RESUMEN

The effect of a promising NO donor, a binuclear nitrosyl iron complex (NIC) with 3,4-dichlorothiophenolyls [Fe2(SC6H3Cl2)2(NO)4], on the adenylate cyclase and soluble guanylate cyclase enzymatic systems was studied. In in vitro experiments, this complex increased the concentration of important secondary messengers, such as cAMP and cGMP. An increase of their level by 2.4 and 4.5 times, respectively, was detected at NIC concentration of 0.1 mM. The ligand of the complex, 3,4-dichlorothiophenol, produced a less pronounced effect on adenylate cyclase. It was shown that the effect of this complex on the activity of soluble guanylate cyclase was comparable to the effect of anionic nitrosyl complex with thiosulfate ligands that exhibits vasodilating and cardioprotective properties.

Asunto(s)

AMP Cíclico , GMP Cíclico , GMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Animales , Hierro/metabolismo , Hierro/química , Adenilil Ciclasas/metabolismo , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Guanilil Ciclasa Soluble/metabolismo , Óxidos de Nitrógeno/farmacología , Óxidos de Nitrógeno/metabolismo , Óxidos de Nitrógeno/química , Ratas

RESUMEN

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.

Asunto(s)

Molsidomina , Fármacos Neuroprotectores , Guanilil Ciclasa Soluble , Vincristina , Vincristina/efectos adversos , Vincristina/farmacología , Vincristina/toxicidad , Animales , Fármacos Neuroprotectores/farmacología , Ratas , Guanilil Ciclasa Soluble/metabolismo , Molsidomina/farmacología , Molsidomina/análogos & derivados , Humanos , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ratas Sprague-Dawley , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología

RESUMEN

In recent years, thanks to the advent of new classes of drugs (ARNI and SGLT2-i), the prognosis of patients suffering from heart failure with reduced ejection fraction (HFrEF) has gradually improved. Nonetheless, there is a residual risk that is not targeted by these therapies. Currently, it is recognized that vericiguat, an oral stimulator of soluble guanylate cyclase (sGC), can restore the NO-sGC-cGMP pathway, through stimulation and activation of sGC, aiming to increase cGMP levels with a reduction in heart failure-related oxidative stress and endothelial dysfunction. Even though the Victoria trial demonstrated that HFrEF patients in treatment with vericiguat showed a 10% reduction in the composite of cardiovascular mortality and rehospitalization for heart failure, statistically significantly reducing heart failure hospitalization, the international guidelines limit its use as a second-line drug for patients with worsening symptomatology despite optimized medical therapy. Furthermore, vericiguat has proved to be a valid therapeutic ally especially in those patients with comorbidities such that they cannot receive the classic four-pillar therapy of HF (in particular renal failure). In this review, the authors report on randomized clinical trials, substudies, and meta-analysis about vericiguat in HFrEF, emphasizing the strengths that would suggest the possible role of vericiguat as the fifth pillar of the HFrEF treatment, acknowledging that there are still gaps in the evidence that need to be clarified.

Asunto(s)

Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Pirimidinas/uso terapéutico , Pirrolidinas/uso terapéutico , Resultado del Tratamiento , Guanilil Ciclasa Soluble/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos Heterocíclicos con 2 Anillos

RESUMEN

BACKGROUND: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.

Asunto(s)

Proteínas Quinasas Dependientes de GMP Cíclico , GMP Cíclico , Medicamentos Herbarios Chinos , Mucosa Intestinal , Ratones Endogámicos C57BL , Transducción de Señal , Animales , Medicamentos Herbarios Chinos/farmacología , GMP Cíclico/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Humanos , Modelos Animales de Enfermedad , Guanilil Ciclasa Soluble/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Funcion de la Barrera Intestinal

RESUMEN

Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.

Asunto(s)

Proteínas del Choque Térmico HSP110 , Guanilil Ciclasa Soluble , Animales , Guanilil Ciclasa Soluble/metabolismo , Humanos , Ratas , Proteínas del Choque Térmico HSP110/metabolismo , Proteínas del Choque Térmico HSP110/antagonistas & inhibidores , Ratas Sprague-Dawley , Descubrimiento de Drogas , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/metabolismo , Masculino , Relación Estructura-Actividad , Hipertensión Pulmonar/tratamiento farmacológico , Remodelación Vascular/efectos de los fármacos

RESUMEN

BACKGROUND & AIMS: The treatment of cardiovascular diseases (CVD) could greatly benefit from using nitric oxide (NO) donors. This study aimed to investigate the mechanisms of action of NONO2P that contribute to the observed responses in the mesenteric artery. The hypothesis was that NONO2P would have similar pharmacological actions to sodium nitroprusside (SNP) and NO. METHODS: Male Wistar rats were euthanized to isolate the superior mesenteric artery for isometric tension recordings. NO levels were measured using the DAF-FM/DA dye, and cyclic guanosine monophosphate (cGMP) levels were determined using a cGMP-ELISA Kit. RESULTS: NONO2P presented a similar maximum efficacy to SNP. The free radical of NO (NO•) scavengers (PTIO; 100 µM and hydroxocobalamin; 30 µM) and nitroxyl anion (NO-) scavenger (L-cysteine; 3 mM) decreased relaxations promoted by NONO2P. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor (ODQ; 10 µM) nearly abolished the vasorelaxation. The cGMP-dependent protein kinase (PKG) inhibition (KT5823; 1 µM) attenuated the NONO2P relaxant effect. The vasorelaxant response was significantly attenuated by blocking inward rectifying K+ channels (Kir), voltage-operated K+ channels (KV), and large conductance Ca2+-activated K+ channels (BKCa). NONO2P-induced relaxation was attenuated by cyclopiazonic acid (10 µM), indicating that sarcoplasmic reticulum Ca2+-ATPase (SERCA) activation is involved in this relaxation. Moreover, NONO2P increased NO levels in endothelial cells and cGMP production. CONCLUSIONS: NONO2P induces vasorelaxation with the same magnitude as SNP, releasing NO• and NO-. Its vasorelaxant effect involves sGC, PKG, K+ channels opening, and SERCA activation, suggesting its potential as a therapeutic option for CVD.

Asunto(s)

Proteínas Quinasas Dependientes de GMP Cíclico , GMP Cíclico , Donantes de Óxido Nítrico , Óxido Nítrico , Canales de Potasio , Ratas Wistar , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Transducción de Señal , Guanilil Ciclasa Soluble , Vasodilatación , Animales , Masculino , Vasodilatación/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Guanilil Ciclasa Soluble/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Ratas , Canales de Potasio/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Transducción de Señal/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Guanilato Ciclasa/metabolismo , Activación Enzimática/efectos de los fármacos

RESUMEN

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days' treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, -3.2 ± 2.7% for 2 mg twice-daily, and -6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates the use of function testing to measure hepatic improvement in clinical trials and the clinic.

Asunto(s)

Hipertensión Portal , Cirrosis Hepática , Hígado , Humanos , Masculino , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/sangre , Femenino , Persona de Mediana Edad , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Hipertensión Portal/diagnóstico , Resultado del Tratamiento , Hígado/efectos de los fármacos , Anciano , Índice de Severidad de la Enfermedad , Administración Oral , Método Doble Ciego , Pruebas de Función Hepática/estadística & datos numéricos , Pruebas de Función Hepática/métodos , Adulto , Guanilil Ciclasa Soluble/metabolismo , Relación Dosis-Respuesta a Droga , Factores de Tiempo

RESUMEN

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease.

Asunto(s)

Proteínas CLOCK , Trastornos Cronobiológicos , GMP Cíclico , Insuficiencia Cardíaca , Guanilil Ciclasa Soluble , Animales , Masculino , Ratones , Trastornos Cronobiológicos/complicaciones , Trastornos Cronobiológicos/metabolismo , Ritmo Circadiano/fisiología , Proteínas CLOCK/metabolismo , Proteínas CLOCK/genética , GMP Cíclico/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Fenotipo , Transducción de Señal , Guanilil Ciclasa Soluble/metabolismo , Volumen Sistólico

RESUMEN

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Asunto(s)

Hipertensión Pulmonar , Pulmón , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Masculino , Anciano , Administración por Inhalación , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Método Doble Ciego , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Adulto , Pulmón/fisiopatología , Pulmón/efectos de los fármacos , Anciano de 80 o más Años , Guanilil Ciclasa Soluble/metabolismo , Inhaladores de Polvo Seco , Factores de Tiempo , Volumen Espiratorio Forzado , Activadores de Enzimas/administración & dosificación , Activadores de Enzimas/efectos adversos , Activadores de Enzimas/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/farmacocinética , Presión Arterial/efectos de los fármacos , Capacidad Vital

RESUMEN

PURPOSE OF REVIEW: Heart failure (HF) is one of the main causes of cardiovascular mortality in the western world. Despite great advances in treatment, recurrence and mortality rates remain high. Soluble guanylate cyclase is an enzyme which, by producing cGMP, is responsible for the effects of vasodilation, reduction of cardiac pre- and after-load and, therefore, the improvement of myocardial performance. Thus, a new therapeutic strategy is represented by the stimulators of soluble guanylate cyclase (sGCs). The aim of this meta-analysis was to analyze the effects deriving from the administration of sGCs, in subjects affected by HF. A systematic literature search of Medline, SCOPUS, and Google Scholar was conducted up to December 2022 to identify RCTs assessing the cardiovascular effects, as NT-pro-BNP values and ejection fraction (EF), and all-cause mortality, of the sGCs. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RECENT FINDINGS: The results obtained documented a statistically significant improvement in NT-proBNP values (SMD: - 0.258; 95% CI: - 0.398, - 0.118; p < 0.001) and EF (WMD: 0.948; 95% CI: 0.485, 1.411; p < 0.001) in subjects treated with sGCs; however, no significant change was found in the all-cause mortality rate (RR 0.96; 95% CI 0.868 to 1.072; I2, p = 0). The sGCs represent a valid therapeutic option in subjects suffering from HF, leading to an improvement in cardiac performance.

Asunto(s)

Insuficiencia Cardíaca , Péptido Natriurético Encefálico , Ensayos Clínicos Controlados Aleatorios como Asunto , Guanilil Ciclasa Soluble , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Guanilil Ciclasa Soluble/metabolismo , Péptido Natriurético Encefálico/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Agonistas de la Guanilato Ciclasa C/uso terapéutico , Resultado del Tratamiento

RESUMEN

Here, by using in vitro and ex vivo approaches, we elucidate the impairment of the hydrogen sulfide (H2S) pathway in vascular complications associated with metabolic syndrome (MetS). In the in vitro model simulating hyperlipidemic/hyperglycemic conditions, we observe significant hallmarks of endothelial dysfunction, including eNOS/NO signaling impairment, ROS overproduction, and a reduction in CSE-derived H2S. Transitioning to an ex vivo model using db/db mice, a genetic MetS model, we identify a downregulation of CBS and CSE expression in aorta, coupled with a diminished L-cysteine-induced vasorelaxation. Molecular mechanisms of eNOS/NO signaling impairment, dissected using pharmacological and molecular approaches, indicate an altered eNOS/Cav-1 ratio, along with reduced Ach- and Iso-induced vasorelaxation and increased L-NIO-induced contraction. In vivo treatment with the H2S donor Erucin ameliorates vascular dysfunction observed in db/db mice without impacting eNOS, further highlighting a specific action on smooth muscle component rather than the endothelium. Analyzing the NO signaling pathway in db/db mice aortas, reduced cGMP levels were detected, implicating a defective sGC/cGMP signaling. In vivo Erucin administration restores cGMP content. This beneficial effect involves an increased sGC activity, due to enzyme persulfidation observed in sGC overexpressed cells, coupled with PDE5 inhibition. In conclusion, our study demonstrates a pivotal role of reduced cGMP levels in impaired vasorelaxation in a murine model of MetS involving an impairment of both H2S and NO signaling. Exogenous H2S supplementation through Erucin represents a promising alternative in MetS therapy, targeting smooth muscle cells and supporting the importance of lifestyle and nutrition in managing MetS.

Asunto(s)

GMP Cíclico , Sulfuro de Hidrógeno , Síndrome Metabólico , Ratones Endogámicos C57BL , Guanilil Ciclasa Soluble , Animales , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , GMP Cíclico/metabolismo , Síndrome Metabólico/metabolismo , Ratones , Masculino , Guanilil Ciclasa Soluble/metabolismo , Vasodilatación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Humanos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Óxido Nítrico/metabolismo , Aorta/efectos de los fármacos , Aorta/metabolismo , Enfermedades Vasculares/metabolismo , Modelos Animales de Enfermedad

RESUMEN

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO-sGC-cGMP pathway, with a focus on PH.

Asunto(s)

Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Guanilil Ciclasa Soluble/metabolismo , Hipertensión Pulmonar/etiología , Óxido Nítrico/metabolismo , Transducción de Señal , GMP Cíclico/metabolismo , Guanilato Ciclasa/metabolismo

RESUMEN

Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor ß (TGFß)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFß1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFß1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFß1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFß1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1ß and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.

Asunto(s)

Fibroblastos , Miofibroblastos , Humanos , Guanilil Ciclasa Soluble/metabolismo , Fibroblastos/metabolismo , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Queratocitos de la Córnea/metabolismo

RESUMEN

Herein, we describe the rational design, synthesis and in vitro functional characterization of new heme-dependent, direct soluble guanylyl cyclase (sGC) agonists. These new compounds bear a 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton, modified to enable efficient sGC binding and stimulation. To gain insights into structure-activity relationships, the N6-alkylation of the skeleton was explored, while a pyrimidine ring, substituted with various C5'-polar groups, was installed at position C3. Among the newly synthesized 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones, derivatives 14b, 15b and 16a display characteristic features of sGC "stimulators" in A7r5 vascular smooth muscle cells in vitro. They strongly synergize with the NO donor, sodium nitroprusside (SNP) in inducing cGMP generation in a manner that requires the presence of a reduced heme moiety associated with sGC, and elevate the cGMP-responsive phosphorylation of the protein VASP at Ser239. In line with their sGC stimulating capacity, docking calculations of derivatives 16a, 15(a-c) on a cryo-EM structure of human sGC (hsGC) in an ΝΟ-activated state indicated the implication of 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton in efficient bonding interactions with the recently identified region that binds known sGC stimulators, while the presence of either a N6-H or N6-methyl group pointed to enhanced binding affinity. Moreover, the in vitro functional effects of our newly identified sGC stimulators were compatible with a beneficial role in vascular homeostasis. Specifically, derivative 14b reduced A7r5 cell proliferation, while 16a dampened the expression of adhesion molecules ICAM-1 and P/E-Selectin in Human Umbilical Vein Endothelial Cells (HUVECs), as well as the subsequent adhesion of U937 leukocytes to the HUVECs, triggered by tumor necrosis factor alpha (TNF-α) or interleukin-1 beta (IL-1ß). The fact that these compounds elevate cGMP only in the presence of NO may indicate a novel way of interaction with the enzyme and may make them less prone than other direct sGC agonists to induce characteristic hypotension in vivo.

Asunto(s)

Células Endoteliales , Guanilato Ciclasa , Humanos , Células Endoteliales/metabolismo , Activación Enzimática , Guanilato Ciclasa/metabolismo , Hemo , Óxido Nítrico/metabolismo , Guanilil Ciclasa Soluble/metabolismo , Vasodilatadores , Alquilación

RESUMEN

Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Here, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms. In organ chamber experiments with isolated canine coronary arteries, prostaglandin F2 α -induced, endothelin-1-induced, 5-hydroxytryptamine-induced, and potassium chloride-induced contractions were suppressed by the sGC activator BAY 60-2770 (0.1, 1, and 10 nM). In isolated pig coronary arteries, BAY 60-2770 (0.1, 1, and 10 nM) could prolong the cycle length of phasic contractions induced by 3,4-diaminopyridine, as well as lower the peak and bottom tension of the contraction in a concentration-dependent manner. Additionally, BAY 60-2770 (1 pM-0.1 µM) evoked a concentration-related relaxation to a greater extent in small (first diagonal branch) coronary arteries than in large (left anterior descending) coronary arteries. In vasopressin-induced angina model rats, pretreatment with BAY 60-2770 (3 µg/kg) suppressed electrocardiogram S-wave depression induced by arginine vasopressin without affecting changes in mean blood pressure and heart rate. These findings suggest that BAY 60-2770 could be valuable in preventing both large and small coronary spasms. Therefore, sGC activators could represent a novel and efficacious therapeutic option for INOCA. SIGNIFICANCE STATEMENT: The soluble guanylate cyclase (sGC) activator BAY 60-2770 exerted antispastic effects on the coronary arteries in animal vasospasm models as proof-of-concept studies. These data can help to support potential clinical development with sGC activators, suitable for human use in patients with vasospastic angina.

Asunto(s)

Benzoatos , Vasos Coronarios , Hidrocarburos Fluorados , Guanilil Ciclasa Soluble , Animales , Guanilil Ciclasa Soluble/metabolismo , Perros , Ratas , Vasos Coronarios/efectos de los fármacos , Masculino , Porcinos , Benzoatos/farmacología , Benzoatos/uso terapéutico , Hidrocarburos Fluorados/farmacología , Guanilato Ciclasa/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Activadores de Enzimas/farmacología , Activadores de Enzimas/uso terapéutico , Vasoconstricción/efectos de los fármacos , Compuestos de Bifenilo

RESUMEN

OBJECTIVES: Ischemic stroke is a common and debilitating disease that can cause permanent neurological damage. Gucy1a3, which encodes the α1 subunit of soluble guanylyl cyclase, has been reported to be associated with functional recovery after ischemic stroke. However, the mechanism is still not well understood. In the present study, we investigated the effects of Gucy1a3 on (i) post-stroke recovery; (ii) vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF-1α) expression; and (iii) angiogenesis after ischemic stroke. MATERIALS AND METHODS: Wild-type and Gucy1a3 knockout C57BL/6J male mice were respectively used to establish the models of permanent middle cerebral artery occlusion (pMCAO). Neurological deficit scores were evaluated at 24 h and 96 h after pMCAO. Cerebral infarct volume was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. For determining microvessel density, immunohistochemical analysis was performed with CD31. The expression of VEGFA and HIF-1α was detected by western blotting. RESULTS: Our results suggest that loss of Gucy1a3 increased the infarct volume and aggravated neurological deficits after pMCAO. In addition, the Gucy1a3 knockout brains exhibited significantly lower microvessel densities and VEGFA and HIF-1α expression levels than the wild-type brains at 96 h post-pMCAO. CONCLUSIONS: Our study indicates that GUCY1A3 might be involved in angiogenesis after ischemic stroke. Further investigation of GUCY1A3 will provide a new therapeutic target for stroke.

Asunto(s)

Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Masculino , Ratones , Angiogénesis , Isquemia Encefálica/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Guanilil Ciclasa Soluble/metabolismo , Guanilil Ciclasa Soluble/farmacología , Guanilil Ciclasa Soluble/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer's vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase-soluble guanylate cyclase-cyclic GMP that is necessary for normal cilia motility and left-right patterning.

Asunto(s)

Proteínas de Pez Cebra , Pez Cebra , Animales , Humanos , Ratones , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Citoglobina/genética , Tipificación del Cuerpo/genética , Óxido Nítrico/metabolismo , Guanilil Ciclasa Soluble/genética , Guanilil Ciclasa Soluble/metabolismo , Cilios/metabolismo , Óxido Nítrico Sintasa/metabolismo

RESUMEN

AIMS: Dysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. METHODS: In this randomized crossover study, 24 healthy participants aged ≥65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. RESULTS: Twenty-four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well-tolerated and penetrated the blood-brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. CONCLUSION: Zagociguat was well-tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.

Asunto(s)

Guanosina Monofosfato , Óxido Nítrico , Anciano , Humanos , Guanilil Ciclasa Soluble/metabolismo , Estudios Cruzados , Transducción de Señal , Vasodilatadores

RESUMEN

Despite recent advances in heart failure (HF) therapy, the risk of cardiovascular (CV) mortality, morbidity, and HF hospitalization (HFH) are major challenges in HF treatment. We aimed to review the potential of vericiguat as a treatment option for HF. A systematic literature review was performed using the PubMed database and ClinicalTrials.gov. Four randomized controlled trials were identified, which study the safety and efficacy of vericiguat in HF patients. Vericiguat activates soluble guanylate cyclase (sGC) by binding to the beta-subunit, bypassing the requirement for NO-induced activation. The nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway plays an essential role in cardiovascular (CV) regulation and the protection of healthy cardiac function but is impaired in HF. Vericiguat reduced the risk of CV death and HFH in HF patients with reduced ejection fraction (HFrEF) but showed no therapeutic effect on HF with preserved ejection fraction (HFpEF). The trials demonstrated a favorable safety profile with most common adverse events such as hypotension, syncope, and anemia. Therefore, vericiguat is recommended for patients with HFrEF and a minimum systolic blood pressure of 100 mmHg. Treatment with vericiguat is considered when the individual patient experiences decompensation despite being on guideline-recommended medication, e.g., angiotensin-converting inhibitor/AT1 receptor antagonist, beta-adrenoceptor antagonist, spironolactone, and sodium-glucose transporter 2 inhibitors. Furthermore, larger studies are required to investigate any potential effect of vericiguat in HFpEF patients. Despite the limitations, vericiguat can be recommended for patients with HFrEF, where standard-of-care is insufficient, and the disease worsens.

Asunto(s)

Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/metabolismo , Resultado del Tratamiento , Volumen Sistólico , Guanilil Ciclasa Soluble/metabolismo , Cardiotónicos/farmacología , Diuréticos/farmacología

RESUMEN

Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.

Asunto(s)

Hipertensión Pulmonar , Humanos , Guanilil Ciclasa Soluble/metabolismo , Transducción de Señal , Isquemia , Reperfusión