Vascular/efeitos dos fármacos , Hiperglicemia/patologia , Estresse Oxidativo/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Acetilcisteína/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Biomarcadores/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dipeptídeos/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperglicemia/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Vasodilatação/efeitos dos fármacos
6.
Biol Pharm Bull ; 42(6): 877-885, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155587

RESUMO

Orthovanadate (OVA), a protein tyrosine phosphatase inhibitor, induces contraction in endothelium-denuded mouse thoracic aortas. OVA-induced contraction was significantly (vs. control rings) suppressed by Rho kinase (Y-27632, 10 µM), extracellular signal-regulated kinase 1 and 2 (Erk1/2, FR180204, 10 µM), Erk1/2 kinase (MEK, PD98059, 10 µM), epidermal growth factor receptor (EGFR, AG1478, 10 µM), and Src inhibitors, and was partially suppressed by c-Jun N-terminal kinase (JNK, AS601245, 10 µM) and p38 (SB203580, 10 µM) inhibitors. However, a myosin light chain kinase inhibitor (ML-7, 10 µM) and a metalloproteinase inhibitor (TAPI-0, 10 µM) had no effect on OVA-induced contraction in mouse thoracic aortas. Phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was abolished by inhibitors of Src, EGFR, MEK, Erk1/2, and Rho kinase, but not by inhibitors of JNK and p38. Erk1/2 phosphorylation by OVA was blocked by inhibitors of EGFR, Src, MEK, and Erk1/2, but not by Rho kinase inhibition. Src phosphorylation at Tyr-416 was abrogated by only Src inhibitor. EGFR phosphorylation at Tyr-1173 was suppressed by a Src inhibitor. These findings suggest that OVA induces contraction via activation of Src, EGFR, MEK, Erk1/2, and Rho kinase, leading to inactivation of myosin light chain phosphatase via MYPT1 phosphorylation.


Assuntos
Aorta Torácica/efeitos dos fármacos , Proteínas Quinases/fisiologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Vanadatos/farmacologia , Animais , Aorta Torácica/fisiologia , Masculino , Camundongos , Vasoconstrição/efeitos dos fármacos
7.
Einstein (Sao Paulo) ; 17(3): eAO4600, 2019 Jun 03.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31166411

RESUMO

OBJECTIVE: To characterize the calcium influx pathways implicated in the sustained elevation of endothelial intracellular calcium concentration, required for the synthesis and release of relaxing factors. METHODS: We evaluated the effect of the newly synthesized pyrazole derivatives, described as selective inhibitors for ORAI (BTP2/Pyr2 and Pyr6) and TRPC3 (Pyr3 and Pyr10) channels, upon endothelium- and extracellular calcium-dependent relaxations stimulated by acetylcholine and thapsigargin, in pre-constricted rat thoracic aortic rings. RESULTS: Acetylcholine and thapsigargin responses were completely reverted by Pyr2 and Pyr6 (1 to 3µM). Pyr3 (0.3 to 3µM) caused a rapid reversal of acetylcholine (6.2±0.08mg.s-1) and thapsigargin (3.9±0.25mg.s-1) relaxations, whereas the more selective TRPC3 blocker Pyr10 (1 to 3µM) had no effect. The recently described TRPC4/5 selective blocker, ML204 (1 to 3µM), reverted completely acetylcholine relaxations, but minimally thapsigargin induced ones. Noteworthy, relaxations elicited by GSK1016790A (TRPV4 agonist) were unaffected by pyrazole compounds or ML204. After Pyr2 and Pyr6 pre-incubation, acetylcholine and thapsigargin evoked transient relaxations similar in magnitude and kinetics to those observed in the absence of extracellular calcium. Sodium nitroprusside relaxations as well as phenylephrine-induced contractions (denuded aorta) were not affected by any of pyrazole compounds (1 to 3µM). CONCLUSION: These observations revealed a previously unrecognized complexity in rat aorta endothelial calcium influx pathways, which result in production and release of nitric oxide. Pharmacologically distinguishable pathways mediate acetylcholine (ORAI/TRPC other than TRPC3/TRPC4 calcium-permeable channels) and thapsigargin (TRPC4 not required) induced calcium influx.


Assuntos
Acetilcolina/farmacologia , Cálcio/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Óxido Nítrico/metabolismo , Tapsigargina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Masculino , Ratos Wistar , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Fatores de Tempo , Vasodilatadores/farmacologia
8.
Biomed Pharmacother ; 112: 108722, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970521

RESUMO

Microvascular and macrovascular complications are major causes of disability and death in diabetic patients. High levels of blood glucose sabotage the integrity of blood vessels and induce endothelial dysfunction. Fenofibrate is an agonist of peroxisome proliferator-activated receptor α and can reduce the incidence of cardiovascular events in diabetic patients. This study tested the hypothesis that fenofibrate could ameliorate endothelium-dependent vasodilation in diabetic mice and relieve high glucose-induced endothelial dysfunction via activating endothelial nitric oxide synthase (eNOS) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. A streptozotocin (STZ)-induced diabetic model was established by intraperitoneal injection of STZ (dissolved in sodium citrate buffer) at a dose of 60 mg/kg for 5 consecutive days. Mice were administered fenofibrate (100 mg/kg/d, i.g.) for 14 days. The endothelial function of extracted mouse aortae was examined by evaluating acetylcholine induced endothelium-dependent relaxation combined with phenylephrine-induced vasoconstriction and sodium nitroprusside-induced endothelium-independent relaxation. Superoxide onion (O2-) was determined using dihydroethidium staining of aortae. Functions of mouse aortic endothelial cells (MAECs) were assessed, and expression levels of eNOS and AMPK were determined by Western blotting. Fenofibrate ameliorated the impaired endothelium-dependent relaxation in diabetic mice and decreased the level of intracellular O2- in diabetic mouse aortae. In-vitro, fenofibrate treatment improved the impaired function of MAECs, increased nitric oxide production, and decreased the O2- level, as well as activated eNOS and AMPK phosphorylation in cultured MAECs by high glucose. Fenofibrate could ameliorate endothelium-dependent vasodilation in diabetic mice and relieve high glucose-induced endothelial dysfunction, which was possibly related to the activation of eNOS and AMPK phosphorylation.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Fenofibrato/uso terapêutico , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/fisiopatologia , Fenofibrato/farmacologia , Glucose/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , PPAR alfa/agonistas , Estreptozocina
9.
Indian J Pharmacol ; 51(1): 45-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031467

RESUMO

OBJECTIVES: Sophorolipids (SLs) are a group of surface-active glycolipids produced by a type of nonpathogenic yeast Candida bombicola in the presence of vegetable oil through fermentation technology. SLs have shown antitumor activity; however, the mechanism of action underlying the anticancer activity of SLs is poorly understood. This work evaluated the anticancer activity of SLs fermented from palm oil by exploring its antiangiogenic activity. MATERIALS AND METHODS: The SLs that were fermented and further characterized for their biochemical activities. Cytotoxicity study was performed to assess cytostatic properties. A series of in vitro and ex vivo angiogenesis assay was also carried out. The relative fold change in the expression of p53 mRNA by SLs was also studied. RESULTS: Altogether, the data show that SLs derived from palm oil fermentation process inhibited neovascularization in the ex vivo tissue segments and also the endothelial cell proliferation between 50% and 65% inhibition as a whole. The palm oil derived SLs also caused downregulation of the suppression level of vascular endothelial growth factor and also upregulate the p53 mRNA level. The analytical studies revealed the presence of high amount of phenolic compounds but with relatively weak antioxidant activity. The gas chromatography-mass spectrometry studies revealed abundant amount of palmitic and oleic acid, the latter an established antiangiogenic agent, and the former being proangiogenic. CONCLUSION: Therefore, it can be concluded from this study that SLs derived from fermented palm oil have potent antiangiogenic activity which may be attributed by its oleic acid component.


Assuntos
Inibidores da Angiogênese/farmacologia , Candida/química , Glicolipídeos/farmacologia , Ácido Oleico/farmacologia , Óleo de Palmeira/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Fermentação , Humanos , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Org Lett ; 21(4): 1197-1201, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30702896

RESUMO

Two novel sesquiterpenoids, curcumanes A (1) and B (2), possessing unprecedented skeletons with a dicyclo[3.2.1]octane and a dicyclo[3.3.1]nonane moiety, respectively, were isolated from Curcuma longa. Both of them had remarkable vasorelaxant activity on rat aorta via blocking extracellular Ca2+ influx through VDCCs and ROCCs. The activity of 1 was endothelium-independent, while that of 2 was endothelium-dependent. Compound 2 also prolonged APTT and TT to inhibit blood coagulation.


Assuntos
Aorta Torácica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Curcuma/química , Receptores de Detecção de Cálcio/antagonistas & inibidores , Vasodilatadores/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Ratos , Receptores de Detecção de Cálcio/metabolismo , Vasodilatadores/química , Vasodilatadores/isolamento & purificação
11.
J Trace Elem Med Biol ; 52: 239-246, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732889

RESUMO

Cadmium (Cd) exposure has been associated with an increased risk of cardiovascular diseases. The diet is a modifiable source of protecting or damaging factors that may affect this risk. Herein we tested the hypothesis that a soybean-based diet (SBD) protects the vascular wall of the aorta against Cd-induced pro-inflammatory and pro-apoptotic effects. To test this hypothesis, we fed male Wistar rats for 60 days with a casein-based diet (CBD) or an SBD. These animals were also exposed to tap-water without (CBD-Co/SBD-Co) or with 15(CBD-15Cd/SBD-15Cd) or 100 (CBD-100Cd/SBD-100Cd) ppm of Cd. Inflammatory parameters (mRNAs and/or proteins) were measured in thoracic aorta tissue. These included inducible and endothelial nitric oxide synthases, cyclooxygenase-2, intracellular-adhesion molecule-1, and vascular cell-adhesion molecule-1. As pro-apoptotic parameters, we measured Bax and Bcl-2 mRNA/protein, as well as TUNEL positive cells in the aorta tissue. Compared to CBD-Co, inflammatory and apoptosis markers increased in the aorta with the concentration of Cd in the drinking water. These effects were not observed in either SBD-15Cd or SBD-100Cd, which were similar to CBD-Co. Cd content in serum and in aortas from animals fed CBD-Co/SBD-15Cd or CBD-Co/SBD-100Cd were similar suggesting that, if any, the effect of SBD is not due to changes in Cd bioaccumulation, but due to secondary effects linked to the composition of the dietary soybean flour. Our findings are consistent with a protective effect of an SBD against Cd-induced inflammation and apoptosis in the thoracic aorta in a rat model.


Assuntos
Aorta Torácica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Dieta , Inflamação/induzido quimicamente , Soja/química , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Cádmio/administração & dosagem , Cádmio/análise , Caseínas/administração & dosagem , Caseínas/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Ratos , Ratos Wistar
12.
Nutrients ; 11(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717220

RESUMO

Susceptibility to develop hypertension may be established during early stages of life that include the intrauterine period, infancy and childhood. We recently showed that blood pressure increased when rats reached adulthood when sucrose was ingested for a short-term critical window from postnatal day 12 to 28 in the rat, which corresponds to days around weaning. Here, we studied several factors that might participate in the increased susceptibility to hypertension when adulthood is reached by analyzing the changes produced at the end of the sucrose ingestion during this critical period. Body weight of the rats at the end of the sucrose period was decreased even if there was an increased ingestion in Kcal. We found an increase in blood pressure accompanied by a decrease in endothelial nitric oxide synthase (eNOS) expression in the aorta. When insulin was administered to rats receiving sucrose, glucose in plasma diminished later than in controls and this slight insulin resistance may reduce nitric oxide synthase action. Oleic acid that modulates eNOS expression was increased, lipoperoxidation was elevated and total non-enzymatic anti-oxidant capacity was decreased. There was also a decrease in SOD2 expression. We also studied the expression of Sirt1, which regulates eNOS expression and Sirt3, which regulates SOD2 expression as possible epigenetic targets of enzyme expression involved in the long- term programming of hypertension. Sirt3 was decreased but we did not find an alteration in Sirt1 expression. We conclude that these changes may underpin the epigenetic programming of increased susceptibility to develop hypertension in the adults when there was exposure to high sucrose levels near weaning in rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Sirtuína 1/metabolismo , Sirtuínas/metabolismo , Sacarose/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Hipertensão/metabolismo , Resistência à Insulina , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Sacarose/administração & dosagem
13.
Vascul Pharmacol ; 115: 33-45, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30790705

RESUMO

Perinatal sodium overload induces endothelial dysfunction in adult offspring, but the underlying mechanisms are not fully known. The involvement of tissue renin-angiotensin system on high sodium-programmed endothelial dysfunction was examined. Acetylcholine and angiotensin I and II responses were analyzed in aorta and mesenteric resistance arteries from 24-week-old male offspring of normal-salt (O-NS, 1.3% NaCl) and high-salt (O-HS, 8% NaCl) fed dams. COX-2 expression, O2- production and angiotensin converting enzyme (ACE) activity were determined. A separated O-HS was treated with losartan (15 mg kg-1/day) for eight weeks. Compared to O-NS, O-HS were normotensive. Acetylcholine-induced relaxation was impaired in O-HS arteries, which was improved by tempol, apocynin or indomethacin. The angiotensin I-induced contraction was greater in O-HS arteries, whereas the angiotensin II responses were unchanged. ACE activity, O2- production and COX-2 expression were increased in O-HS arteries. In this group, the increased O2- production was inhibited by apocynin or losartan. Chronic losartan decreased COX-2 expression and restored the endothelium-dependent vasodilation in O-HS. Our findings reiterate that perinatal sodium overload programs endothelial dysfunction in adult offspring through a blood pressure-independent mechanism. Our results also suggest that vascular angiotensin II is the main mediator of high sodium-programmed endothelial dysfunction, promoting COX-2 expression and oxidative stress.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Aorta Torácica/fisiopatologia , Endotélio Vascular/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta/efeitos adversos , Fatores Etários , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Gravidez , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Superóxidos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
14.
Biomed Pharmacother ; 112: 108651, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784931

RESUMO

The protective role of alkaloids from Nelumbinis Plumula (AFNP) on the aorta during hypertension is not yet fully understood. We hypothesize that AFNP exerts protective effects against Ang II-induced hypertension by mediating RhoA/ROCK pathway and phenotypic switching during hypertension. In the present study, we evaluated the effect of AFNP on angiotensin II (Ang II)-induced actin cytoskeleton reorganization and aorta remodeling, as well as the involvement of RhoA/Rho-associated coiled kinase (ROCK) pathway in protecting against hypertension. We used rat aortic tissues to investigate the vasodilatation effect of AFNP on Ang II-induced constriction. AFNP was shown to significantly relax the endothelium-intact arteries induced by Ang II. We further investigated the vasodilation effect of AFNP in endothelium denuded arteries, which showed that the action of AFNP was endothelial independent. Male SHR rats were treated with saline or AFNP and morphological changes were examined following 8 weeks. AFNP treatment normalized the effects of hypertension in SHRs. HE staining showed that AFNP treatment improved the tunica media and wall thickness and ratio of MT/LD and MA/LA. Western blotting showed that AFNP treatment markedly decreased the Ang II-induced expression of collagen I and increased α-SMA in aorta. Furthermore, MTT assay showed that AFNP inhibited the proliferation of Ang II treated VSMCs in a concentration-dependent manner. AFNP treatment also ameliorated F-actin cytoskeleton remodeling in Ang II treated VSMCs, as visualized under fluorescence microscopy. Western blot analysis showed that RhoA transposition and ROCK activation and phosphorylation of MYPT1 was increased following Ang II treatment but were inhibited by AFNP treatment, showing that the cardio-protective effect of AFNP is likely mediated by the RhoA/ROCK signaling pathway. The anti-hypertension and aortic protection effects of AFNP are due to non-endothelial dependent inhibition of the VSMC cytoskeleton remodeling and regulation of RhoA/ROCK pathway.


Assuntos
Alcaloides/farmacologia , Aorta Torácica/efeitos dos fármacos , Nelumbo , Remodelação Vascular/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/fisiologia , Quinases Associadas a rho/fisiologia , Alcaloides/isolamento & purificação , Animais , Aorta Torácica/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Sementes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Vascular/fisiologia
15.
Environ Toxicol Pharmacol ; 66: 43-54, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597379

RESUMO

The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showed significant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-ß indices demonstrated impaired insulin sensitivity and glucose utilization in HFrD-fed rats. SFN and PIO treatments significantly reduced OGTTAUC (Glass's Delta values = 1.12 and 0.84, respectively), decreased ITTAUC (Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-ß value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactive protein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.


Assuntos
Aorta Torácica/efeitos dos fármacos , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Isotiocianatos/uso terapêutico , Pioglitazona/uso terapêutico , Animais , Aorta Torácica/fisiologia , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/análise , Dislipidemias/sangue , Dislipidemias/patologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Frutose/administração & dosagem , L-Lactato Desidrogenase/sangue , Masculino , Ratos Sprague-Dawley
16.
Life Sci ; 219: 1-10, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30620894

RESUMO

AIMS: The vasodilatory effects of the anti-diabetic drug, linagliptin in phenylephrine-precontracted aortic rings were investigated. MATERIALS AND METHODS: Male New Zealand White rabbits were used in the experiment and its arterial tone was measured by using myogragh system. KEY FINDINGS: Linagliptin induced vasodilation in a concentration-dependent manner. The vasodilatory effect of linagliptin was not affected by the absence of the endothelium, or by pretreatment with a nitric oxide synthase inhibitor (L-NAME) or a small-conductance Ca2+-activated K+ channel inhibitor (apamin). Moreover, application of the adenylyl cyclase inhibitor SQ22536, protein kinase A (PKA) inhibitor KT5720, guanylyl cyclase inhibitor ODQ, or protein kinase G (PKG) inhibitor KT5823 did not alter the vasodilatory effect of linagliptin. However, inhibition of Rho-associated protein kinase by Y-27632 significantly attenuated linagliptin-induced vasodilation. Ion channel involvement in the vasodilatory effect of linagliptin was also investigated. Pretreatment with the vascular K+ channel inhibitors glibenclamide (ATP-sensitive K+ channels), Ba2+ (inwardly rectifying K+ channels), 4-AP (voltage-dependent K+ channels), and paxilline (large conductance Ca2+-activated K+ channels) did not affect linagliptin-induced vasodilation. Furthermore, the L-type Ca2+ channel inhibitor, nifedipine, and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor, thapsigargin, did not change the vasodilatory effect of linagliptin. SIGNIFICANCE: We suggests that linagliptin-induced vasodilation was mediated by the inhibition of Rho-associated kinase, but not with the endothelium, cAMP-PKA or cGMP-PKG-dependent signaling pathways, K+ channels, Ca2+ influx, or SERCA pump.


Assuntos
Hipoglicemiantes/farmacologia , Linagliptina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Masculino , Miografia , Coelhos
17.
J Oleo Sci ; 68(1): 79-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30606956

RESUMO

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the weakening of the vascular walls and the progressive dilation of the abdominal aorta. Nicotine, a primary component of cigarette smoke, is associated with AAA development and rupture. Nicotine induces AAA development by weakening vascular walls. However, little is known about preventive methods using functional food factors for nicotine-induced vascular destruction. Sesamin and sesamolin are functional food factors that are fat-soluble lignans found in Sesamum indicum seeds. Previous reports indicated that sesamin and sesamolin have anti-oxidative and anti-inflammatory effects. In this study, we evaluated the effects of sesamin and sesamolin-rich sesame extract on the weakening of vascular walls in nicotine-administered mice. Sesame extract attenuated the degradation of collagen and elastin fibers caused by nicotine. In addition, sesame extract decreased the area positive for matrix metalloproteinase 12 (MMP-12) and oxidative stress in the vascular walls. These results suggest that sesame extract may decrease the weakening of vascular walls by suppressing the nicotine-induced degradation of collagen and elastin fibers. Sesame extract may be effective in preventing AAA development by decreasing both, MMP-12 expression and oxidative stress in vascular walls.


Assuntos
Aorta Torácica/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Colágeno/metabolismo , Elastina/metabolismo , Extratos Vegetais/uso terapêutico , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Dioxóis/uso terapêutico , Ingestão de Alimentos/efeitos dos fármacos , Lignanas/uso terapêutico , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Nicotina , Estresse Oxidativo/efeitos dos fármacos , Sesamum/química
18.
Cardiovasc Drugs Ther ; 33(1): 25-33, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30663009

RESUMO

PURPOSE: The role of endoplasmic reticulum (ER) stress in cardiovascular disease is now recognized. Tauroursodeoxycholic acid (TUDCA) is known to have cardiovascular protective effects by decreasing ER stress. This study aimed to assess the ability of TUDCA to decrease ER stress, inhibit dedifferentiation of vascular smooth muscle cells (VSMCs), and reduce in-stent restenosis. METHODS: The effect of TUDCA on dedifferentiation of VSMCs and ER stress was investigated in vitro using wound-healing assays, MTT assays, and western blotting. For in vivo studies, 18 rabbits were fed an atherogenic diet to induce atheroma formation. Bare metal stents (BMS), BMS+TUDCA or Firebird stents were implanted in the left common carotid artery. Rabbits were euthanized after 28 days and processed for scanning electron microscope (SEM), histological examination (HE), and immunohistochemistry. RESULTS: In vitro TUDCA (10-1000 µmol/L) treatment significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration in VSMCs in a concentration-dependent manner and decreased ER stress markers (IRE1, XBP1, KLF4, and GRP78). In vivo, we confirmed no significant difference in neointimal coverage on three stents surfaces; neointimal was significantly lower with BMS+TUDCA (1.6 ± 0.2 mm2) compared with Firebird (1.90 ± 0.1 mm2) and BMS (2.3 ± 0.1 mm2). Percent stenosis was lowest for BMS+TUDCA, then Firebird, and was significantly higher with BMS (28 ± 4%, 35 ± 7%, 40 ± 1%; respectively; P < 0.001). TUDCA treatment decreased ER stress in the BMS+TUDCA group compared with BMS. CONCLUSIONS: TUDCA inhibited dedifferentiation of VSMCs by decreasing ER stress and reduced in-stent restenosis, possibly through downregulation of the IRE1/XBP1 signaling pathway.


Assuntos
Doenças das Artérias Carótidas/cirurgia , Desdiferenciação Celular/efeitos dos fármacos , Stents Farmacológicos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Procedimentos Endovasculares/instrumentação , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Administração Oral , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Procedimentos Endovasculares/efeitos adversos , Masculino , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neointima , Proteínas Serina-Treonina Quinases/metabolismo , Coelhos , Ratos Sprague-Dawley , Recidiva , Transdução de Sinais/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/administração & dosagem , Proteína 1 de Ligação a X-Box/metabolismo
19.
J Ethnopharmacol ; 232: 135-144, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30543913

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Citrus reticulatae Pericarpium (Chen pi) was widely used as an important ingredient in the prescription of TCM to treat phlegm fluid retention type hypertension. Since Chen pi is involved in treatment as antihypertensive TCM formula, we have reasonable expectation in believing that it might possess vasorelaxant activity. AIM OF THE STUDY: This study is designed to investigate the vasorelaxant effect of Chen pi and to study its pharmacology effects. MATERIALS AND METHODS: The vasorelaxant effect of water extract of Chen pi (CRW) were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. The fingerprint of Chen pi and the extracts were developed with quantification of hesperidin content by HPTLC. RESULTS: CRW exhibited the strongest vasorelaxant activity. CRW caused the relaxation of the phenylephrine pre-contracted aortic rings in the presence and absence of endothelium as well as in potassium chloride pre-contracted endothelium-intact aortic ring. The incubation of propranolol (ß-adrenergic receptor blocker), atropine (muscarinic receptor blocker), Nω-nitro-L-arginine methyl ester (NO synthase inhibitor), ODQ (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV blocker), barium chloride (Kir blocker), and glibenclamide (KATP blocker) significantly reduced the vasorelaxant effects of CRW. CRW was also found to be active in reducing Ca2+ releases from the sarcoplasmic reticulum and suppressing the voltage-operated calcium channels. CONCLUSION: The vasorelaxant effect of CRW on rat aorta involves NO/sGC, calcium and potassium channels, muscarinic and ß-adrenergic receptors.


Assuntos
Aorta Torácica/efeitos dos fármacos , Citrus , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Canais de Cálcio/fisiologia , Citrus/química , Técnicas In Vitro , Masculino , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Canais de Potássio/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/fisiologia , Vasodilatadores/química
20.
Biomed Pharmacother ; 109: 2090-2099, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551466

RESUMO

Tiliacorinine 12'-O-acetate is a modified analog of Tiliacorinine, a major compound in Tiliacora triandra. The present study explored the vasorelaxation property of tiliacorinine 12'-O-acetate and its mechanism in isolated rat aorta using the organ bath technique. Tiliacorinine 12'-O-acetate exhibited concentration-dependent (10-15-10-3.5 M) vasorelaxation in endothelium-intact rings (Emax = 93.53 ± 2.79%) and endothelium-denuded rings (Emax = 74.31 ± 5.09%). The effects of tiliacorinine 12'-O-acetate were attenuated by pre-incubation with N(ω)-nitro-l-arginine methyl ester (L-NAME, endothelium nitric oxide synthase inhibitor) (100 µM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, soluble quanylylcyclase inhibitor) (1 µM), and 4-aminopyridine (1 mM, Kv channel blocker). However, this effect was not impacted by indomethacin (10 µM, cyclooxygenase inhibitor), tetraethylammonium (5 mM, Kca channel blocker), barium chloride (1 mM, KIR channel blocker), or glibenclamide (10 µM, KATP channel blocker). Moreover, pretreatment with tiliacorinine 12'-O-acetate reduced the effect of L-NAME (100 µM) on acetylcholine-induced vasorelaxation. Tiliacorinine 12'-O-acetate showed inhibitory effects on CaCl2-induced contracted rings and reduced the contraction induced by phenylephrine (10 µM) and caffeine (20 mM) in a Ca2+-free solution. The results of this study suggest that tiliacorinine 12'-O-acetate induced endothelium-dependent vasorelaxation through the eNOS/NO/sGC pathway, and also induced endothelium independent vasorelaxation involving the modulation of sGC activity, Kv channels, Ca2+ influx through Ca2+ channels and intracellular Ca2+ release. The data concerning the benefits of tiliacorinine 12'-O-acetate might be further investigated for the application of tiliacorinine 12'-O-acetate as an antihypertensive compound.


Assuntos
Ácido Acético/farmacologia , Aorta Torácica/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Ácido Acético/síntese química , Animais , Aorta Torácica/fisiologia , Benzilisoquinolinas/síntese química , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Vasodilatação/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA