scholarly journals Immunohistochemical assessment of cyclic guanosine monophosphate (cGMP) and soluble guanylate cyclase (sGC) within the rostral ventrolateral medulla

2008 ◽  
Vol 15 (6) ◽  
pp. 801-812 ◽  
Author(s):  
Kellysan Powers-Martin ◽  
Anna M. Barron ◽  
Clare H. Auckland ◽  
John K. McCooke ◽  
Douglas J. McKitrick ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Rostral Ventrolateral Medulla ◽  
Guanosine Monophosphate ◽  
Ventrolateral Medulla ◽  
Immunohistochemical Assessment

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.

scholarly journals Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3418
Author(s):  
Grzegorz Grześk ◽  
Alicja Nowaczyk
Keyword(s):  
Guanylate Cyclase ◽  
Natriuretic Peptides ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Pharmacological Intervention ◽  
First Line ◽  
Phosphodiesterase Type ◽  
Activity Mechanism

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

scholarly journals Nitric oxide — soluble guanylate cyclase — cyclic guanosine monophosphate signaling pathway in the pathogenesis of heart failure and search for novel therapeutic targets

2021 ◽  
Vol 20 (6) ◽  
pp. 3035
Author(s):  
Zh. D. Kobalava ◽  
P. V. Lazarev
Keyword(s):  
Heart Failure ◽  
Signaling Pathway ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Severe Disease ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Phase Iii ◽  
Beneficial Effects ◽  
Stimulation Of

Heart failure is a severe disease with an unfavorable prognosis, which requires intensification of therapy and the search for novel approaches to treatment. In this review, the physiological significance of soluble guanylate cyclase-related signaling pathway, reasons for decrease in its activity in heart failure and possible consequences are discussed. Pharmacological methods of stimulating the production of cyclic guanosine monophosphate using drugs with different mechanisms of action are considered. Data from clinical studies regarding their effectiveness and safety are presented. A promising approach is stimulation of soluble guanylate cyclase, which showed beneficial effects in preclinical studies, as well as in the recently completed phase III VICTORIA study.

scholarly journals Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator

2018 ◽  
Vol 13 (1) ◽  
pp. 35 ◽  
Author(s):  
Hiroshi Watanabe ◽  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pharmacological Action ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type

Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension.

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 Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2514
Author(s):  
Santiago Andrés Plano ◽  
Fernando Martín Baidanoff ◽  
Laura Lucía Trebucq ◽  
Sebastián Ángel Suarez ◽  
Fabio Doctorovich ◽  
...  
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Phase Locking ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Circadian Phase ◽  
Subjective Night ◽  
Circadian Time ◽  
Electron Reduction ◽  
Locomotor Rhythms ◽  
The One

The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli’s salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.

The nitric oxide–cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine

2011 ◽  
Vol 89 (2) ◽  
pp. 89-95 ◽  
Author(s):  
Ercan Ozdemir ◽  
Ihsan Bagcivan ◽  
Nedim Durmus ◽  
Ahmet Altun ◽  
Sinan Gursoy
Keyword(s):  
Nitric Oxide ◽  
Analgesic Effect ◽  
Soluble Guanylate Cyclase ◽  
Morphine Tolerance ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Albino Rats ◽  
Tail Flick ◽  
Analgesic Effects ◽  
Cgmp Signaling

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180–210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), NG-nitro-l-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide–cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.

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