Potentiation of YC-1 activation of soluble guanylate cyclase by NO donors and the increase of the synergistic effect of YC-1 on the NO-dependent activation of the enzyme by 1,2,3-triazolyl-1,2,5-oxadiazole derivatives

2014 ◽  
Vol 8 (1) ◽  
pp. 27-33
Author(s):  
I. S. Severina ◽  
N. V. Pyatakova ◽  
A. Yu. Shchegolev ◽  
V. Yu. Rozhkov ◽  
L. V. Batog ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
No Donors ◽  
Oxadiazole Derivatives

scholarly journals Potentiation of activation of soluble guanylate cyclase by YC-1, NO-donors and increase of the synergistic effect of YC-1 on NO-dependent activation of the enzyme by 1,2,3-triazolyl-1,2,5-oxadiazole derivatives

2015 ◽  
Vol 61 (6) ◽  
pp. 705-711
Author(s):  
I.S. Severina ◽  
N.V. Pyatakova ◽  
A.Yu. Shchegolev ◽  
V.Yu. Rozhkov ◽  
L.V. Batog ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Human Platelet ◽  
Enzyme Activation ◽  
No Donors ◽  
Oxadiazole Derivatives ◽  
Guanylate Cyclase Activation ◽  
Synergistic Increase ◽  
Stimulation Of

The influence of (1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole derivatives: 4-amino-3-(5-methyl-4- ethoxycarbonyl-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole (TF 4 CH 3 ) and 4,4’-bis(5-methel-4-ethoxycarbonyl-1H- 1,2,3-triazol-1-yl)-3,3’-azo-1,2,5-oxadiazole (2TF 4 CH 3 ) on stimulation of human platelet soluble guanylate cyclase by YC-1, NO-donors (sodium nitroprusside, SNP, and spermine NONO ) and on a synergistic increase of NO-dependent enzyme activation in the presence of YC-1 has been investigated. Both compounds increased guanylate cyclase activation by YC-1, potentiated guanylate cyclase stimulation by NO-donors and increased the synergistic effect of YC-1 on NO-dependent activation of soluble guanylate cyclase. The similarity in the properties of the examined TF 4 CH 3 and 2TF 4 CH 3 with that of YC-1 and the possible mechanism underlying the revealed properties of compounds used are discussed.

scholarly journals Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

2012 ◽  
Vol 58 (1) ◽  
pp. 32-42 ◽  
Author(s):  
N.V. Pyatakova ◽  
I.S. Severina
Keyword(s):  
Sodium Nitroprusside ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Human Platelet ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Rat Lung ◽  
Concentration Dependent Manner ◽  
No Donors ◽  
Stimulation Of

The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

Effects of nitric oxide on red blood cell deformability

2003 ◽  
Vol 284 (5) ◽  
pp. H1577-H1584 ◽  
Author(s):  
Melek Bor-Kucukatay ◽  
Rosalinda B. Wenby ◽  
Herbert J. Meiselman ◽  
Oguz K. Baskurt
Keyword(s):  
Nitric Oxide ◽  
Blood Cell ◽  
Guanylate Cyclase ◽  
Red Blood Cell ◽  
Soluble Guanylate Cyclase ◽  
Shear Stresses ◽  
No Donors ◽  
Nos Inhibitors ◽  
Deta Nonoate ◽  
Rbc Deformability

In addition to its known action on vascular smooth muscle, nitric oxide (NO) has been suggested to have cardiovascular effects via regulation of red blood cell (RBC) deformability. The present study was designed to further explore this possibility. Human RBCs in autologous plasma were incubated for 1 h with NO synthase (NOS) inhibitors [ N ω-nitro-l-arginine methyl ester (l-NAME) and S-methylisothiourea], NO donors [sodium nitroprusside (SNP) and diethylenetriamine (DETA)-NONOate], an NO precursor (l-arginine), soluble guanylate cyclase inhibitors (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one and methylene blue), and a potassium channel blocker [triethylammonium (TEA)]. After incubation, RBC deformability at various shear stresses was determined by ektacytometry. Both NOS inhibitors significantly reduced RBC deformability above a threshold concentration, whereas the NO donors increased deformability at optimal concentrations. NO donors, as well as the NO precursor l-arginine and the potassium blocker TEA, were able to reverse the effects of NOS inhibitors. Guanylate cyclase inhibition reduced RBC deformation, with both SNP and DETA-NONOate able to reverse this effect. These results thus indicate the importance of NO as a determinant of RBC mechanical behavior and suggest its regulatory role for normal RBC deformability.

Activation of soluble guanylate cyclase by NO donors—S-nitrosothiols, and dinitrosyl-iron complexes with thiol-containing ligands

Nitric Oxide ◽  
2003 ◽  
Vol 8 (3) ◽  
pp. 155-163 ◽  
Author(s):  
Irina S. Severina ◽  
Olga G. Bussygina ◽  
Natalya V. Pyatakova ◽  
Irina V. Malenkova ◽  
Anatoly F. Vanin
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Iron Complexes ◽  
Dinitrosyl Iron Complexes ◽  
No Donors ◽  
Dinitrosyl Iron

scholarly journals Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrea de la Fuente-Alonso ◽  
Marta Toral ◽  
Alvaro Alfayate ◽  
María Jesús Ruiz-Rodríguez ◽  
Elena Bonzón-Kulichenko ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Marfan Syndrome ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Aortic Tissue ◽  
Wild Type ◽  
Dependent Protein Kinase ◽  
No Donors ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.

scholarly journals Therapeutic Applications and Mechanisms of YC-1: A Soluble Guanylate Cyclase Stimulator

2020 ◽  
Author(s):  
Chieh-Hsi Wu ◽  
Chun-Hsu Pan ◽  
Ming-Jyh Sheu
Keyword(s):  
Guanylate Cyclase ◽  
Molecular Mechanisms ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Regulatory Mechanisms ◽  
No Donors ◽  
Cgmp Pathway ◽  
Soluble Guanylate Cyclase Stimulator ◽  
Favorable Safety

Nitric oxide (NO) is an essential endogenous vasodilator to maintain vascular homeostasis, whose effects are mainly mediated by NO-dependent soluble guanylate cyclase (sGC) which catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a critical mediator of vascular relaxation. YC-1, a novel NO-independent sGC stimulator, was first introduced as an inhibitor of platelet aggregation and thrombosis. Accumulating studies revealed that YC-1 has multiple medication potentials to use for a broad spectrum of diseases ranging from cardiovascular diseases to cancers. In contrast to NO donors, YC-1 has a more favorable safety profile and low medication tolerance. In this chapter, we introduce canonical and pathological roles of NO, review activations, and regulatory mechanisms of YC-1 on NO-independent sGC/cGMP pathway and present the potential pharmacological applications and molecular mechanisms of YC-1.

scholarly journals Vasodilator responses to acetylcholine are not mediated by the activation of soluble guanylate cyclase or TRPV4 channels in the rat

2014 ◽  
Vol 306 (11) ◽  
pp. H1495-H1506 ◽  
Author(s):  
Edward A. Pankey ◽  
Modar Kassan ◽  
Soo-Kyoung Choi ◽  
Khalid Matrougui ◽  
Bobby D. Nossaman ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Independent Manner ◽  
No Donor ◽  
No Donors ◽  
Vasoconstrictor Agents ◽  
Vascular Beds ◽  
Transient Receptor ◽  
Target Effects

The effects of 1H-[1,2,4]-oxadizaolo[4,3-]quinoxaline-1-one (ODQ), an inhibitor of the activation of soluble guanylate cyclase (sGC) on responses to NO donors acetylcholine (ACh) and bradykinin (BK) were investigated in the pulmonary and systemic vascular beds of the rat. In these studies the administration of ODQ in a dose of 5 mg/kg iv attenuated vasodilator responses to five different NO donors without inhibiting responses to ACh and BK in the systemic and pulmonary vascular beds of the rat. Vasodilator responses to ACh were not inhibited by l-NAME or the transient receptor vanilloid type 4 (TRPV4) antagonist GSK-2193874, which attenuated vasodilator responses to the TRPV4 agonist GSK-1016790A. ODQ did not inhibit vasodilator responses to agents reported to act in an NO-independent manner or to vasoconstrictor agents, and ODQ did not increase blood methemoglobin levels, suggesting that off target effects were minimal. These results show that ODQ in a dose that inhibited NO donor-mediated responses did not alter vasodilator responses to ACh in the pulmonary and systemic vascular beds and did not alter systemic vasodilator responses to BK. The present results indicate that decreases in pulmonary and systemic arterial pressures in response to ACh are not mediated by the activation of sGC or TRPV4 channels and that ODQ can be used to study the role of the activation of sGC in mediating vasodilator responses in the rat.

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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