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1.
J Med Chem ; 66(11): 7280-7303, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37040336

RESUMO

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.


Assuntos
Guanilato Ciclase , Hipertensão , Humanos , Guanilil Ciclase Solúvel/metabolismo , Guanilato Ciclase/metabolismo , Hipertensão/tratamento farmacológico , Vasodilatadores , Piridinas/farmacologia , Piridinas/uso terapêutico , Óxido Nítrico/metabolismo
2.
J Ethnopharmacol ; 300: 115705, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36099983

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zhenwu Decoction (ZWD) is a traditional Chinese medicine (TCM) formula which has wide scope of indications related to Yang deficiency and dampness retention in TCM syndrome. Cardiac hypertrophy can induce similar symptoms and signs to the clinical features of Yang deficiency and dampness retention syndrome. ZWD can increase the left ventricular ejection fraction, reduce cardiac hypertrophy of patients with chronic heart failure. However, its underlying pharmacological mechanism remains unclear. AIM OF THE STUDY: The study aimed to confirm the protective effects of ZWD on cardiac hypertrophy and explore the underlying mechanisms. MATERIALS AND METHODS: The potential targets and pathways of ZWD in cardiac hypertrophy were highlighted by network pharmacology and validated by mechanistic and functional studies. RESULTS: Our network pharmacology analysis suggests that the protective effects of ZWD on cardiac hypertrophy are related to cyclic guanosine monophosphate (cGMP) - protein kinase G (PKG) pathway. Subsequent animal studies showed that ZWD significantly ameliorated cardiac function decline, cardiac hypertrophy, cardiac fibrosis and cardiomyocyte apoptosis. To explore the underlying mechanisms of action, we performed Western blotting, immunohistochemical analysis, and detection of inflammatory response and oxidative stress. Our results showed that ZWD activated the soluble guanylate cyclase (sGC) - cGMP - PKG signaling pathway. The sGC inhibitor ODQ that blocks the sGC-cGMP-PKG signaling pathway in zebrafish abolished the protective effects of ZWD, suggesting sGC-cGMP-PKG is the main signaling pathway mediates the protective effect of ZWD in cardiac hypertrophy. In addition, three major ingredients from ZWD, poricoic acid C, hederagenin and dehydrotumulosic acid, showed a high binding energy with prototype sGC. CONCLUSION: ZWD reduces oxidative stress and inflammation and exerts cardioprotective effects by activating the sGC-cGMP-PKG signaling pathway.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico , Guanosina Monofosfato , Animais , Cardiomegalia/tratamento farmacológico , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Medicamentos de Ervas Chinesas , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Volume Sistólico , Função Ventricular Esquerda , Deficiência da Energia Yang , Peixe-Zebra
3.
Eur J Pharmacol ; 927: 175052, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35643304

RESUMO

BACKGROUND AND PURPOSE: Chronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60-2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. EXPERIMENTAL APPROACH: Forty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8-20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60-2770 or a combination of celecoxib and BAY 60-2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. KEY RESULTS: Induction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60-2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60-2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. CONCLUSION AND IMPLICATIONS: Induction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60-2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.


Assuntos
Benzoatos , Compostos de Bifenilo , Cistite , Hidrocarbonetos Fluorados , Prostatite , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Celecoxib/farmacologia , Doença Crônica , Cistite/tratamento farmacológico , Cistite/fisiopatologia , Guanilato Ciclase/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Masculino , Dor Pélvica , Prostatite/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Guanilil Ciclase Solúvel/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia
4.
Molecules ; 26(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34299422

RESUMO

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein-protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.


Assuntos
Toxinas Bacterianas/metabolismo , Enterotoxinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Holarrhena/metabolismo , Receptores de Enterotoxina/metabolismo , Alcaloides/metabolismo , Antidiarreicos/farmacologia , Sítios de Ligação , Simulação por Computador , Diarreia/tratamento farmacológico , Escherichia coli Enterotoxigênica/metabolismo , Enterotoxinas/fisiologia , Proteínas de Escherichia coli/fisiologia , Guanilato Ciclase/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Casca de Planta/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos
5.
Biomed Pharmacother ; 118: 109216, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319371

RESUMO

The osseointegration process of implant is seriously impaired in type 2 diabetes mellitus (T2DM) that causes high failure rate, and insufficiency exists in current insulin therapy, creating a demand for new bone-synergistic agent. Cinaciguat, a novel type of soluble guanylate cyclase (sGC) activator, plays a vital role in glucose metabolism, inflammation control and bone regeneration. We hypothesized that the combined application of cinaciguat and insulin could reverse poor implant osseointegration in diabetes. To test this hypothesis, streptozotocin-induced diabetic rats were placed implants in the femur, and divided into five groups: control, T2DM, cinaciguat-treated T2DM (7 µg/kg), insulin-treated T2DM (12 IU/kg), cinaciguat plus insulin combination-treated T2DM (7 µg/kg and 12 IU/kg respectively), according to different treatment received. The weight and glucose levels of rats were evaluated at fixed times, and plasma level of cyclic guanosine monophosphate (cGMP) was determined before euthanasia. Three months after therapy, the femurs were isolated for pull-out test, environmental scanning electron microscope observation, microscopic computerized tomography evaluation and various histology analysis. Results revealed that diabetic rats showed the highest blood glucose level and lowest cGMP content, which led to the worst structural damage and least osseointegration. Combined treatment could attenuate the diabetes induced hyperglycemia to be normal, restore the cGMP content, protein kinase G II (PKG II) expression, phosphodiesterase-5 (PDE5) activity and ameliorate the mechanical strength, the impaired bone microarchitecture and osseointegration to the highest level. Meanwhile, monotreatment (insulin or cinaciguat) also showed restorative effect, but less. Our findings demonstrated that the cGMP/PKG II signaling pathway activated by cinaciguat mediated the favorable effects of the combined application on improving implant fixation under T2DM condition.


Assuntos
Benzoatos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Osseointegração/efeitos dos fármacos , Próteses e Implantes , Animais , Benzoatos/administração & dosagem , Glicemia/análise , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Guanilato Ciclase/metabolismo , Insulina/administração & dosagem , Masculino , Ratos Sprague-Dawley
6.
Am J Physiol Lung Cell Mol Physiol ; 317(2): L222-L234, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166128

RESUMO

We have analyzed the effect of the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV) hypertrophy than those who continued CS exposure, but they did not recover from the emphysema and the inflammatory cell infiltrate. Conversely, oral BAY 41-2272 administration stopped progression or even reversed the CS-induced emphysema in both current and former smokers, respectively. Furthermore, BAY 41-2272 produced a reduction in the RV hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested perforin/granzyme pathway downregulation as an action mechanism capable of stopping the progression of emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent serine/kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for chronic obstructive pulmonary disease treatment that deserves further evaluation.


Assuntos
Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumaça , Guanilil Ciclase Solúvel/uso terapêutico , Animais , Guanilato Ciclase/metabolismo , Cobaias , Hipertensão Pulmonar/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Nicotiana , Vasodilatadores/farmacologia
7.
Dig Dis Sci ; 64(11): 3104-3114, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31127443

RESUMO

BACKGROUND AND AIM: Simaba ferruginea A.St.-Hil. Popularly known as "calunga," is a typical Brazilian cerrado plant whose rhizomes are popular for treating diarrhea. AIMS: The aim of this study was to evaluate the spasmolytic activity and the antidiarrheal effect of the ethanolic extract obtained from S. ferruginea (Sf-EtOH). METHODS: Ileal segments (1-2 cm) from male Wistar rats were mounted in isolated organ baths and connected to a force transducer, and then to an amplifier which was connected to a computer (AVS Projetos/São Paulo-SP). After stabilization for 60 min, under tension (1 gf), two submaximal contractions were induced with KCl 40 mM or carbachol 10-6 M on ileal segments. During the third tonic and sustained contraction, Sf-EtOH was added in cumulative concentrations to the organ bath. Incubations with L-NAME (10-4 M), ODQ (10-5 M), TEA+ (5 or 1 mM), glibenclamide (10-5 M), or apamine (100 nM) were prepared (n = 5), separately and used to verify the involvement of the nitric oxide synthase, guanylate cyclase, and potassium channels in the relaxing effect. The results were expressed as mean ± standard error of the mean and were statistically evaluated using one-way ANOVA followed by Bonferroni test, when necessary *p < 0.05. RESULTS: Sf-EtOH promotes relaxation on rat isolated ileum pre-contracted with CCh and KCl in a concentration-dependent manner. Sf-EtOH also inhibited ileum contractions against cumulative concentrations of carbachol (CCh), KCl, and CaCl2, shifting the curves to the right in a non-parallel manner with an Emax reduction. In the presence of potassium channel blockers, Sf-EtOH shifted the curves to the right with a reduction of Emax, suggesting the involvement of BKCa, KATP, and SKCa in its spasmolytic effect. In the presence of L-NAME or ODQ, the relaxation curves were shifted to the right, suggesting the involvement of this pathway in Sf-EtOH spasmolytic effect. CONCLUSIONS: Sf-EtOH acts in a concentration-dependent manner, involving the positive modulation of K+ channels and NO pathway.


Assuntos
Guanilato Ciclase/metabolismo , Íleo/metabolismo , Óxido Nítrico Sintase/metabolismo , Parassimpatolíticos/farmacologia , Canais de Potássio/metabolismo , Simaroubaceae , Animais , Relação Dose-Resposta a Droga , Íleo/efeitos dos fármacos , Masculino , Relaxantes Musculares Centrais/isolamento & purificação , Relaxantes Musculares Centrais/farmacologia , Técnicas de Cultura de Órgãos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta , Ratos , Ratos Wistar
8.
Biomed Res Int ; 2019: 1345402, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984775

RESUMO

Remodelling of the peripheral lung tissue and fibrotic foci are the main pathologies of idiopathic pulmonary fibrosis (IPF), a disease that is difficult to treat. TGF-ß activation of peripheral lung fibroblasts is indicated as the major cause of tissue remodelling in IPF and is resulting in fibroblast hyperplasia and deposition of extracellular matrix. Soluble guanylate cyclase (sGC) stimulators combined with cyclic AMP (cAMP) activators have been reported to reduce proliferation and matrix deposition in other conditions than IPF. Therefore, this drug combination may present a novel therapeutic concept for IPF. This study investigated the effect of BAY 41-2272 and forskolin on remodelling parameters in primary human lung fibroblasts. The study determined TGF-ß induced proliferation by direct cell counts after 3 days; and deposition of collagen type-I, type III, and fibronectin. BAY 41-2272 significantly reduced TGF-ß induced fibroblast proliferation, but did not reduce viability. This inhibitory effect was further supported by forskolin. Both BAY 41-2272 and forskolin alone reduced TGF-ß induced collagen and fibronectin de novo synthesis as well as deposition. This effect was significantly stronger when the two compounds were combined. Furthermore, the TGF-ß induced expression of fibrilar α-smooth muscle actin was reduced by BAY 41-2272 and this effect was strengthened by forskolin. In addition, BAY 41-2272 and forskolin reduced TGF-ß induced ß-catenin. All effects of BAY 41-2272 were concentration dependent. The findings suggest that BAY 41-2272 in combination with cAMP stimulation may present a novel therapeutic strategy to reduce tissue remodelling in IPF.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Colforsina/farmacologia , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , AMP Cíclico/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Cultura Primária de Células , Pirazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , beta Catenina/genética
9.
Eur J Haematol ; 97(6): 499-510, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27526684

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B-cell-like phenotype (GCB) and an activated B-cell-like phenotype (ABC). Particularly ABC-DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo-immune therapy. Through the availability of novel experimental technologies, such as next-generation sequencing and cutting-edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC-DLBCL. Currently, a picture is emerging which suggests that ABC-DLBCL critically depends on sustained activity of the NFκB pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B-, CARD11-, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC-DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non-physiological NFκB activity and repressing anti-apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials.


Assuntos
Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Apoptose/genética , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores Tumorais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Antígenos CD79/genética , Antígenos CD79/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Variação Genética , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Humanos , Imunofenotipagem , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fenótipo , Plasmócitos/metabolismo , Plasmócitos/patologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
10.
J Med Chem ; 59(14): 6838-47, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27390919

RESUMO

Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC50 of 50 nM and more than hundred-fold selectivity over other PRMTs. These results indicate that virtual screening strategies can be successfully applied to Rossmann-fold protein methyltransferases.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Guanilato Ciclase/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
11.
Am J Physiol Lung Cell Mol Physiol ; 310(7): L658-69, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26873974

RESUMO

Infants with congenital diaphragmatic hernia (CDH) fail to adapt at birth because of persistent pulmonary hypertension (PH), a condition characterized by excessive muscularization and abnormal vasoreactivity of pulmonary vessels. Activation of soluble guanylate cyclase by BAY 41-2272 prevents pulmonary vascular remodeling in neonatal rats with hypoxia-induced PH. By analogy, we hypothesized that prenatal administration of BAY 41-2272 would improve features of PH in the rabbit CDH model. Rabbit fetuses with surgically induced CDH at day 23 of gestation were randomized at day 28 for an intratracheal injection of BAY 41-2272 or vehicle. After term delivery (day 31), lung mechanics, right ventricular pressure, and serum NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) levels were measured. After euthanasia, lungs were processed for biological or histological analyses. Compared with untouched fetuses, the surgical creation of CDH reduced the lung-to-body weight ratio, increased mean terminal bronchial density, and impaired lung mechanics. Typical characteristics of PH were found in the hypoplastic lungs, including increased right ventricular pressure, higher serum NT-proBNP levels, thickened adventitial and medial layers of pulmonary arteries, reduced capillary density, and lower levels of endothelial nitric oxide synthase. A single antenatal instillation of BAY 41-2272 reduced mean right ventricular pressure and medial thickness of small resistive arteries in CDH fetuses. Capillary density, endothelial cell proliferation, and transcripts of endothelial nitric oxide synthase increased, whereas airway morphometry, lung growth, and mechanics remained unchanged. These results suggest that pharmacological activation of soluble guanylate cyclase may provide a new approach to the prenatal treatment of PH associated with CDH.


Assuntos
Ativadores de Enzimas/farmacologia , Hérnias Diafragmáticas Congênitas/fisiopatologia , Hipertensão Pulmonar/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Anormalidades Múltiplas/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Ativadores de Enzimas/uso terapêutico , Feminino , Doenças Fetais/tratamento farmacológico , Guanilato Ciclase/metabolismo , Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Pulmão/anormalidades , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pneumopatias/tratamento farmacológico , Gravidez , Cuidado Pré-Natal , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Coelhos , Resultado do Tratamento
12.
J Ethnopharmacol ; 175: 422-31, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26429073

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Alstonia scholaris has a long history of use in the Ayurveda traditional treatment of various ailments including hypertension. We have reported the blood pressure lowering activity of the extract of A. scholaris. The following research aim to delineate the pharmacological mechanism involve in the antihypertensive action. MATERIALS AND METHOD: Vasorelaxant effect of the n-butanol fraction of A. scholaris (NBF-ASME) was evaluated on rat aorta pre-contracted with phenyelphrine (PE, 1 µM). Aortic rings preparation were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ 10 µM), methylene blue (MB 10 µM), Nω-nitro-L-arginine methyl ester hydrochloride (l-NAME 10 µM), atropine (10 µM), indomethacin (1 µM), ML-9 and various K(+) channel blockers such as glibenclamide (10 µM) and tetraethyl ammonium (TEA 10 µM) for mechanism study. RESULT: The results showed that pre-incubation of aortic rings with the extract (0.5, 1 and 2mg/mL) significantly inhibit the contractile response of the rings to phenylephrine-induced contraction (p<0.05-0.001). Removal of endothelium, incubation with L-NAME, indomethacin, atropine and propranolol did not significantly affect the relaxation effect of NBF-ASME. Furthermore, the K(+) channel blockers, TEA and glibenclamide showed no inhibitory effect. However, aortic rings pretreated with ODQ and ML-9 showed a significant suppression of the relaxation curve of NBF-ASME (p<0.01-0.001). In Ca(2+)-free solution, NBF-ASME inhibits the release of intracellular Ca(2+) from the sarcoplasmic reticulum. NBF-ASME also inhibits calcium chloride (CaCl2)-induced contraction in endothelium-denuded aortic rings. CONCLUSION: The results from this study suggests that A. scholaris exerts vasodilation via calcium channels blockade, direct activation of soluble guanylate cyclase and possibly by also inhibiting the formation of inositol 1, 4, 5-triphosphate.


Assuntos
Alstonia , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , 1-Butanol/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Antagonistas Muscarínicos/farmacologia , Óxido Nítrico/metabolismo , Casca de Planta , Bloqueadores dos Canais de Potássio/farmacologia , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Guanilil Ciclase Solúvel , Solventes/química , Vasoconstrição/efeitos dos fármacos
13.
Pharmacol Res ; 100: 242-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26296533

RESUMO

Pterodon spp. Vogel (Fabaceae), popularly known as "sucupira", has ethnopharmacological application which is described as having antispasmodic and relaxant effects. Hence, it was hypothesized that sucupira oil-resin (SOR) could induce smooth muscle relaxation. So, this study investigated the mechanisms involved in the vasorelaxant effect of SOR and its isolated diterpene (methyl-6α-acetoxy-7ß-hydroxyvouacapan-17ß-oate). Vascular reactivity experiments were performed using rat aortic rings (n=5-8) with (E+) or without endothelium (E-) in an isolated bath organ. The SOR (0-56 µg/mL) relaxed phenylephrine (E+: 86.7±7.1%; E-: 92.3±4.7%) and KCl contracted rings (E-: 97.1±2.8%). In the same way, diterpene (0-48 µg/mL) also relaxed phenylephrine (E+: 94.5±3.6%; E-: 92.2±3.4%) and KCl contracted rings (E-: 99.7±0.2%). The pre-incubation of arterial rings with cyclopiazonic acid (reticular Ca2+-ATPase inhibitor), tetraethylammonium (K+ channels blocker) or MDL-12,330A (adenylyl cyclesinhibitor) did not modify either SOR- or diterpeneinduced vasorelaxation. However, ODQ (guanylyl cyclase inhibitor) impaired only diterpene-induced vasorelaxation. SOR and diterpene significantly reduced CaCl2-induced contraction stimulated by Bay K8644 (1 µM), phenylephrine (0.1 µM) or KCl solution (40 mM). Computational molecular docking studies demonstrated that the vasodilator effect of diterpene relies on blocking the Cav 1.2 channel, and patch clamp results showed that diterpene substantially decreased the ionic current through Cav 1.2 in freshly dissociated vascular smooth muscle cells. These findings suggest that SOR and its isolated diterpene induce endothelium-independent vascular relaxation by blocking the L-type Ca2+ channel (Cav 1.2).


Assuntos
Canais de Cálcio Tipo L/metabolismo , Diterpenos/farmacologia , Fabaceae/química , Extratos Vegetais/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Guanilato Ciclase/metabolismo , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenilefrina/farmacologia , Canais de Potássio/metabolismo , Ratos , Ratos Wistar
14.
Am J Physiol Lung Cell Mol Physiol ; 309(6): L537-42, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26254425

RESUMO

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCß1 expression, BAY 60-2770 did increase sGCß1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.


Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Hiperóxia/tratamento farmacológico , Miócitos de Músculo Liso/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Brônquios/patologia , Sinalização do Cálcio , Células Cultivadas , GMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Guanilato Ciclase/metabolismo , Humanos , Hiperóxia/enzimologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/embriologia , Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Oxigênio/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Guanilil Ciclase Solúvel , Traqueia/patologia
15.
J Ethnopharmacol ; 172: 395-401, 2015 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-26164074

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Scutia buxifolia, a native tree popularly known as "coronilha", is widely used in Brazilian folk medicine for diuretic and anti-hypertensive purposes. AIM OF THE STUDY: We investigated the effects of a butanolic (BuOH) soluble fraction of the hydroethanolic extract (HESB) of bark of Scutia buxifolia on both blood pressure and urinary excretion of rats. The involvement of the nitric oxide/guanylate cyclase pathway in the hypotensive effect found was also explored. MATERIAL AND METHODS: We tested the effect of the BuOH soluble fraction of HESB on the mean arterial pressure (MAP) of anesthetized rats. The fraction was administered at doses of 1, 3 and 10mg/kg (i.v.) in normotensive rats during continuous infusion of vehicle (10 µl/min), or phenylephrine (4 µg/kg/min), or l-NAME (7 mg/kg/min), two approaches able to induce a sustained hypertensive state. In some experiments, a bolus injection of ODQ (2mg/kg) was administered in animals infused with phenylephrine before the administration of the BuOH soluble fraction of HESB. We also measured the effects of the BuOH soluble fraction on the MAP of spontaneously hypertensive rats (SHR). Separate groups of rats were treated orally with either HESB (10, 30 or 100mg/kg), or its BuOH soluble fraction (3, 10 or 30 mg/kg), and were subjected to measurement of diuresis and blood pressure. RESULTS: The BuOH soluble fraction of HESB (10mg/kg, i.v.) reduced the MAP of both phenylephrine-infused and SHR rats by 20.6 ± 6.0 and 41.8 ± 8.3 mm Hg, respectively. However, no hypotensive effect was found in normotensive animals infused with l-NAME, a non-selective inhibitor of nitric oxide synthase, or animals previously treated with the soluble guanylate cyclase inhibitor ODQ. The urinary excretion was increased by 70% at 6-8h after a single oral administration of the BuOH soluble fraction of HESB (10mg/kg), without change in urinary density, pH, or Na(+) and K(+) concentrations. In addition, MAP was lower 3h after the acute oral treatment with the BuOH soluble fraction (82.1 ± 3.8 mm Hg), compared with MAP of animals from the control group (97 ± 3.2 mm Hg). CONCLUSION: This study demonstrates that the BuOH soluble fraction of the hydroethanolic bark of Scutia buxifolia, which has its bark used in folk medicine for the treatment of hypertension mainly by its presumed diuretic properties, possesses both diuretic and hypotensive effects in rats, and that at least the hypotensive effect is fully dependent on activation of the nitric oxide/guanylate cyclase pathway.


Assuntos
Anti-Hipertensivos/farmacologia , Diuréticos/farmacologia , Extratos Vegetais/farmacologia , Rhamnaceae/química , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Brasil , Modelos Animais de Doenças , Diuréticos/administração & dosagem , Diuréticos/isolamento & purificação , Relação Dose-Resposta a Droga , Guanilato Ciclase/metabolismo , Hipertensão/tratamento farmacológico , Masculino , Medicina Tradicional , Óxido Nítrico/metabolismo , Casca de Planta , Extratos Vegetais/administração & dosagem , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
16.
Nat Commun ; 6: 7235, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-26011238

RESUMO

Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing ß1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Guanilato Ciclase/metabolismo , Morfolinas/uso terapêutico , Obesidade/tratamento farmacológico , Pirimidinas/uso terapêutico , Adipócitos/efeitos dos fármacos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Obesidade/prevenção & controle , Pirimidinas/farmacologia , Termogênese , Redução de Peso
17.
Vascul Pharmacol ; 71: 181-91, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25869522

RESUMO

Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance.


Assuntos
Guanilato Ciclase/metabolismo , Nitratos/metabolismo , Nitroglicerina/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Hidrocarbonetos Fluorados/farmacologia , Masculino , Morfolinas/farmacologia , Técnicas de Cultura de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Guanilil Ciclase Solúvel
18.
Clin Pharmacol Ther ; 97(1): 88-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25670386

RESUMO

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.


Assuntos
Desenho de Fármacos , Guanilato Ciclase/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Animais , Benzoatos/efeitos adversos , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Doença Crônica , GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Óxido Nítrico/metabolismo , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , Guanilil Ciclase Solúvel , Tromboembolia/tratamento farmacológico , Tromboembolia/fisiopatologia
19.
Neurourol Urodyn ; 34(8): 787-93, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25230878

RESUMO

AIMS: To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO). METHODS: Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization. RESULTS: Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue. CONCLUSIONS: Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.


Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Obstrução Uretral/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Obstrução Uretral/complicações , Obstrução Uretral/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/metabolismo
20.
Am J Respir Cell Mol Biol ; 52(6): 762-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25353067

RESUMO

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.


Assuntos
Guanilato Ciclase/metabolismo , Pneumopatias Obstrutivas/enzimologia , Lesão Pulmonar/enzimologia , Resistência das Vias Respiratórias , Animais , Benzoatos/farmacologia , Benzoatos/uso terapêutico , GMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Guanilato Ciclase/antagonistas & inibidores , Pneumopatias Obstrutivas/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL
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