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1.
J Agric Food Chem ; 67(37): 10313-10320, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31502448

RESUMO

A peptide fraction with molecular masses below 3 kDa (PSH-3 kDa) from a peach seed hydrolysate demonstrated high angiotensin converting enzyme (ACE) inhibitory activity (concentration to inhibit 50% ACE (IC50) = 16.4 µg/mL) in our previous work. This work proposes a further study of this highly active fraction. RP-HPLC enabled two fractions (F3 and F4) with high inhibitory activity (IC50 = 2.0 ± 0.5 and 1.2 ± 0.2 µg/mL, respectively) to be isolated. Peptide analysis by LC-Q-TOF-MS/MS using reverse-phase and hydrophilic interaction chromatography enabled 33 peptides within both fractions to be identified. Among them, peptide isoleucine-tyrosine-serine-proline-histidine (IYSPH) showed the highest capacity. The lack of cytotoxicity of peptides was demonstrated in three different cell lines (HeLa, HT-29, and HK-2). Oral administration of PSH-3 kDa fraction or peptide IYSPH caused a significant systolic blood pressure reduction (-30 mmHg) on spontaneously hypertensive rats after 3-6 h treatment.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Hipertensão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Prunus persica/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/isolamento & purificação , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR , Sementes/química
2.
Sheng Li Xue Bao ; 71(4): 505-513, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31440747

RESUMO

Activation of peripheral respiratory chemoreceptors provokes respiratory and cardiovascular reflexes, providing a novel understanding of pathogenic mechanism of hypertension. Here we hypothesize that activation of peripheral respiratory chemoreceptors by hypoxia causes enhanced cardiorespiratory activity in conscious spontaneously hypertensive rats (SHRs). Using whole body plethysmography in combination with radio telemetry, pulmonary ventilation, arterial blood pressure and heart rate were examined in SHRs and Wistar-Kyoto (WKY) rats. We found that exposure to hypoxia induced greater increases in tidal volume and minute ventilation volume in SHRs compared to WKY rats. In addition, hypoxia caused a robust increase in arterial blood pressure and heart rate in SHRs relative to WKY counterparts. After carotid body denervation, the hypoxic ventilatory response was significantly decreased in both SHRs and WKY rats, but without significant difference between the two strains; moreover, the differences of arterial blood pressure and heart rate changes during hypoxic exposure were statistically insignificant between SHRs and WKY rats. It is concluded that hypoxia remarkably potentiates cardiorespiratory activity in the SHRs, suggesting an enhanced sensitivity of carotid bodies to hypoxia.


Assuntos
Pressão Sanguínea , Frequência Cardíaca , Hipertensão/fisiopatologia , Hipóxia/fisiopatologia , Animais , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
3.
Anticancer Res ; 39(8): 4503-4509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366552

RESUMO

BACKGROUND/AIM: Oral administration of Pantoea agglomerans-derived lipopolysaccharide (LPSp) has been reported to have a preventive effect against various lifestyle-related diseases. Therefore, we examined the preventive effect on high blood pressure, which is a kind of reserve arm for lifestyle-related diseases. MATERIALS AND METHODS: Spontaneous hypertensive rat (SHR) and WKY rat were bred from 6 to 16 weeks of age. SHR were orally administered 100 µg/kg LPSp and 0.1% NaCl, and blood pressure was measured at 6, 10, 13 and 16 weeks. Furthermore, at 16 weeks of age, blood biochemical markers were measured and microbial community composition was analyzed. RESULTS: SHRs developed hypertension with age, which was exacerbated by salt loading. Although there was almost no reduction in blood pressure in SHRs that received LPSp. It was suppressed at 13-16 weeks of age in those with salt loading. CONCLUSION: Oral administration of LPSp showed a preventive effect on salt-loaded hypertension.


Assuntos
Citocinas/genética , Hipertensão/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Pantoea/química , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipertensão/genética , Hipertensão/patologia , Lipopolissacarídeos/química , Masculino , Fagocitose/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Sais/toxicidade
4.
Adv Exp Med Biol ; 1193: 1-33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368095

RESUMO

Several review articles have been published on the neurobehavioral actions of acetaldehyde and other ethanol metabolites as well as in major alcohol-related disorders such as cancer and liver and lung disease. However, very few reviews dealt with the role of alcohol metabolism in the adverse cardiac and autonomic effects of alcohol and their potential underlying mechanisms, particularly in vulnerable populations. In this chapter, following a brief overview of the dose-related favorable and adverse cardiovascular effects of alcohol, we discuss the role of ethanol metabolism in its adverse effects in the brainstem and heart. Notably, current knowledge dismisses a major role for acetaldehyde in the adverse autonomic and cardiac effects of alcohol because of its low tissue level in vivo. Contrary to these findings in men and male rodents, women and hypertensive individuals are more sensitive to the adverse cardiac effects of similar amounts of alcohol. To understand this discrepancy, we discuss the autonomic and cardiac effects of alcohol and its metabolite acetaldehyde in a model of hypertension, the spontaneously hypertensive rat (SHR) and female rats. We present evidence that enhanced catalase activity, which contributes to cardioprotection in hypertension (compensatory) and in the presence of estrogen (inherent), becomes detrimental due to catalase catalysis of alcohol metabolism to acetaldehyde. Noteworthy, studies in SHRs and in estrogen deprived or replete normotensive rats implicate acetaldehyde in triggering oxidative stress in autonomic nuclei and the heart via (i) the Akt/extracellular signal-regulated kinases (ERK)/nitric oxide synthase (NOS) cascade and (ii) estrogen receptor-alpha (ERα) mediation of the higher catalase activity, which generates higher ethanol-derived acetaldehyde in female heart. The latter is supported by the ability of ERα blockade or catalase inhibition to attenuate alcohol-evoked myocardial oxidative stress and dysfunction. More mechanistic studies are needed to further understand the mechanisms of this public health problem.


Assuntos
Acetaldeído/farmacologia , Fármacos do Sistema Nervoso Autônomo/farmacologia , Etanol/metabolismo , Coração/efeitos dos fármacos , Animais , Feminino , Masculino , Miocárdio , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR
5.
Chem Biol Interact ; 311: 108778, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31377058

RESUMO

The aim of the present study was to evaluate the diuretic effect of 1,3,5,6-tetrahydroxyxanthone (THX), isolated from preparations of Garcinia achachairu Rusby (Clusiaceae) branches, in rats. Wistar normotensive (NTR) and spontaneously hypertensive rats (SHR) received a single oral treatment with THX, hydrochlorothiazide (HCTZ) or just vehicle (VEH). The effects of THX in combination with diuretics of clinical use, as well as with l-NAME, atropine, and indomethacin were also explored. Cumulative urine volume and urinary parameters were measured at the end of the 8-h or 24-h experiment. THX was able to stimulate 8-h and 24-h diuresis in both NTR and SHR, as well as urinary Na+ and K+ excretion, at a dose of 0.1 mg/kg; while 8-h urinary Cl- levels were only significantly increased in the group of animals treated with THX at the dose of 0.3 mg/kg. In addition, Ca2+ content was reduced in the 24-h urine of THX-treated NTR and SHR, like that obtained in the HCTZ (10 mg/kg) group. The combination with HCTZ or furosemide, but not with amiloride, significantly enhanced THX-induced diuresis. The diuretic effect with HCTZ plus THX treatment was accompanied by an increase of the urinary Na+, K+, and Cl- excretion. On the other hand, when given THX in combination with amiloride, there was a significant increase in Na+ and a decrease in K+ excretion, an effect characteristic of this class of diuretics. Moreover, the diuretic effect of THX was heightened after pretreatment with l-NAME, and its ability to induce diuresis was prevented neither in the presence of indomethacin nor in the presence of atropine. However, the pretreatment with atropine completely avoided the saluretic effect stimulated by THX, suggesting, at least in part, the role of muscarinic receptors in the renal effects of THX disclosed in this study.


Assuntos
Diurese/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Xantonas/farmacologia , Animais , Atropina/farmacologia , Clusiaceae/química , Clusiaceae/metabolismo , Feminino , Hidroclorotiazida/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Potássio/urina , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sódio/urina , Xantonas/uso terapêutico
6.
J Agric Food Chem ; 67(28): 7810-7820, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31264418

RESUMO

Antihypertensive peptides were screened from thermolysin hydrolysate of Cassia obtusifolia seeds (Jue Ming Zi) using two independent bioassay-guided fractionations, reversed-phase high-performance liquid chromatography (RP-HPLC), and strong cation-exchange (SCX) liquid chromatography coupled with angiotensin I-converting enzyme (ACE) inhibitory assay. The identical peptide in the most active RP-HPLC and SCX fractions was simultaneously de novo sequenced as FHAPWK with high-resolution mass spectrometry. FHAPWK (IC50 = 16.83 ± 0.90 µM) was further identified as a competitive inhibitor and a true inhibitor on ACE by a Lineweaver-Burk plot and preincubation experiment, respectively. The molecular docking simulation indicated that FHAPWK could interact with several key residues of the ACE active site, which is consistent with the result of the inhibitory kinetics study. Moreover, its antihypertensive effect was demonstrated using the animal model of spontaneously hypertensive rats. It is concluded that FHAPWK is the first reported antihypertensive peptide derived from thermolysin hydrolysate of C. obtusifolia seeds.


Assuntos
Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Cassia/química , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Peptídeos/química , Proteínas de Plantas/química , Animais , Descoberta de Drogas , Humanos , Masculino , Espectrometria de Massas , Simulação de Acoplamento Molecular , Ratos , Ratos Endogâmicos SHR , Sementes/química
7.
Life Sci ; 231: 116576, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211998

RESUMO

AIMS: Studies suggest that cardiovascular function in offspring can be epigenetically programmed by environmental changes during pregnancy. CaV1.2 channel plays a major role in the regulation of the vascular tone. This study investigated the effects and underlying mechanisms of exercise during pregnancy on CaV1.2 channel functional remodeling in hypertensive offspring. MAIN METHODS: Exercise groups were subjected to swimming at the first day of pregnancy and on a regular schedule thereafter for 3 weeks. Their offspring (6-month-old, male) were tested for baseline blood pressure, cardiovascular response, and vascular tone of the mesenteric artery. Mesenteric artery smooth muscle cells were taken to study the whole-cell current of the CaV1.2 channel. Western blotting, RT-PCR and DNA bisulfite sequencing PCR were performed to study the protein, mRNA expression and DNA methylation of the CaV1.2 channel α1C subunit. KEY FINDINGS: Exercise during pregnancy reduced the pressor response to norepinephrine and Bay K8644, and the depressor response to nifedipine in offspring of hypertensive rats. The level of the CaV1.2 channel in norepinephrine-induced vasoconstrictions decreased, and the whole-cell current of the CaV1.2 channel declined in the SHR-EX group. Further studies found that exercise during pregnancy reduced the protein and mRNA expression of the CaV1.2 channel α1C subunit and upregulated DNA methylation of the Cacna1c gene promoter region in the hypertensive offspring. SIGNIFICANCE: These data suggest that exercise during pregnancy improves vascular functional remodeling in offspring of hypertensive rats, downregulating the CaV1.2 channel function and protein expression, a change that is most likely caused by DNA methylation.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Hipertensão/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo , Epigênese Genética/genética , Repressão Epigenética , Feminino , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Gravidez , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
8.
J Agric Food Chem ; 67(24): 6757-6764, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31184153

RESUMO

In the present study we purified and identified peptides from broccoli protein hydrolysates and evaluated their angiotensin-converting enzyme (ACE) inhibitory activity in vitro and hypotensive effect in vivo. Three ACE inhibitory peptides were isolated and identified as IPPAYTK, LVLPGELAK, and TFQGPPHGIQVER, and their inhibitory IC50 values were 23.5, 184.0, and 3.4 µM, respectively. We then investigated the effect of gastrointestinal digestion on ACE inhibitory activity. We detected almost two times the ACE inhibitory activity of the peptide LVLPGELAK following simulated digestion than prior to digestion. LVLPGE and LAK, two novel peptides exhibiting high ACE inhibitory activity, were discovered following digestion and possessed IC50 values of 13.5 and 48.0 µM, respectively. The hypotensive effect of the peptides was assessed after oral administration to spontaneous hypertensive rats (SHRs). We found that LVLPGE and LAK demonstrated a significant hypotensive effect in vivo. Protein from broccoli may thus constitute a potential antihypertensive peptide source.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Brassica/química , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Proteínas de Plantas/química , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Mapeamento de Peptídeos , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
9.
Gen Physiol Biophys ; 38(3): 265-270, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184313

RESUMO

This study investigated the effect of lisinopril (angiotensin-converting enzyme inhibitor) on potential behavioural alterations in spontaneously hypertensive rats (SHR). Three groups of 15-17-week-old rats were investigated for 2 weeks: Wistar control group, SHR group and SHR+lisinopril group. Systolic blood pressure (SBP) was normal in Wistar rats, SHR expressed hypertension and lisinopril normalized the SBP. We observed increased time spent in and increased frequency of entries to the central area of the open field in SHR, while lisinopril induced a trend to reduce the time spent in the central area of the open field and reduced the frequency of entries there. There was a positive correlation between SBP and reduced anxiety-like behaviour in normotensive rats; no correlations in the SHR or SHR+lisinopril groups were observed. We conclude that lisinopril normalized the increase in SBP and partly reversed the alterations of anxiety-like behaviour in SHR.


Assuntos
Anti-Hipertensivos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/psicologia , Lisinopril/farmacologia , Animais , Ansiedade/prevenção & controle , Pressão Sanguínea , Hipertensão/fisiopatologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
10.
Sheng Li Xue Bao ; 71(3): 395-404, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31218330

RESUMO

The present study was designed to examine whether Ramipril (an inhibitor of angiotensin-converting enzyme) affected spontaneous hypertension-induced injury of cerebral artery by regulating connexin 43 (Cx43) expression. Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were randomly divided into WKY, WKY + Ramipril, SHR, and SHR + Ramipril groups (n = 8). The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin-eosin (HE) staining was used to show vascular remodeling. The expression and distribution of Cx43 was determined by using immunofluorescence and immunohistochemistry analysis. The protein and mRNA levels of Cx43 were examined by Western blot and real-time PCR analysis, respectively. The results showed that chronic Ramipril treatment significantly attenuated blood pressure elevation (P < 0.01, n = 8) and blood vessel wall thickness in SHR (P < 0.01, n = 8). The cerebral artery contraction rate in the SHR group was higher than that in the WKY group (P < 0.05, n = 8). The cerebral artery contraction rate in the SHR + Ramipril group was lower than that in the SHR group (P < 0.05, n = 8). Pretreatment with 2-APB (Cx43 non-specific blocker) or Gap26 (Cx43 specific blocker) significantly decreased the vasoconstriction rate, while pretreatment with AAP10 (Cx43 non-specific agonist) significantly increased the vasoconstriction in the SHR + Ramipril group (P < 0.05, n = 8). In addition, the expression of Cx43 mRNA and protein in cerebral arteries of SHR group was higher than that of WKY group (P < 0.05, n = 8). The mRNA and protein expression of Cx43 in cerebral arteries of SHR + Ramipril group was significantly lower than that of SHR group (P < 0.05, n = 8). These results suggest that Ramipril can down-regulate the expression of Cx43 mRNA and protein in cerebral arterial cells of SHR, lower blood pressure, promote vasodilation, and improve arterial damage and vascular dysfunction caused by hypertension.


Assuntos
Artérias Cerebrais/efeitos dos fármacos , Conexina 43/metabolismo , Ramipril/farmacologia , Remodelação Vascular , Animais , Pressão Sanguínea , Artérias Cerebrais/metabolismo , Hipertensão/tratamento farmacológico , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
11.
Acta Cir Bras ; 34(5): e201900505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166461

RESUMO

PURPOSE: To evaluate the cardioprotective response of the pharmacological modulation of ß-adrenergic receptors (ß-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. METHODS: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with ß-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with ß-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. RESULTS: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of ß-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of ß-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). CONCLUSION: The pharmacological modulation of ß-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Cardiotônicos/farmacologia , Isoproterenol/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Endogâmicos SHR , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
12.
Braz J Med Biol Res ; 52(6): e8009, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116256

RESUMO

The progression of myocardial injury secondary to hypertension is a complex process related to a series of physiological and molecular factors including oxidative stress. This study aimed to investigate whether moderate-intensity exercise (MIE) could improve cardiac function and oxidative stress in spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs and age-matched male Wistar-Kyoto rats were randomly assigned to exercise training (treadmill running at a speed of 20 m/min for 1 h continuously) or kept sedentary for 16 weeks. Cardiac function was monitored by polygraph; cardiac mitochondrial structure was observed by scanning electron microscope; tissue free radical production was measured using dihydroethidium staining. Expression levels of SIRT3 and SOD2 protein were measured by western blot, and cardiac antioxidants were assessed by assay kits. MIE improved the cardiac function of SHRs by decreasing left ventricular systolic pressure (LVSP), and first derivation of LVP (+LVdP/dtmax and -LVdP/dtmax). In addition, exercise-induced beneficial effects in SHRs were mediated by decreasing damage to myocardial mitochondrial morphology, decreasing production of reactive oxygen species, increasing glutathione level, decreasing oxidized glutathione level, increasing expression of SIRT3/SOD2, and increasing activity of superoxide dismutase. Exercise training in SHRs improved cardiac function by inhibiting hypertension-induced myocardial mitochondrial damage and attenuating oxidative stresses, offering new insights into prevention and treatment of hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Cardiomiopatias/prevenção & controle , Hipertensão/fisiopatologia , Mitocôndrias Cardíacas/fisiologia , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Masculino , Microscopia Eletrônica de Varredura , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Superóxido Dismutase/fisiologia
13.
Mol Med Rep ; 19(6): 4553-4560, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059021

RESUMO

Cardiac fibrosis secondary to long­term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin­angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long­term hypertension­induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala­treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd­treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II­induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala­mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas­related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti­hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.


Assuntos
Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Cardiomegalia/etiologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose/etiologia , Ventrículos do Coração/metabolismo , Hipertensão/complicações , Imidazóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina
14.
J Agric Food Chem ; 67(25): 7147-7156, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31140270

RESUMO

Egg proteins are recognized as excellent sources of bioactive peptides, such as angiotensin-converting enzyme inhibitory (ACEi) peptides. Oral administration of a thermolysin-digested egg white hydrolysate (T-EWH) caused a significant blood pressure reduction in spontaneously hypertensive rats; a further ACEi assay implied that its ACEi activity was enhanced after in vitro gastrointestinal (GI) digestion. These results indicated that T-EWH contained ACEi peptides resisting GI digestion and/or being further released during GI digestion. Therefore, the objective of this study was to identify these responsible ACEi peptides from T-EWH. The conventionally activity-guided fractionation was applied, coupled with a synchronized GI digestion throughout, during which both peptide yield and ACEi activity before and after the GI digestion were measured. Finally, six ACEi peptides (LAPYK, LKISQ, LKYAT, INKVVR, LFLIKH, and LGHWVY) with good GI resistance were identified with IC50 values <20 µM, especially LKYAT (0.09 µM). The structure-activity relationship of these peptides was discussed. The discovery of GI-resistant ACEi peptides could further support the application of egg white proteins as functional food ingredients.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Proteínas do Ovo/química , Trato Gastrointestinal/metabolismo , Hipertensão/metabolismo , Peptídeos/química , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Galinhas , Digestão , Clara de Ovo/química , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
15.
Food Chem Toxicol ; 130: 317-325, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128217

RESUMO

Triterpenoids are well known modulators of metabolic syndrome. One of the suggested modes of action (MoAs) involves peroxisome proliferator-activated receptor gamma (PPARγ) binding. In this study we aimed to: (i) evaluate in silico potential metabolites and PPARγ-mediated MoA of the sapogenin of the main saponin present in a purified saponins' mixture (PSM) from Astragalus glycyphylloides; (ii) estimate in silico and in vivo PSM's toxicity; and (iii) investigate in vivo antihyperglycaemic, hypolipidaemic, antioxidant and hepatoprotective effects of PSM. Metabolites and toxicity were predicted using Meteor and Derek Nexus expert systems (Lhasa Limited) and PPARγ binding was investigated using the software MOE (CCG Inc.). PSM's acute oral toxicity was evaluated in mice and the pharmacological effects were assessed in streptozotocin-induced diabetic spontaneously hypertensive rats (SHRs). Liver histopathology was studied as well. PPARγ weak partial agonism was predicted in silico for 24 probable/plausible Phase I metabolites which docking poses were clustered in 12 different binding modes with characteristic protein-ligand interactions. PSM's beneficial effects on the levels of blood glucose, triglycerides, and total cholesterol, on oxidative stress markers and liver histology in diabetic SHRs were comparable to those of the PPARγ ligand pioglitazone. PSM's safety profile was confirmed in silico and in vivo.


Assuntos
Astrágalo (Planta)/química , Síndrome Metabólica/tratamento farmacológico , Saponinas/química , Saponinas/farmacologia , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Diabetes Mellitus Experimental/tratamento farmacológico , Descoberta de Drogas , Feminino , Masculino , Camundongos , Estrutura Molecular , Estresse Oxidativo , PPAR gama/agonistas , Ligação Proteica , Conformação Proteica , Ratos , Ratos Endogâmicos SHR , Saponinas/toxicidade
16.
J Biochem ; 166(3): 223-230, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004484

RESUMO

Vinegar soaked black soybean is a traditional Chinese food widely used for the treatment of hypertension. While its pharmacodynamic substance was not fully unveiled. It contained abundant glutelin, thus the purpose of this study was to obtain potent antihypertensive peptides from vinegar soaked black soybean. Black soybean was soaked with vinegar and then glutelin was first catalyzed by alcalase. Ultrafiltration, ion exchange chromatography and reversed-phase high performance liquid chromatography were sequentially applied to separate and purify the angiotensin-I converting enzyme (ACE) inhibitory peptides from glutelin hydrolysates. As a result, the fraction L1-4 with the highest ACE inhibitory activity (83.41%) at the final concentration of 0.01 mg/ml was obtained and five peptides were then identified. These peptides were further optimized by virtual screening combining with in silico proteolysis. Finally, a novel tetrapeptide Phe-Gly-Ser-Phe (FGSF) was obtained. FGSF exhibited high in vitro ACE inhibitory activity (IC50 = 117.11 µM) and in vivo hypotensive effect which maximally reduced systolic blood pressure of 21.95 mmHg at 20 mg/kg body weight in spontaneously hypertensive rats. Our study demonstrated that FGSF derived from vinegar soaked black soybean might be used as a promising ingredient for pharmaceuticals against hypertension and its related diseases.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Glutens/química , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Soja/química , Ácido Acético/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Relação Dose-Resposta a Droga , Glutens/isolamento & purificação , Hipertensão/metabolismo , Masculino , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade
17.
Eur J Pharmacol ; 853: 336-344, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30978321

RESUMO

Despite the success which was achieved in the treatment of arterial hypertension, the problem remains actual. At the departments of pharmaceutical chemistry and pharmacology of the Zaporozhye State Medical Institute (Ukraine), our research team isolated the compound 1-(ß-phenylethyl)-4-amino-1,2,4-triazolium bromide (Hypertril) as derivative of 4-amino-1,2,4-triazole. The objectives of this investigation were the study of cardioprotective and antihypertensive activities of this new compound Hypertril and we used the Spontaneously hypertensive rats (SHR) as an experimental model. We discovered that Hypertril has a reliable dose-dependent antihypertensive effect in the dose range 5-20 mg/kg after 30-day administration and this antihypertensive effect of Hypetril competes or significantly exceeds Metoprolol (20 mg/kg). Our studies obtained evidence of a dose-dependent improvement of myocardial energy metabolism. Hypertril reduces the manifestations of secondary mitochondrial dysfunction due to arterial hypertension. Hypertril can prevent oxidative modification of the protein; also Hypertril reduces the insufficiency of mitochondrial pores. As a result, Hypertril increases the content of ATP in the myocardium of SHR, normalizes the activity of mitochondrial enzymes, decreases lactate production and increases pyruvate. Hypertril enhances the cardioprotective effects of NO and increases the resistance of the cardiomyocytes to ischemia. The use of Hypertril leads to a dose-dependent increase of the density of cardiomyocyte nuclei, significant increase RNA content in nuclei and the cytoplasm of cardiomyocytes, and an increase of the nuclear-cytoplasmic index. These changes indicate a decrease of myocardial hypertrophy.


Assuntos
Anti-Hipertensivos/farmacologia , Cardiotônicos/farmacologia , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Endogâmicos SHR
18.
Biomed Pharmacother ; 114: 108799, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30951948

RESUMO

S-amlodipine has been broadly used to treat hypertension, but its protective effects and underlying mechanism remain controversial. The purpose of our study was to investigate the mechanism by which S-amlodipine improves endothelial dysfunction. Specifically, we investigated if S-amlodipine regulates RANK/RANKL/OPG and micro-RNA 155 (miR-155) levels. Spontaneous hypertensive rats (SHR) were randomly divided into two groups: SHR (n = 12) and S-amlodipine (n = 12). We found that left ventricular ejection fraction (LVEF) increased significantly in the S-amlodipine group compared to the SHR group. After 10 weeks of S-amlodipine treatment, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were significantly lower and eNOS and NO production was significantly higher in the S-amlodipine group compared to the SHR group. In human umbilical vein endothelial cells (HUVECs), miR-155, RANK, and RANKL levels were significantly decreased, while OPG mRNA levels were significantly increased in the S-amlodipine group. HUVECs were transfected with miR-155 mimics or an inhibitor to determine the relationship between miR-155 and RANK/RANKL/OPG and NF-κB signaling. OPG mRNA levels following miR-155 inhibition were significantly higher compared to levels following treatment with miR-155 mimics. S-amlodipine significantly inhibited RANKL expression and NF-κB phosphorylation, and there were no significant differences in response to the NF-κB inhibitor (Bay110785). RANKL expression and NF-κB phosphorylation significantly decreased in the miR-155 inhibitor group. Furthermore, OPG protein expression significantly increased in response to miR-155 inhibition and S-amlodipine treatment (all p < 0.05). Our results indicate that S-amlodipine inhibits inflammation and protects against endothelial dysfunction, likely via regulating the RANK/RANKL/OPG pathway, which appears to be downstream of miR-155.


Assuntos
Anlodipino/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , MicroRNAs/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Linhagem Celular , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Interleucina-6/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Disfunção Ventricular Esquerda/dietoterapia , Disfunção Ventricular Esquerda/metabolismo
19.
Physiology (Bethesda) ; 34(3): 178-188, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30968750

RESUMO

One of the mechanisms responsible for blood pressure (BP) regulation is thought to be oxidative stress. In this review, we highlight preclinical studies that strongly support a role for oxidative stress in development and maintenance of hypertension in male animals, based on depressor responses to antioxidants, particularly tempol and apocynin. In females, oxidative stress seems to be important in the initial development of hypertension. However, whether maintenance of hypertension in females is mediated by oxidative stress is not clear. In clinical studies, pharmacological intervention to reduce BP with antioxidants has conflicting results, mostly negative. This review will discuss the uncertainties regarding blood pressure control and oxidative stress and potential reasons for these outcomes.


Assuntos
Antioxidantes/administração & dosagem , Hipertensão/metabolismo , Estresse Oxidativo , Caracteres Sexuais , Acetofenonas/administração & dosagem , Animais , Óxidos N-Cíclicos/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/etiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Marcadores de Spin
20.
Nutrients ; 11(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934575

RESUMO

Protocatechuic acid (PCA), a strong antioxidant, has been reported for its cardiovascular-protective effects. This study aimed to investigate the effects of PCA administration on vascular endothelial function, mediated by insulin and insulin-like growth factor-1 (IGF-1), and antioxidant activities in aging hypertension. Thirty-six-week-old male aging spontaneously hypertensive rats were randomly divided into vehicle control (SHR) and PCA (SHR+PCA) groups, while age-matched Wistar⁻Kyoto rats (WKY) served as the normotensive vehicle control group. The oral PCA (200 mg/kg/day) was administered daily for a total of 12 weeks. When the rats reached the age of 48 weeks, the rat aortas were isolated for the evaluation of vascular reactivity and Western blotting. Also, nitric oxide (NO) production and antioxidant activities were examined among the three groups. The results showed that, when compared with the SHR group, the insulin-induced and IGF-1-induced vasorelaxation were significantly improved in the SHR+PCA group. There was no significant difference in the endothelium-denuded vessels among the three groups. After the pre-incubation of phosphatidylinositol 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the vasorelaxation was abolished and comparable among the three groups. The protein levels of insulin receptors, IGF-1 receptors, phospho-protein kinase B (p-Akt)/Akt, and phospho-endothelial NOS (p-eNOS)/eNOS in aortic tissues were significantly enhanced in the SHR+PCA group when compared with the SHR group. Moreover, significant improvements of nitrate/nitrite concentration and antioxidant activities, including superoxide dismutase, catalase, and total antioxidants, were also found in the SHR+PCA group. In conclusion, the 12 weeks of PCA administration remarkably improved the endothelium-dependent vasorelaxation induced by insulin and IGF-1 in aging hypertension through enhancing the PI3K⁻NOS⁻NO pathway. Furthermore, the enhanced antioxidant activities partly contributed to the improved vasorelaxation.


Assuntos
Envelhecimento , Hidroxibenzoatos/farmacologia , Insulina/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca , Humanos , Hidroxibenzoatos/administração & dosagem , Fator de Crescimento Insulin-Like I , Masculino , Polienos , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
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