Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.161
Filtrar
1.
Behav Pharmacol ; 35(7): 399-407, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39230435

RESUMO

The l -arginine ( l -Arg)/nitric oxide/cyclic GMP/potassium channel (K ATP ) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l -Arg/nitric oxide/cyclic GMP/K ATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l -Arg/nitric oxide/cyclic GMP/K ATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l -Arg (a precursor of nitric oxide), S-nitroso- N -acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro- l -arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a K ATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20 min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/K ATP channel pathway.


Assuntos
Analgésicos , Arginina , GMP Cíclico , Canais KATP , NG-Nitroarginina Metil Éster , Óxido Nítrico , Receptores Opioides , Rutina , Transdução de Sinais , Animais , Masculino , Camundongos , Arginina/farmacologia , Óxido Nítrico/metabolismo , Rutina/farmacologia , Analgésicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides/efeitos dos fármacos , Canais KATP/metabolismo , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Glibureto/farmacologia , Citrato de Sildenafila/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Naloxona/farmacologia , Sulfonas/farmacologia , Piperazinas/farmacologia , Purinas/farmacologia , S-Nitroso-N-Acetilpenicilamina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Antagonistas de Entorpecentes/farmacologia , Relação Dose-Resposta a Droga , Doadores de Óxido Nítrico/farmacologia
2.
PLoS One ; 19(9): e0308338, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39240961

RESUMO

There is evidence that nitric oxide (NO) modulates the metabolism of glucose and lipid, and some antihypertensive medications have been shown to affect glucose and lipid metabolism. Peristrophe bivalvis is a medicinal plant that has been shown to have antihypertensive properties. The study investigated the effect of aqueous extract of Peristrophe bivalvis leaf (APB) on fasting blood glucose level (FBG) and lipid profile in rats pretreated with nitro-L-arginine methyl ester (L-NAME). Male Wistar rats (150-170 g, n=30) were randomly divided into two groups: control (CT, n=5) and L-NAME pretreated (n=25). CT received 5 mL/kg of distilled water [DW]) while L-NAME pretreated group received 60 mg/kg of L-NAME (L-NAME60) for eight weeks. After eight weeks, the L-NAME pretreated group was randomly subdivided into L-NAME group (LN), L-NAME recovery group (LRE), L-NAME ramipril group (LRA), and L-NAME APB group (LAPB). The groups received L-NAME60+DW, DW, L-NAME60+10 mg/kg ramipril, and L-NAME60+APB (200 mg/kg), respectively, for five weeks. Serum NO, lipid profile, cyclic guanosine monophosphate (cGMP), and insulin were measured by spectrophotometry, assay kits, and ELISA, respectively. Data were analysed using ANOVA at p < 0.05. At the eighth week, a fall in FBG and an increase in triglyceride, total cholesterol, and low-density lipoprotein cholesterol were recorded in L8 compared to CT. The same effects were also noticed in the thirteenth week in LN. However, FBG was significantly increased and lipid levels were decreased in LAPB compared to LN. A significant increase was observed in cGMP level in LAPB compared to LN. The study showed that APB corrected the hyperlipidemia and hypoglycemia caused by L-NAME, and this effect might be via the activation of cGMP.


Assuntos
Glicemia , Lipídeos , NG-Nitroarginina Metil Éster , Extratos Vegetais , Folhas de Planta , Ratos Wistar , Animais , Masculino , Extratos Vegetais/farmacologia , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Folhas de Planta/química , Ratos , Lipídeos/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/sangue , Inibidores Enzimáticos/farmacologia
3.
Cell Biochem Funct ; 42(7): e4119, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39244707

RESUMO

In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.


Assuntos
Curcumina , Hipertensão , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , NG-Nitroarginina Metil Éster , Animais , Masculino , Ratos , Curcumina/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Nefropatias/patologia , Nefropatias/metabolismo , Nefropatias/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
4.
Bull Exp Biol Med ; 177(5): 610-615, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39342010

RESUMO

Intrauterine hypoxia (gestation days 15-19, pO2 65 mm Hg, duration 4 h) led to an increase in the expression of p53, beclin-1, endothelial NO synthase (eNOS), and caspase-3 proteins in cardiomyocytes and reduced the number of mast cells in the heart of 60-day-old albino rats. Administration of a non-opiate analogue of leu-enkephalin (NALE peptide: Phe-D-Ala-Gly-Phe-Leu-Arg, 100 µg/kg) on days 2-6 of the neonatal period decreased the severity of delayed posthypoxic myocardial reaction. The content of eNOS+ cardiomyocytes and the total number of mast cells of these animals did not differ from the control parameters; the content of p53+ cardiomyocytes was significantly lower than in animals exposed to intrauterine hypoxia. The cardioprotective activity of NALE was partially neutralized by co-administration with the NO synthase inhibitor (L-NAME, 50 mg/kg). Correction of the delayed posthypoxic changes, similar to the effects of NALE peptide, was observed after neonatal administration of its arginine-free analogue, G peptide (Phe-D-Ala-Gly-Phe-Leu-Gly; 100 µg/kg). Non-opiate analogues of leu-enkephalin NALE and G peptides can be considered as promising substances capable of preventing long-term cardiac consequences of intrauterine hypoxia.


Assuntos
Animais Recém-Nascidos , Hipóxia Fetal , Miócitos Cardíacos , Animais , Ratos , Feminino , Hipóxia Fetal/tratamento farmacológico , Hipóxia Fetal/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Gravidez , Encefalina Leucina/farmacologia , Encefalina Leucina/metabolismo , Caspase 3/metabolismo , Caspase 3/genética , Óxido Nítrico Sintase Tipo III/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia
5.
J Nutr Sci ; 13: e34, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39314530

RESUMO

Coffee is one of the most popular beverages worldwide, and there is an increasing concern of the health risk of coffee consumption in pregnancy. Preeclampsia (PE) is a serious pregnancy disease that causes elevated blood pressure and proteinuria in pregnant women and growth restriction of fetuses due to poorly developed placental vasculature. The aim of our study is to investigate the possible effect of coffee intake during pregnancy in rats with potential underlying vasculature conditions. The endothelial nitric oxide synthase inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME) at a high dose (125 mg/kg/d) was used to induce PE in pregnant rats, which were used as the positive control group. In addition, low-dose L-NAME (10 mg/kg/d) was used to simulate the compromised placental vasculature function in pregnant rats. Coffee was given together with low-dose L-NAME to the pregnant rats from gestational day 10.5-18.5. Our results show that the pregnant rats treated with low-dose L-NAME + coffee, but not low-dose L-NAME alone, developed PE symptoms such as prominent fetal growth restriction, hypertension, and proteinuria. Therefore, our findings suggest that coffee intake during pregnancy may cause an increased risk of PE in susceptible women.


Assuntos
Café , NG-Nitroarginina Metil Éster , Pré-Eclâmpsia , Proteinúria , Animais , Gravidez , Feminino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Retardo do Crescimento Fetal , Pressão Sanguínea , Placenta , Ratos Sprague-Dawley , Inibidores Enzimáticos/farmacologia , Hipertensão , Óxido Nítrico Sintase Tipo III/metabolismo , Modelos Animais de Doenças
6.
Life Sci ; 355: 122995, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39159720

RESUMO

AIMS: Tacrolimus is an effective immunosuppressant commonly used post-transplantation and in certain autoimmune diseases. However, its long-term administration is associated with renal fibrosis through transforming growth factor-beta/suppressor of mother against decapentaplegic (TGF-ß/Smad) signaling that could be partly attributed to endothelial dysfunction alongside decreased nitric oxide (NO) release. Our study aimed to investigate the prospective renal anti-fibrotic effect of enhanced NO production by nebivolol against tacrolimus-stimulated TGF-ß1/Smad3 signaling. MATERIALS AND METHODS: To illustrate the proposed mechanism of nebivolol, Nω-nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administered with nebivolol. Rats were treated for 30 days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups. KEY FINDINGS: Our results revealed that renal NO content was reduced in tacrolimus-treated rats, while treatment with tacrolimus/nebivolol enhanced NO content via up-regulated endothelial nitric oxide synthase (eNOS), but down-regulated inducible nitric oxide synthase (iNOS) expression. That participated in the inhibition of TGF-ß1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the defensive effects of nebivolol. Subsequently, the deposition of collagen I and alpha-smooth muscle actin (α-SMA) was retarded by nebivolol, emphasized by reduced Masson's trichrome staining. In accordance, there was a strong negative correlation between eNOS and both TGF-ß1 and collagen I protein expression. The protective effects of nebivolol were further confirmed by the improvement in kidney function biomarkers and histological features. SIGNIFICANCE: It can be suggested that treatment with nebivolol along with tacrolimus could effectively suppress renal TGF-ß1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.


Assuntos
Colágeno Tipo I , Rim , Nebivolol , Óxido Nítrico Sintase Tipo III , Óxido Nítrico , Transdução de Sinais , Proteína Smad3 , Tacrolimo , Fator de Crescimento Transformador beta1 , Animais , Nebivolol/farmacologia , Proteína Smad3/metabolismo , Óxido Nítrico/metabolismo , Tacrolimo/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Ratos , Óxido Nítrico Sintase Tipo III/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Colágeno Tipo I/metabolismo , Imunossupressores/farmacologia , Fibrose , NG-Nitroarginina Metil Éster/farmacologia , Ratos Wistar , Ratos Sprague-Dawley
7.
Redox Biol ; 76: 103308, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39167912

RESUMO

In rats decreased bioavailability of nitric oxide induces oxidative stress and right heart failure. Oxidative stress can activate matrix metalloproteinase-2 (MMP2). We addressed the question whether increasing oxidative defense by administration of the SOD mimetic Tempol or direct inhibition of MMP2 activity by SB-3CT mitigates right heart failure. Rats received l-NAME for four weeks and during week three and four treatment groups received either Tempol or SB-3CT in addition. After four weeks heart function was analyzed by echocardiography, organ weights and expression of NPPB and COL1A1 were analyzed, oxidative stress was monitored by DHE-staining and MMP2 activity was quantified by proteolytic auto-activation, zymography, and troponin I degradation. l-NAME induced oxidative stress and MMP2 activity stronger in the right ventricle than in the left ventricle. Troponin I, a MMP2 substrate, was degraded in right ventricles. Tempol reduced oxidative stress and preferentially affected the expression of fibrotic genes (i.e. COL1A1) and fibrosis. Tempol and SB-3CT mitigated right but not left ventricular hypertrophy. Neither SB-3CT nor Tempol alone strongly improved right ventricular function. In conclusion, both MMP2 activity and oxidative stress contribute to right ventricular failure but neither is MMP2 activation linked to oxidative stress nor does oxidative stress and MMP2 activity have common targets.


Assuntos
Óxidos N-Cíclicos , Insuficiência Cardíaca , Metaloproteinase 2 da Matriz , NG-Nitroarginina Metil Éster , Estresse Oxidativo , Marcadores de Spin , Animais , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Estresse Oxidativo/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Masculino , Colágeno Tipo I/metabolismo , Fibrose , Cadeia alfa 1 do Colágeno Tipo I , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Troponina I/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Modelos Animais de Doenças , Compostos Heterocíclicos com 1 Anel , Sulfonas
8.
Physiol Rep ; 12(15): e16147, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39097984

RESUMO

The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.


Assuntos
Animais Recém-Nascidos , Pós-Condicionamento Isquêmico , Traumatismo por Reperfusão Miocárdica , NG-Nitroarginina Metil Éster , Óxido Nítrico , Ratos Wistar , Animais , Óxido Nítrico/metabolismo , Pós-Condicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , NG-Nitroarginina Metil Éster/farmacologia , Precondicionamento Isquêmico Miocárdico/métodos , Doadores de Óxido Nítrico/farmacologia , Masculino , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Molsidomina/farmacologia , Molsidomina/análogos & derivados
9.
Sci Rep ; 14(1): 19347, 2024 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164321

RESUMO

The aim of this study was to investigate the possible protective effects of apelin, which is known to have antioxidant and anti-inflammatory effects, on changes in neurogenesis in newborns of pregnant rats with L-NAME-induced preeclampsia. Wistar albino female rats were divided into four experimental groups: Control, Apelin, Preeclampsia and Preeclampsia + Apelin. Blood pressure was measured on the 5th, 11th and 17th days of gestation, urine protein was analyzed from urine samples collected for 24 h on the 6th, 12th and 18th days and serum creatinine was analyzed from serum samples. Maternal kidney and placenta tissues were obtained to establish the preeclampsia model, and neonatal brain tissues including the cortex, hippocampus and cerebellum regions were obtained to investigate neurogenesis and examined by histological and immunohistochemical methods. The number of newborns, body weight and brain weight of the newborns were measured. eNOS, IL-10, nNOS and NO levels in the brain analyzed via ELISA. Mean arterial pressure, urine protein and serum creatinine increased in the preeclampsia. Newborn weight decreased in the Preeclampsia group, the values in the Preeclampsia + Apelin group were closer to the Control and Apelin groups. In the Preeclampsia group, edema and dilatation in the proximal and distal tubules of kidneys, perivillous fibrin deposition and increase in syncytial nodules of placenta were observed. VEGF immunoreactivity decreased and iNOS immunoreactivity increased in both kidney and placenta. In neonatal brain tissue examinations, cytotoxic edema accompanied by thinning of cortex, delayed migration and lower cell counts in the hippocampus, and increase in intercellular spaces and EGL thickening in the cerebellum were observed in the preeclampsia. Expression of NeuN, GFAP, MBP, IL-10, eNOS, nNOS and NO levels decreased, whereas expression of Iba-1 increased in the preeclampsia. In the Preeclampsia + Apelin group, these findings were similar to the Control and Apelin groups. Apelin administration was found to be beneficial for preventing the adverse consequences of preeclampsia, but further experimental and clinical studies are needed to better understand these effects.


Assuntos
Animais Recém-Nascidos , Apelina , Encéfalo , NG-Nitroarginina Metil Éster , Neurogênese , Pré-Eclâmpsia , Ratos Wistar , Feminino , Gravidez , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/metabolismo , Animais , Apelina/metabolismo , Neurogênese/efeitos dos fármacos , Ratos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Placenta/metabolismo , Modelos Animais de Doenças , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Interleucina-10/metabolismo , Interleucina-10/sangue , Óxido Nítrico Sintase Tipo I/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 327(4): H793-H803, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39058435

RESUMO

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.


Assuntos
Diabetes Gestacional , Insulina , Microvasos , Óxido Nítrico Sintase Tipo III , Óxido Nítrico , Vasodilatação , Feminino , Diabetes Gestacional/fisiopatologia , Diabetes Gestacional/metabolismo , Humanos , Gravidez , Vasodilatação/efeitos dos fármacos , Insulina/farmacologia , Adulto , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Microvasos/metabolismo , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Acetilcolina/farmacologia , Vasodilatadores/farmacologia , Fosforilação , Estresse Oxidativo/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Tirosina/análogos & derivados , Tirosina/metabolismo , Estudos de Casos e Controles , NG-Nitroarginina Metil Éster/farmacologia , Pele/irrigação sanguínea
11.
Cell Biochem Funct ; 42(5): e4095, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39004810

RESUMO

This study aimed to investigate the effects of the n-hexane fraction of the ethanolic seed extract of PG (NFESEPG) on hypertension induced by Nω-nitro-L-arginine methyl ester (L-NAME) in rats. Specifically, the study examined the impact of NFESEPG on blood pressure, oxidative stress markers, NO concentration, angiotensin-converting enzyme (ACE) and arginase activities, and cardiac biomarkers in hypertensive rats. The study involved collecting, identifying, and processing the PG plant to obtain the ethanolic seed extract. The extract was then partitioned with solvents to isolate the n-hexane fraction. Hypertension was induced in rats by oral administration of L-NAME for 10 days, while concurrent treatment with NFESEPG at two doses (200 and 400 mg/kg/day) was administered orally. Blood pressure was measured using a noninvasive tail-cuff method, and various biochemical parameters were assessed. Treatment with both doses of NFESEPG significantly reduced systolic and diastolic blood pressure in L-NAME-induced hypertensive rats. Additionally, NFESEPG administration increased NO concentration and decreased ACE and arginase activities, malondialdehyde (MDA) levels, and cardiac biomarkers in hypertensive rats. The findings indicate that NFESEPG effectively lowered blood pressure in hypertensive rats induced by L-NAME, potentially through mechanisms involving the modulation of oxidative stress, NO bioavailability, and cardiac biomarkers. These results suggest the therapeutic potential of NFESEPG in managing hypertension and related cardiovascular complications.


Assuntos
Hexanos , Hipertensão , NG-Nitroarginina Metil Éster , Piper , Extratos Vegetais , Sementes , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Ratos , NG-Nitroarginina Metil Éster/farmacologia , Masculino , Sementes/química , Hexanos/química , Piper/química , Pressão Sanguínea/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Óxido Nítrico/metabolismo , Arginase/metabolismo , Peptidil Dipeptidase A/metabolismo
12.
Int J Mol Sci ; 25(13)2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-39000349

RESUMO

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.


Assuntos
Aorta , GMP Cíclico , Emulsões , Labetalol , Óxido Nítrico Sintase Tipo III , Vasodilatação , Animais , Vasodilatação/efeitos dos fármacos , Ratos , Aorta/efeitos dos fármacos , Aorta/metabolismo , Labetalol/farmacologia , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ratos Sprague-Dawley , Humanos , Lipídeos , Fosforilação/efeitos dos fármacos , Cálcio/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo
13.
Clin Sci (Lond) ; 138(14): 901-920, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38949825

RESUMO

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.


Assuntos
Pressão Sanguínea , Hipertensão , Inflamação , Rim , Camundongos Endogâmicos C57BL , Cloreto de Sódio na Dieta , Animais , Hipertensão/imunologia , Hipertensão/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Masculino , Feminino , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Rim/imunologia , Rim/efeitos dos fármacos , Inflamação/imunologia , Linfangiogênese/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Camundongos , Hidralazina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Modelos Animais de Doenças , Gônadas/efeitos dos fármacos
14.
Food Res Int ; 191: 114717, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39059914

RESUMO

To reveal the interaction of oxidative stress and protein S-nitrosylation on mitochondrial pathway apoptosis and tenderness development in postmortem yak meat. Herein, we selected yak longissimus dorsi muscle as the research object and treated hydrogen peroxide (H2O2) with S-nitrosoglutathione agent (GSNO) as well as Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) in mixed injections with 0.9 % saline as a control group, followed by incubation at 4 °C for 12, 24, 72, 120 and 168 h. Results showed that this interaction significantly increased mitochondrial ROS and NO content (P < 0.05) while weakening the antioxidant capacity of GSH and TRX redox response systems or accelerating the Ca2+ release process, leading to mitochondrial functional impairment and increased apoptosis rate. Notably, the H2O2 + L-NAME group showed more pronounced apoptosis. Hence, we suggest that the interaction between oxidative stress and protein S-nitrosylation could positively regulate yak meat tenderization.


Assuntos
Apoptose , Peróxido de Hidrogênio , Estresse Oxidativo , Animais , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bovinos , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Óxido Nítrico/metabolismo , Carne/análise , Mudanças Depois da Morte , Espécies Reativas de Oxigênio/metabolismo , S-Nitrosoglutationa/farmacologia , S-Nitrosoglutationa/metabolismo , Antioxidantes/metabolismo , Antioxidantes/farmacologia
15.
Int J Mol Sci ; 25(14)2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39062939

RESUMO

Recently, we compared an interplay of the adenosine system and nitric oxide (NO) in the regulation of renal function between male normoglycaemic (NG) and streptozotocin-induced diabetic rats (DM). Considering the between-sex functional differences, e.g., in the NO status, we present similar studies performed in female rats. We examined if the theophylline effects (non-selective adenosine antagonist) in NG and DM females with or without active NO synthases differed from the earlier findings. In anaesthetised female Sprague Dawley rats, both NG and DM, untreated or after NO synthesis blockade with L-NAME, theophylline effects, on blood pressure, renal hemodynamics and excretion, and renal tissue NO were investigated. Renal artery blood flow (Transonic probe), cortical, outer-, and inner-medullary flows (laser-Doppler technique), and renal tissue NO signal (selective electrode) were measured. In contrast to males, in female NG and DM rats, theophylline induced renal vasodilation. In NO-deficient females, theophylline induced comparable renal vasodilatation, confirming the vasoconstrictor influence of the renal adenosine. In NG and DM females with intact NO synthesis, adenosine inhibition diminished kidney tissue NO, contrasting with an increase reported in males. Lowered baseline renal excretion in DM females suggested stimulation of renal tubular reabsorption due to the prevalence of antinatriuretic over natriuretic tubular action of adenosine receptors. An opposite inter-receptor balance pattern emerged previously from male studies. The study exposed between-sex functional differences in the interrelation of adenosine and NO in rats with normoglycaemia and streptozotocin diabetes. The findings also suggest that in diabetes mellitus, the abundance of individual receptor types can distinctly differ between females and males.


Assuntos
Adenosina , Diabetes Mellitus Experimental , Hemodinâmica , Rim , Óxido Nítrico , Ratos Sprague-Dawley , Teofilina , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Feminino , Óxido Nítrico/metabolismo , Masculino , Adenosina/metabolismo , Ratos , Rim/metabolismo , Teofilina/farmacologia , Estreptozocina , Caracteres Sexuais , NG-Nitroarginina Metil Éster/farmacologia , Pressão Sanguínea/efeitos dos fármacos
16.
Arch Biochem Biophys ; 758: 110059, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38936683

RESUMO

BACKGROUND: It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. OBJECTIVE: To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.


Assuntos
Óxido Nítrico , Animais , Concentração de Íons de Hidrogênio , Óxido Nítrico/metabolismo , Masculino , Ratos , Ratos Wistar , Óxido Nítrico Sintase Tipo III/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NG-Nitroarginina Metil Éster/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Óxido Nítrico Sintase/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 327(2): H364-H369, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38847757

RESUMO

The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10-10 to 10-1 M, 33°C) alone and in combination with 15 mM NG-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.


Assuntos
Estudos Cross-Over , Microcirculação , NF-kappa B , Óxido Nítrico , Pele , Humanos , Feminino , Adulto , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/metabolismo , NF-kappa B/metabolismo , Método Simples-Cego , Microcirculação/efeitos dos fármacos , Óxido Nítrico/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Vasodilatação/efeitos dos fármacos , Adulto Jovem , Acetilcolina/farmacologia , Voluntários Saudáveis , Vasodilatadores/farmacologia , Inibidores Enzimáticos/farmacologia , Salicilatos/farmacologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos
18.
Cell Tissue Res ; 397(2): 111-124, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38829397

RESUMO

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-L-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.


Assuntos
Peixes-Gato , Gametogênese , Kisspeptinas , NG-Nitroarginina Metil Éster , Óxido Nítrico , Animais , Óxido Nítrico/metabolismo , Peixes-Gato/metabolismo , Kisspeptinas/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Feminino , Gametogênese/efeitos dos fármacos , Esteroides/biossíntese , Óxido Nítrico Sintase/metabolismo , Testículo/metabolismo , Testículo/efeitos dos fármacos , Gônadas/metabolismo , Gônadas/efeitos dos fármacos , Ovário/metabolismo
19.
J Vasc Res ; 61(4): 166-178, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880090

RESUMO

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality but without available evidence-based therapies. It is essential to investigate changes in gene expression profiles in preclinical HFpEF animal models, with the aim of searching for novel therapeutic targets. METHODS: Wild-type male C57BL/6J mice were administrated with a combination of high-fat diet (HFD) and inhibition of constitutive nitric oxide synthase using N-nitro-l-arginine methyl ester (l-NAME) for 5 and 7 weeks. RNA sequencing was conducted to detect gene expression profiles, and bioinformatic analysis was performed to identify the core genes, pathways, and biological processes involved. RESULTS: A total of 1,347 genes were differentially expressed in the heart at week 5 and 7 post-intervention. Gene Ontology enrichment analysis indicated that these greatly changed genes were involved mainly in cell adhesion, neutrophil chemotaxis, cell communication, and other functions. Using hierarchical cluster analysis, these differentially expressed genes were classified into 16 profiles. Of these, three significant profiles were ultimately identified. Gene co-expression network analysis suggested troponin T type 1 (Tnnt1) directly regulated 31 neighboring genes and was considered to be at the core of the associated gene network. CONCLUSION: The combined application of RNA sequencing, hierarchical cluster analysis, and gene network analysis identified Tnnt1 as the most important gene in the development of HFpEF.


Assuntos
Modelos Animais de Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Insuficiência Cardíaca , Camundongos Endogâmicos C57BL , Volume Sistólico , Transcriptoma , Função Ventricular Esquerda , Animais , Masculino , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/metabolismo , RNA-Seq , Transdução de Sinais , Dieta Hiperlipídica , Regulação da Expressão Gênica , NG-Nitroarginina Metil Éster/farmacologia , Troponina T/genética , Troponina T/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Fenótipo , Camundongos
20.
Biomed Pharmacother ; 175: 116683, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705130

RESUMO

OBJECTIVE: Blockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Mice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). RESULTS: sACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. CONCLUSIONS: Blockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.


Assuntos
Receptores de Activinas Tipo II , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster , Transdução de Sinais , Animais , Transdução de Sinais/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Masculino , Camundongos , Receptores de Activinas Tipo II/metabolismo , Humanos , Dieta Ocidental/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA