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Vericiguat is a soluble guanylate cyclase stimulator, acting on nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway. Vericiguat can improve the sensitivity soluble guanylate cyclase sensitivity to nitric oxide, stimulate soluble guanylate cyclase without relying on nitric oxide, leading to increased formation of cyclic guanosine monophosphate, which results in multi-dimensional protection effects for the heart. It provides a new therapeutic approach for patients with heart failure. This review provides an overview of mechanism, preclinical studies, pharmacokinetics, clinical efficacy, drug-drug interactions and limitations of vericiguat.
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The soluble guanylate cyclase (s GC) is a key signal transduction enzyme in the nitric oxide (NO) -sGC-cyclic guanosine monophosphate (cGMP) pathway, which can be activated by NO and thus catalyzes the conversion of guanosine triphosphate (GTP) into the c GMP. As a second messenger, cGMP modulates the activity of downstream effectors, including the cGMP-dependent protein kinases (cGK), cGMP-dependent phosphodiesterases (PDE) and ion-gated channels, and ultimately participates in the regulation of several physiological functions, including the function of cardiovascular, gastrointestinal and central nervous systems. sGC stimulators could not only directly stimulate s GC but also synergistically act with NO to increase the sGC enzyme activity, which has shown a great potential to treat various diseases via regulating the NO-s GC-cGMP signaling pathway. Here, we give an overview of NOindependent sGC stimulators in clinical trial.
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Os AINEs são um dos principais agentes que contribuem para a patogênese da úlcera gastrintestinal e representam um importante fator etiológico por serem comum enteutilizados na prática clínica. Objetivo: Avaliar o efeito protetor do complexo de rutênio (II)(cis-[RuCl(qui)(bpy)2]PF6), contra a lesão gástrica induzida por na proxeno (NPX) em camundongos. Métodos: Foram utilizados camundongos Swiss (18-22g). Mensuramos os níveis de GMPc incubando amostras de tecidos gástricos com DMSO, com o complexo de Ru (II) e com ODQ, 30 μm de cada composto, por 5 minutos. Os grupos avaliados foram: grupo controle que recebeu CMC, grupo veículo, em que foi administrado NPX (300 mg/kg)e o que recebeu complexo de Ru (II), todos por gavagem. Os animais foram tratados com o complexo de Ru (II), nas doses de 0,3, 3 e 30 mg/kg. Após 30 minutos, seguiu-se com a indução da lesão com NPX. Seguindo o mesmo protocolo,avaliou-se o efeito do composto em estudo e de seus precursores, na dose de 3mg/kg, por gavagem.Verificou-se o efeito do composto na adesão e rolamento leucocitários; seguindo os protocolos descritos, tanto o rolamento quanto a adesão foram avaliados 3h após a indução de gastropatia e de modulação com ODQ (10 mg/kg) por gavagem. Analisou-se o efeito do complexo de Ru (II)em artérias mesentéricas de ratos wistar(200-250g) pré-contraídas com fenilefrina(PHE)(0,3 μM). Simulou-sea ligação entre o composto e a enzima GCs a partir de recursos disponíveis em site que contém banco de dados de proteínas...
NSAIDs contribute to the pathogenesis of gastrointestinal ulcers and represent an important etiologic factor because iscommonly used in clinical practice. Aim:To evaluate the protective effect of the ruthenium complex (II) (cis-[RuCl(qui)(bpy)2]PF6), against the gastric damageinduced by naproxen(NPX)in mice. Methods: Swiss mice were used (18-22g). Measure the GMPc levels incubating samples of gastric tissues with DMSO, with the complex of RU (II) and with ODQ, 30 μm of each compound, for 5 minutes. The groups evaluated were: control group that received CMC, group vehicle, in which was administered NPX (300 mg/kg) and who received complex of RU (II), all by gavage. The animals were treated with the complex of RU (II), in the doses of 0.3, 3 and 30 mg/kg. After 30 minutes, was followed with the induction of the lesion with NPX. Following the same protocol, it was evaluated the effect of the compound and its precursors, in dose of 3mg/kg, by gavage. It was verified theeffect of compound in accession and leukocyte bearing; following the protocols described, both the bearing for accession were evaluated 3h after the induction of gastropathy and modulation with ODQ (10 mg/kg) by gavage. It examined the effect of the complex of RU (II) in mesenteric arteries of Wistar rats (200-250 g) pre-contracted with phenylephrine (PHE) (0.3 μM). Simulated-If the connection between the compound and the enzyme GCs from resources available in the site that contains the database of proteins...
Asunto(s)
Humanos , Rutenio , Guanilato Ciclasa , Sustancias ProtectorasRESUMEN
@#Soluble guanylate cyclase is a key signal transduction enzyme in the body, which can activate the NO-sGC-cGMP signaling pathway and inhibit the TGF-β signaling pathway. cGMP is one of the most important second messengers and also involved in a series of physiological or pathological responses including vasodilation, inhibition of platelet aggregation, inhibition of cell proliferation and so on. When TGF-β signaling pathway is inhibited, it can inhibit issue fibrosis and cell proliferation. Recent studies have shown that sGC can be activated directly to treat a variety of diseases. As a new class of potential drugs, sGC stimulators have shown many unique advantages. Herein, the mechanism and the latest research progress of sGC stimulators are reviewed, which could provide a useful information for further research of sGC stimulators.
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OBJECTIVE To investigate the protective effect of sGC003,a novel agonist of soluble guanylate cyclase,on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy. METHODS Cardiomy?ocytes were isolated from neonatal Sprague-Dawley rats using serial enzymatic digestion and then incubated with ET-1 10 nmol·L-1 in the absence or presence of sGC003 0.01,0.1 and 1.0μmol·L-1. Hyper?trophic responses including the cardiomyocyte area(Image-Pro Plus 6.0),the expression of atrial natri?uretic peptide gene(ANP)mRNA(RT-PCR method)and total protein content(BCA method)were detect?ed. RESULTS After 48 h stimulation with ET-1 10 nmol·L-1,the cardiomyocyte area increased by 80%(P<0.01),the total protein content increased by 120%(P<0.01) and the expression of ANP mRNA up-regulated by 140%(P<0.01). sGC003 0.01,0.1 and 1.0μmol · L-1 elicited antihypertrophic actions, including inhibition of ET-1-mediated increase in the cardiomyocyte area(P<0.01),raised total protein content(P<0.05)and upregulation of ANP mRNA(P<0.05). CONCLUSION sGC003 has protective,car?diomyocyte-selective antihypertrophic effects in vitro.
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AIM: To investigate the expression of soluble guanylate cyclase protein and its mRNA in rat pulmonary artery after exposure to hypoxia and hypercapnia. METHODS: Male Sprague-Dawley rats were randomly split into 4 group, which were hypoxic hypercapnic (HH 1 week, HH 2 weeks, HH 4 weeks) group and control group, to copy pulmonary hypertensive animal model. The expression of sGC? 1 and ? 1 subunits protein of medial and small pulmonary artery was performed by immunohistochemistry with a polycolonal antibody. In situ hybridization was performed on the rat lung tissue using sGC oligonuclear probe to assay the expression of sGC? 1 subunit mRNA. RESULTS: The sGC? 1 and ? 1 subunits protein and sGC? 1 subunit mRNA were faint staining in the pulmonary small and medium artery in HH1 week, HH 2 weeks and HH 4 weeks groups compared with control group (all P