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1.
Food Chem Toxicol ; 135: 111038, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825855

RESUMO

The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.


Assuntos
Antioxidantes/metabolismo , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Oxidantes/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Acetilcisteína/administração & dosagem , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Nefropatias/enzimologia , Nefropatias/metabolismo , Masculino , Camundongos , Estresse Oxidativo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
2.
Int Braz J Urol ; 45(5): 1033-1042, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31408283

RESUMO

Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.


Assuntos
Acroleína/análogos & derivados , Cinnamomum zeylanicum/química , Relaxamento Muscular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Pênis/efeitos dos fármacos , Acroleína/farmacologia , Idoso , Análise de Variância , Animais , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/fisiologia , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/fisiopatologia , Fenilefrina/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Citrato de Sildenafila/farmacologia , Vasoconstritores/farmacologia
3.
Free Radic Res ; 53(9-10): 993-1004, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31455116

RESUMO

Sildenafil is a phosphodiesterase type 5 inhibitor which confers cardioprotection against myocardial ischaemia/reperfusion (I/R) injury. The aim of this study was to determine if Trx1 participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics and cellular redox status. Langendorff-perfused hearts from wild type (WT) mice and a dominant negative (DN-Trx1) mutant of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischaemia followed by 120 min of reperfusion. WT + S showed a significant reduction of infarct size (51.2 ± 3.0% vs. 30 ± 3.0%, p < .001), an effect not observed in DN-Trx. After I/R, sildenafil preserved state 3 oxygen consumption from WT, but had a milder effect in DN-Trx1 only partially protecting state 3 values. Treatment restored respiratory control (RC) after I/R, which resulted 8% (WT) and 24% (DN-Trx1) lower than in basal conditions. After I/R, a significant increase in H2O2 production was observed both for WT and DN-Trx (WT: 1.17 ± 0.13 nmol/mg protein and DN-Trx: 1.38 ± 0.12 nmol/min mg protein). With sildenafil, values were 21% lower only in WT I/R. Treatment decreased GSSG levels both in WT and DN-Trx1. In addition, GSSG/GSH2 ratio was partially restored by sildenafil. Also, an increase in p-eNOS/eNOS even before the myocardial ischaemia was observed with sildenafil, both in WT (14%, p > .05) and in DN-Trx (35%, p < .05). Active Trx1 is required for the onset of the cardioprotective effects of sildenafil on I/R injury, together with the preservation of cellular redox balance and mitochondrial function.


Assuntos
Mitocôndrias/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Transgênicos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia
4.
Andrologia ; 51(9): e13364, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31304987

RESUMO

A cross-sectional survey was conducted in Egypt from November 2015 to June 2016. Sexually active adult men were interviewed by a questionnaire designed by the authors. All the participants were evaluated by the abridged 5-item version of the International Index of Erectile Function (IIEF). A total of 3,000 sexually active Egyptian males participated in this study, 946 (31.53%) reported using PDE5Is at least once, and 2054 (68.47%) have never used them. The majority of those who used PDE5Is obtained them for recreational purposes mainly for pleasure (58.35%) and to increase duration/frequency of the intercourse (15.6%). Only 26.05% used PDE5Is to treat ED. The main source of obtaining PDE5Is was friends, relatives and colleagues (62.79%); 25.16% of users obtained the drug by themselves, and 6.66% were prescribed the drug by a pharmacist. Only 5.39% of users obtained the drug after a specialist physician consultation. Sildenafil was the most commonly used PDE5I (90.6%), and most of the users (88.05%) used them in an occasional manner even in the presence of erectile dysfunction, while 11.95% used the drug in a regular manner for every intercourse. PDE5Is are frequently used by the Egyptian male population, and most of them seemed to take them as recreational medications.


Assuntos
Coito/psicologia , Disfunção Erétil/epidemiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prazer , Adulto , Estudos Transversais , Egito/epidemiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/psicologia , Inibidores da Fosfodiesterase 5/farmacologia , Prevalência , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Inquéritos e Questionários/estatística & dados numéricos
5.
PLoS One ; 14(7): e0219732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339910

RESUMO

BACKGROUND: The number of studies associating the use of sildenafil in gestation is increasing. This drug inhibits phosphodiesterase type 5 (PDE5), an enzyme responsible for degradation of nitric oxide, and its efficacy is greater in the placental territory, as the maternal side of the placenta have more PDE5 than other sites. For this reason, promising results have been observed related to the prevention of preeclampsia and intrauterine growth restriction and to improvement of maternal-fetal morbidity in cases of placental insufficiency. OBJECTIVE: To evaluate the benefits of using sildenafil in pregnancy. SEARCHED STRATEGY: MEDLINE, ClinicalTrials.gov, Embase, LILACS and Cochrane databases were searched through September 2018. There was no restriction in language or year of publication. This study was registered in PROSPERO (CRD42017060288). SELECTION CRITERIA: Randomized clinical trials which used sildenafil for treatment or prevention of obstetric diseases compared with placebo were selected. DATA COLLECTION AND ANALYSIS: The results were obtained using the inverse variance method for continuous variables and Man-Whitney for categorical variables. MAIN RESULTS: Among a population of 598 pregnant women from the seven clinical trials included, 139 had pre-eclampsia, 275 had intrauterine growth restriction, and 184 had oligohydramnios. A significant increase of 222.58 grams [27.75 to 417.41] was observed in the fetal weight at birth of patients taking sildenafil. The other outcomes did not show any statistical significance. This may be due to the small number of patients used in each study and the great heterogeneity between the groups. CONCLUSIONS: Sildenafil could be associated with increasing fetal weight at birth in placental insufficiency despite the limitations of this meta-analysis, even though more studies in this field are needed to introduce this drug into obstetric clinical practice.


Assuntos
Feto/efeitos dos fármacos , Resultado da Gravidez , Citrato de Sildenafila/farmacologia , Peso ao Nascer , Parto Obstétrico , Feminino , Idade Gestacional , Cefaleia/induzido quimicamente , Humanos , Lactente , Mortalidade Infantil , Trabalho de Parto , Gravidez , Viés de Publicação , Risco , Citrato de Sildenafila/efeitos adversos , Artérias Umbilicais/fisiologia
6.
Int J Biol Macromol ; 136: 154-164, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31195040

RESUMO

Autologous and synthetic bone grafts showed some limitations during their usage in bone tissue regeneration. This is attributed to several drawbacks such as difficulty of finding a donor in addition to the autoimmune rejection. This study aims to fabricate a well-designed biocompatible double-layered structure of highly porous poly(lactic acid)-based electrospun nanofibers (NFs) as scaffolds for bone tissue regeneration. Poly(lactic acid) was chosen to fabricate the main matrix of the NFs scaffold as it is one of the FDA approved and highly recommended biopolymers for biomedical applications owing to its high biodegradability and biocompatibility Each layer is loaded with a different drug (Phenytoin and Sildenafil) to stimulate bone healing process. The solvents and the parameters of electrospinning were manipulated to produce highly porous structures in order to enhance the in-situ biodegradability of the NFs mats as well as the drug release rate. The produced NFs mats were fully characterized morphologically (SEM), chemically (FTIR), physically (DSC) and physicochemically (biodegradability, swellability, porosity and water vapor permeability) as well as studying the drug release profiles of both drugs. Cytotoxicity of the fabricated NFs was tested using fibroblast cells to detect their biocompatibility. Cell adhesion and proliferation were examined using SEM before using the NFs as scaffolds in mice animal model. The efficiency of the developed NFs scaffolds in healing bone fractures was assessed after 14 and 28 days through visual inspection, SEM investigation and bone mineral density assessment. Finally, sections from the bone fracture sites were isolated for histopathological examination. The study revealed the efficiency of the drugs-loaded NFs in enhancing cell adherence, cell proliferation, angiogenesis formation and finally tissue restoration of bone fractures.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Nanofibras/química , Fenitoína/química , Fenitoína/farmacologia , Poliésteres/química , Citrato de Sildenafila/química , Citrato de Sildenafila/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Masculino , Fenômenos Mecânicos , Camundongos , Modelos Moleculares , Conformação Molecular , Osteogênese/efeitos dos fármacos , Porosidade , Coelhos , Temperatura , Engenharia Tecidual
7.
Pharmacol Rep ; 71(4): 659-668, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195343

RESUMO

BACKGROUND: Sildenafil (PDE5-inhibitor) and alprostadil (PGE1) are used in combination clinically for the management of some cases of erectile dysfunction. Despite the roles of prostaglandins (PG) and nitric oxide (NO) pathways in contractility of bladder smooth muscle are frequently studied, the effect of sildenafil/alprostadil combination and the crosstalk between NO/cGMP and PG pathways on bladder activity is not documented. METHODS: Organ-bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS, 4Hz, 80V, 1ms), respectively. The contractile responses in absence and presence of the tested drugs at different concentrations were compared. Results are expressed as mean ± SEM (n = 5-7). RESULTS: Alprostadil (0.01-10 µM) concentration-dependently potentiated ACh (100µM)- and EFS (4 Hz)- induced contraction. Maximum potentiation of ACh-contraction in presence of alprostadil was 40 ± 5%. Sildenafil potentiated ACh-induced contraction at low concentrations (0.01-1 µM), but inhibited it at higher ones (10-100 µM). IBMX (non-selective PDE-inhibitor, 0.01-100µM) and SNP (NO-donor, 1nM-1 mM) produced the same biphasic pattern. The potentiatory phase of sildenafil was inhibited by atropine (0.1µM), L-NAME (non-selective NOS-inhibitor, 100µM), N-PLA (nNOS-inhibitor, 30µM) or MB (nonselective GC-inhibitor, 10µM). In presence of sildenafil (0.1µM), the concentration-response curve of alprostadil (0.01-10µM) on both ACh and EFS-induced contraction was clearly shifted downward. CONCLUSIONS: A crosstalk between PGE1 and NO/cGMP pathways may exist. At low concentrations only, the effect of sildenafil on bladder contractility is dependent on NO/cGMP. cGMP intracellularly-elevated by sildenafil, may inhibit the activity of PLC and hence the cascade of EP1-receptors, thus masking the hyperactivity of bladder caused by alprostadil, which adds to the advantages of this combination.


Assuntos
Alprostadil/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Bexiga Urinária/efeitos dos fármacos , Animais , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Estimulação Elétrica , Técnicas In Vitro , Masculino , Músculo Liso/metabolismo , Músculo Liso/fisiopatologia , Óxido Nítrico/metabolismo , Ratos Wistar , Receptor Cross-Talk , Transdução de Sinais , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia
8.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248114

RESUMO

Sirt1 (Sirtuin 1), AMPK (AMP-activated protein kinase), and eNOS (endothelial nitric oxide synthase) modulate hepatic energy metabolism and inflammation and play a major role in the development of NASH. Cyclic nucleotide phosphodiesterases (PDEs) play an important role in signal transduction by modulating intracellular levels of cyclic nucleotides. We previously found the PDE5 inhibitor sildenafil to synergize with leucine and leucine-metformin combinations in preclinical studies of NASH and obesity. However, efficacy is diminished at higher sildenafil concentrations. Herein, we have successfully modeled the U-shaped sildenafil dose-response in vitro and utilized this model to assess potential mechanisms of this dose-response relationship. Adipocytes and liver cells were treated with leucine (0.5 mM) and different concentrations of sildenafil (1 nM to 100 µM). cAMP, cGMP, and P-AMPK protein expression were used to demonstrate the biphasic response for increasing concentrations of sildenafil. The reversal with higher sildenafil levels was blunted by PDE2 inhibition. These data indicate that sildenafil-mediated increases in cGMP inhibits PDE3 at lower concentrations, which increases cAMP. However, further increases in cGMP from higher sildenafil concentrations activate PDE2 and consequently decrease cAMP, which demonstrates crosstalk between cAMP and cGMP via PDE2, PDE3, and PDE5. These changes in cAMP concentration are further reflected in downstream effects, including AMPK activation.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Humanos , Camundongos
9.
J Headache Pain ; 20(1): 48, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060491

RESUMO

BACKGROUND: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. METHODS: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. RESULTS: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. CONCLUSIONS: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies. TRIAL REGISTRATION: The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Angiografia Cerebral/métodos , Angiografia por Ressonância Magnética/métodos , Artérias Meníngeas/diagnóstico por imagem , Transtornos de Enxaqueca/diagnóstico por imagem , Citrato de Sildenafila/farmacologia , Adulto , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Artérias Meníngeas/efeitos dos fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Citrato de Sildenafila/uso terapêutico , Adulto Jovem
10.
Pharmacol Rep ; 71(3): 422-429, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003152

RESUMO

BACKGROUND: High plasma cholesterol levels are able to trigger several pathophysiological events, including inflammation, cell damage and especially oxidative stress. Previously, studies have shown that sildenafil exhibited antioxidant effects in several experimental models. Here we evaluate the role of sildenafil in liver redox equilibrium of apolipoprotein E knockout (apoE-KO) mice. METHODS: ApoE-KO mice were divided in two groups: one group received the PDE5 inhibitor sildenafil (40 mg/kg/day) for 3 weeks (apoE-KO + Sil) and was compared to a second group of apoE-KO mice, which received only the vehicle (water) for 3 weeks (apoE-KO). Control group (C57 mice) received only a standard chow diet. At the age of 18 weeks, mice livers were collected for the measurement of intracellular ROS levels and apoptotic cells by flow cytometry analysis, and mitochondria isolation for proteomic analysis. RESULTS: Compared to the control group, liver cells from apoE-KO presented some typical redox imbalance features: higher levels of intracellular ROS (global oxidative stress ˜60%, superoxide anion ˜82%, and peroxynitrite/hydroxyl radical ˜53%), higher amounts of apoptotic cells (up to ˜19%) and higher mitochondrial intensity of catalase (+339%) and transferrin spots (+914%). After treatment with sildenafil, apoE-KO presented ROS levels and the number of apoptotic cells similar to those observed in C57. In addition, when compared to apoE-KO, apoE-KO + Sil showed lower spots volumes of catalase (-23%) and transferrin (-71%) and up-regulation of urate oxidase (+94%). CONCLUSION: The treatment with sildenafil is able to induce beneficial changes in liver mitochondrial protein dynamics, which restores the redox homeostasis contributing to a potential hepatoprotection.


Assuntos
Antioxidantes/farmacologia , Apolipoproteínas E/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Citrato de Sildenafila/farmacologia , Animais , Aterosclerose/metabolismo , Catalase/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteômica/métodos , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Triglicerídeos/metabolismo
11.
Pharmacol Rep ; 71(3): 517-521, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009843

RESUMO

BACKGROUND: Cyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3',5' cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. METHODS: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 µg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NOx) were also measured in serum. RESULTS: Pre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NOx and increased the levels of GSH in serum. CONCLUSIONS: Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.


Assuntos
Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Animais , Asma/metabolismo , Brônquios/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
12.
Acta Biochim Pol ; 66(1): 115-117, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816368

RESUMO

Sildenafil is used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Numerous  studies revealed beneficial effects of its use in renal, liver, heart and bone marrow transplant recipients. Some reports suggested that the drug modulates the function of the immune system, however, its influence on antigen-induced proliferation of lymphocytes remains unknown. Thus, the aim of the study was to investigate the effects of sildenafil on human peripheral blood mononuclear cells (PBMCs) proliferation in a mixed lymphocyte reaction. It was demonstrated that the drug did not affect auto- and alloantigen-induced proliferation of PBMCs and showed no cytotoxic effect.


Assuntos
Proliferação de Células/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia
13.
Hypertension ; 73(5): 1120-1127, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30827146

RESUMO

Fetal growth restriction (FGR) is associated with increased risk for cardiovascular and renal disorders in later life. Prenatal sildenafil improves birth weight in FGR animal models. Whether sildenafil treatment protects against long-term cardiovascular and renal disease in these offspring is unknown. The aim of this study is to test the hypothesis that prenatal sildenafil ameliorates cardiovascular and renal function in FGR offspring of Dahl salt-sensitive rats. Sildenafil citrate (60 mg/kg per day) or control gel diet (containing 0.3% salt) was administered from gestational day ten until birth. In male and female offspring, the mean arterial pressure was measured by telemetry in 1 subset from week 5 until week twenty. Echocardiographic parameters, glomerular filtration rate, and fractional electrolyte excretion were determined in another subset at week 9. Aortic and mesenteric artery rings were prepared to assess endothelial-dependent (acetylcholine) and -independent (sodium nitroprusside) vasorelaxation (week 10). The rise in mean arterial pressure per week was attenuated in treated versus untreated male offspring. Mesenteric arteries showed an increased endothelium-dependent relaxation and improved endothelium-independent relaxation in treated versus control male offspring. No differences in aortic relaxation, echocardiographic parameters or renal function were observed between groups. Prenatal sildenafil treatment subtly improves cardiovascular but not renal function in the offspring of this FGR rat model. Translationally, in utero treatment could be beneficial for cardiovascular programming in a sex-specific manner; however, caution is warranted since recent human trials have been halted because of potentially deleterious neonatal side effects when treating pregnancies complicated with severe FGR with sildenafil.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Retardo do Crescimento Fetal/prevenção & controle , Prenhez , Cuidado Pré-Natal/métodos , Citrato de Sildenafila/farmacologia , Animais , Sistema Cardiovascular/embriologia , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Gravidez , Ratos , Ratos Endogâmicos Dahl , Vasodilatadores/farmacologia
14.
Biomed Pharmacother ; 111: 1029-1035, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841416

RESUMO

Sexual dysfunction is a side effect of the antidepressant drug paroxetine. Anogeissus leiocarpus is a medicinal plant with a wide range of biological activities which include antioxidant and antiulcer properties. With these in mind, we investigated the effect of Anogeissus leiocarpus stem bark extract on paroxetine-induced sexual dysfunction in male Wistar rats. Forty-two adult male Wistar rats were divided into seven experimental groups: normal control, PAR (10 mg/kg), PAR + sildenafil (5 mg/kg), ALE (50 and 100 mg/kg) and PAR + ALE (50 and 100 mg/kg). The experiment lasted for 21 days, after which the rats were subjected to sexual behavioral test. Various biochemical assays (phosphodiesterase-5, arginase, acetylcholinesterase, nitric oxide and MDA) were carried out on the penile tissue homogenate. From our findings, paroxetine significantly altered sexual behavior in male rats and increased phosphodiesterase-5, arginase and acetylcholinesterase activities with a concomitant decrease in nitric oxide level. Furthermore, paroxetine altered antioxidant status which revealed by increased MDA level and reduced thiol level. However, treatment with Anogeissus leiocarpus stem bark extract reversed the altered sexual behavior in male rats and boosted antioxidant status. In addition, administration of Anogeissus leiocarpus stem bark extract resulted in a significant attenuation of phosphodiesterase-5, arginase and acetylcholinesterase activities in paroxetine-induced rats. In view of the aforementioned findings, Anogeissus leiocarpus could be considered a promising natural agent in erectile dysfunction management.


Assuntos
Antioxidantes/metabolismo , Óxido Nítrico/metabolismo , Paroxetina/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Comportamento Sexual/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Animais , Arginase/metabolismo , Combretaceae/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Masculino , Malondialdeído/metabolismo , Pênis/efeitos dos fármacos , Pênis/metabolismo , Ratos , Ratos Wistar , Disfunções Sexuais Fisiológicas/metabolismo , Citrato de Sildenafila/farmacologia
15.
Biomed Pharmacother ; 111: 1458-1466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841461

RESUMO

INTRODUCTION: Prostaglandins (PGs) play an important role in corpus cavernosum relaxation, as evidenced by alprostadil being used as a drug for erectile dysfunction. Reports about the effect of cyclooxygenase (COX) inhibitors on erectile function are highly contradictory. AIM: To compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen and diclofenac) with that of the selective COX-2 inhibitor (DFU) on corpus cavernosal tone in-vitro. The role played by PGE1, PGI2-analogue and PGE4 receptor (EP4)-agonist in controlling corpus cavernosum function and the modulation of their action by sildenafil is also studied. METHODS: Organ bath experiments were performed using isolated rat corpus cavernosum. Direct relaxations and changes to electric field stimulation (EFS, 2-16 Hz, 60 V, 0.8 ms, 10 s train)-induced relaxation by the effect of the selected drugs were studied. Strips were precontracted using phenylephrine (PE, 10-5 M). Results are expressed as mean ± SEM of 5-9 rats. RESULTS: Alprostadil, iloprost and L902688 (selective EP4 agonist) induced direct relaxation where L902688 showed greater relaxant effect. Sildenafil potentiated the Emax of alprostadil and iloprost but not L902688. EFS and acetylcholine (ACh)-induced relaxations were significantly potentiated in presence of indomethacin, ketoprofen and diclofenac (20, 100 µM) but not in presence of selective COX-2 inhibitor (DFU, 1 µM). GR32191B (Thromboxane A2 receptor antagonist, 10-6 M) significantly reduced the potentiatory effect of indomethacin. Only diclofenac succeeded to potentiate sodium nitroprusside (SNP)-induced relaxation. CONCLUSIONS: EP4 receptors may play an important nitric oxide (NO)/cGMP-independent role in corpus cavernosal relaxation. Nonselective COX inhibitors seem of no harm concerning cavernosal tissue relaxation, possibly because they inhibit the synthesis of the highly contracting mediator thromboxane A2.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Pênis/efeitos dos fármacos , Prostaglandinas/metabolismo , Alprostadil/farmacologia , Animais , GMP Cíclico/metabolismo , Diclofenaco/farmacologia , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Iloprosta/farmacologia , Indometacina/farmacologia , Cetoprofeno/farmacologia , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/metabolismo , Piperazinas/farmacologia , Ratos , Citrato de Sildenafila/farmacologia , Sulfonas/farmacologia
16.
Eur J Pharmacol ; 849: 96-105, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30721701

RESUMO

Since the original description as potent antianginal compounds, phosphodiesterase 5A inhibitors have continuously increased their possible therapeutic applications. In the heart, Sildenafil was shown to protect against an ischemic insult by decreasing cardiac Na+/H+ exchanger (NHE1) activity, action that was mediated by protein kinase G. p38 mitogen activated protein kinase (p38MAPK) activation was described in cardiac ischemia, but its precise role remains elusive. It has been shown that p38MAPK is activated by protein kinase G (PKG) in certain non-cardiac tissues, while in others modulates NHE1 activity. Current study was aimed to seek the role of p38MAPK in the Sildenafil-triggered pathway leading to NHE1 inhibition in myocardium. Rat isolated papillary muscles were used to evaluate NHE1 activity during intracellular pH recovery from an acidic load. Protein kinases phosphorylation (activation) was determined by western blot. Sustained acidosis promoted NHE1 hyperactivity by enhancing Ser703 phosphorylation, effect that was blunted by Sildenafil. p38MAPK inhibition reversed the effect of Sildenafil on NHE1. Activation of p38MAPK, by Sodium Arsenite or Anisomycin, mimicked the inhibitory effect of Sildenafil on the exchanger. Consistently, Sildenafil induced p38MAPK phosphorylation/activation during acidosis. Neither Sildenafil nor p38MAPK inhibition affected extracellular signal-regulated kinases 1/2 phosphorylation, kinases upstream NHE1. Furthermore, inhibition of NHE1 after p38MAPK activation was precluded by preventing the activation of protein phosphatase 2A with Okadaic Acid. Taken together, these results suggest that activation of p38MAPK is a necessary step to trigger the inhibitory effect of Sildenafil on cardiac NHE1 activity, thorough a mechanism that involves protein phosphatase 2A-mediated exchanger dephosphorylation.


Assuntos
Coração/efeitos dos fármacos , Miocárdio/metabolismo , Citrato de Sildenafila/farmacologia , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Acidose/enzimologia , Acidose/metabolismo , Acidose/patologia , Animais , Ativação Enzimática/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocárdio/citologia , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Trocador 1 de Sódio-Hidrogênio/metabolismo
17.
BJU Int ; 124(1): 163-173, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30636087

RESUMO

OBJECTIVES: To investigate the influence of low-dose sildenafil, a phosphodiesterase type 5 inhibitor (PDE5-I), on the function of the mouse lower urinary tract (LUT). MATERIALS AND METHODS: Adult male mice were decerebrated and arterially perfused with a carbogenated Ringer's solution to establish the decerebrate arterially perfused mouse (DAPM). To allow distinction between central neural and peripheral actions of sildenafil, experiments were conducted in both the DAPM and in a 'pithed' DAPM, which has no functional brainstem or spinal cord. The action of systemic and intrathecal sildenafil on micturition was assessed in urethane-anaesthetised mice. RESULTS: In the DAPM, systemic perfusion of sildenafil (30 pm) decreased the voiding threshold pressure [to a mean (sem) 84.7 (3.8)% of control] and increased bladder compliance [to a mean (sem) 140.2 (8.3)% of control, an effect replicated in the pithed DAPM]. Sildenafil was without effect on most voiding variables but significantly increased the number of bursts of the external urethral sphincter (EUS) per void in DAPM [to a mean (sem) 130.1 (6.9)% of control at 30 pm] and in urethane-anaesthetised mice [to a mean (sem) 117.5 (5.8)% of control at 14 ng/kg]. Sildenafil (10 and 30 pm) increased pelvic afferent activity during both bladder filling and the isovolumetric phase [to a mean (sem) 205.4 (30.2)% of control at 30 pm]. Intrathecal application of sildenafil (5 µL of either 150 pm or 1.5 nm) did not alter cystometry and EUS-electromyography variables in urethane-anaesthetised mice. CONCLUSIONS: Low-dose sildenafil increases bladder compliance, increases pelvic nerve afferent activity, and augments the bursting activity of the EUS. We propose that the novel actions on afferent traffic and sphincter control may contribute to its beneficial actions to restore storage and voiding efficiency in LUT dysfunction.


Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Camundongos , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Pressão , Citrato de Sildenafila/administração & dosagem , Bexiga Urinária/fisiologia
18.
PLoS One ; 14(1): e0210841, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653578

RESUMO

Sildenafil is a pulmonary vasodilator that has potential to mitigate the decrement in endurance performance caused by hypoxic pulmonary vasoconstriction. The purpose of this study was to determine the effects of sildenafil on pulmonary artery pressure, cardiac output, pulse oxygen saturation, and exercise performance at moderate simulated altitude. We hypothesized that sildenafil would reduce the decline in exercise performance in hypoxia by blunting the rise in pulmonary artery pressure and causing a relative increase in cardiac output and oxygen saturation. Twelve endurance trained men performed three experimental cycling trials at sea level and simulated moderate altitude of 3,000m (FIO2 = 0.147) after ingesting either a placebo or sildenafil 50 mg capsule in a double blinded fashion. Each test consisted of a warmup period, a 15-minute steady state period at 60% of peak power output, and a 16.1 km time-trial. All subjects experienced a decline in maximal exercise capacity in hypoxia that ranged from 6% to 24%. This decline was correlated with the reduction in pulse oxygen saturation in hypoxic maximal exercise. Sildenafil had no effect on pulmonary artery pressure, cardiac output, or pulse oxygen saturation measured during steady state exercise. There was no effect of sildenafil on mean power output during the time-trial. During high intensity cycle exercise in acute, moderate hypoxia pulmonary artery pressure is unaffected by sildenafil and does not appear to influence cardiovascular function or exercise performance.


Assuntos
Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Desempenho Físico Funcional , Citrato de Sildenafila/farmacologia , Vasodilatadores/farmacologia , Adulto , Altitude , Pressão Arterial/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Aptidão Cardiorrespiratória/fisiologia , Teste de Esforço , Tolerância ao Exercício/efeitos dos fármacos , Tolerância ao Exercício/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia
19.
J Ethnopharmacol ; 233: 179-189, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30605740

RESUMO

ETHNOPHARMACOLOGICAL USAGES: Leaves and roots of Pfaffia glomerata areused as aphrodisiacs, tranquilizers and antirheumatics. Due to the lack of experimental scientific data, studies are necessary to identify its medicinal properties. AIMS: The present study aimed to evaluate the effect of hydroalcoholic root extract of P. glomerata (Brazilian ginseng extract - BGE) on testicular parenchyma, and evaluate possible harmful effects through testicular oxidative stress analysis. MATERIALS AND METHODS: Adult mice were divided into 6 groups: control (water), sildenafil citrate, BGE (100, 200 and 400 mg/kg/day), and BGE (200 mg/kg every three days). RESULTS: The treatment reduced the volumetric proportions of seminiferous tubules and epithelium, the number of Sertoli cells, and increased hydrogen peroxide levels, without affecting sperm production. It also caused cell death and changes in the frequency of stages of the seminiferous epithelium cycles. The 100 mg/kg dose responds in a similar way to sildenafil citrate, promoting changes in the gonadal structure, but with efficient response to contain the damage. CONCLUSIONS: Doses of 200 mg/kg, continuous or discontinuous, induced an increase in testicular nitric oxide, as well as sildenafil citrate, showing be efficient as aphrodisiac, but promotes cell death regardless of the form of administration.


Assuntos
Amaranthaceae , Extratos Vegetais/farmacologia , Testículo/efeitos dos fármacos , Amaranthaceae/química , Animais , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Raízes de Plantas/química , Citrato de Sildenafila/farmacologia , Testículo/metabolismo , Testículo/patologia
20.
Int J Impot Res ; 31(2): 57-60, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30258189

RESUMO

The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.


Assuntos
Arteriopatias Oclusivas/complicações , Disfunção Erétil/tratamento farmacológico , Induração Peniana/complicações , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Animais , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Disfunção Erétil/etiologia , Humanos , Masculino , Músculo Liso/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Pesquisa Médica Translacional
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