scholarly journals Comparison of Soluble Guanylate Cyclase Stimulators and Activators in Models of Cardiovascular Disease Associated with Oxidative Stress

2012 ◽  
Vol 3 ◽  
Author(s):  
Melissa H. Costell ◽  
Nicolas Ancellin ◽  
Roberta E. Bernard ◽  
Shufang Zhao ◽  
John J. Upson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase

scholarly journals Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease

2015 ◽  
Vol 309 (10) ◽  
pp. L1037-L1040 ◽  
Author(s):  
Gerry T. M. Wagenaar ◽  
Pieter S. Hiemstra ◽  
Reinoud Gosens
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Guanylate Cyclase ◽  
Premature Birth ◽  
Soluble Guanylate Cyclase ◽  
Therapeutic Potential ◽  
Vascular Development ◽  
Supplemental Oxygen ◽  
Neonatal Lung

Supplemental oxygen after premature birth results in aberrant airway, alveolar, and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia, and development of wheeze and asthma, pulmonary hypertension, and chronic obstructive pulmonary disease in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway has significant beneficial effects on disease development in animal models, so far this could not be translated to the clinic. Oxidative stress reduces the NO-sGC-cGMP pathway by oxidizing heme-bound sGC, resulting in inactivation or degradation of sGC. Reduced sGC activity and/or expression is associated with pathology due to premature birth, oxidative stress-induced lung injury, including impaired alveolar maturation, smooth muscle cell (SMC) proliferation and contraction, impaired airway relaxation and vasodilation, inflammation, pulmonary hypertension, right ventricular hypertrophy, and an aggravated response toward hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca2+ responses were significantly elevated in hyperoxia-exposed fetal human airway SMCs compared with normoxic controls and that this hyperoxia-induced increase in the response was strongly reduced by NO-independent stimulation and activation of sGC. These recent studies highlight the therapeutic potential of sGC modulators in the treatment of preterm infants for respiratory distress with supplemental oxygen. Such treatment is aimed at improving aberrant alveolar and vascular development of the neonatal lung and preventing the development of wheezing and asthma in survivors of premature birth. In addition, these studies highlight the suitability of fetal human airway SMCs as a translational model for pathological airway changes in the neonate.

Tetrahydrobiopterin protects soluble guanylate cyclase against oxidative inactivation

Pteridines ◽  
2013 ◽  
Vol 24 (1) ◽  
pp. 47-50
Author(s):  
Kurt Schmidt ◽  
Ernst R. Werner ◽  
Bernd Mayer
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Vascular Effects ◽  
Aortic Endothelial Cells ◽  
Beneficial Effects ◽  
Oxidative Inactivation ◽  
Porcine Aortic Endothelial Cells ◽  
And Oxidative Stress

AbstractTetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Accordingly, administration of BH4 is considered as a promising therapy of cardiovascular diseases associated with endothelial dysfunction and oxidative stress. In a recent study we identified a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. As demonstrated with cultured porcine aortic endothelial cells, oxidative inactivation of soluble guanylate cyclase with nitroglycerin or the heme-site inhibitor ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one) resulted in a decrease in NO-induced cGMP accumulation that was insensitive to scavengers of reactive oxygen species but prevented upon supplementation of the cells with BH4. Tetrahydroneopterin had the same effect and virtually identical results were obtained with RFL-6 fibroblasts, suggesting that our observation reflects a general feature of tetrahydropteridines that is unrelated to NO synthase function and not limited to endothelial cells. Protection of soluble guanylate cyclase against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.

scholarly journals Soluble guanylate cyclase stimulation reduces oxidative stress in experimental Chronic Obstructive Pulmonary Disease

PLoS ONE ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. e0190628 ◽  
Author(s):  
Tanja Paul ◽  
Anna Salazar-Degracia ◽  
Victor I. Peinado ◽  
Olga Tura-Ceide ◽  
Isabel Blanco ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

Modulation of Soluble Guanylate Cyclase for the Treatment of Erectile Dysfunction

Physiology ◽  
2013 ◽  
Vol 28 (4) ◽  
pp. 262-269 ◽  
Author(s):  
George F. Lasker ◽  
Edward A. Pankey ◽  
Philip J. Kadowitz
Keyword(s):  
Oxidative Stress ◽  
Erectile Dysfunction ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Heme Iron ◽  
New Class ◽  
No Formation ◽  
Sgc Activators ◽  
Sgc Stimulators ◽  
Cgmp Formation

Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article.

scholarly journals The importance of the nitric oxide‐cGMP pathway in age‐related cardiovascular disease: Focus on phosphodiesterase‐1 and soluble guanylate cyclase

2019 ◽  
Vol 127 (2) ◽  
pp. 67-80 ◽  
Author(s):  
Keivan Golshiri ◽  
Ehsan Ataei Ataabadi ◽  
Eliana C. Portilla Fernandez ◽  
A. H. Jan Danser ◽  
Anton J. M. Roks
Keyword(s):  
Nitric Oxide ◽  
Cardiovascular Disease ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Age Related ◽  
Cgmp Pathway ◽  
Disease Focus

Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

2019 ◽  
Vol 19 (18) ◽  
pp. 1544-1557 ◽  
Author(s):  
Sijia Xiao ◽  
Qianbin Li ◽  
Liqing Hu ◽  
Zutao Yu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Smooth Muscle Relaxation ◽  
Secondary Messenger ◽  
Physiological Processes ◽  
Cgmp Pathway ◽  
Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

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