Cyclic guanosine monophosphate signalling pathway in pulmonary arterial hypertension

2013 ◽  
Vol 58 (3) ◽  
pp. 211-218 ◽  
Author(s):  
Chien-nien Chen ◽  
Geoffrey Watson ◽  
Lan Zhao
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cyclic Guanosine Monophosphate ◽  
Signalling Pathway ◽  
Guanosine Monophosphate ◽  
Pulmonary Arterial

scholarly journals Nitrogen oxide biochemical pathway in pulmonary arterial hypertension therapy and REPLACE trial results

2018 ◽  
Vol 15 (2) ◽  
pp. 72-76 ◽  
Author(s):  
A A Shmalts ◽  
S V Gorbachevsky
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Controlled Trial ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Controlled Study ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Hypertension Therapy

Endogen nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) deficiency in pulmonary vessels walls plays essential role in pulmonary arterial hypertension (PAH) pathogenesis. Soluble guanylate cyclase stimulator riociguat and phosphodiesterase-5 (PDE5) inhibitor sildenafil increase cGMP content and have proven clinical efficacy in PAH treatment. The potentially beneficial mechanisms of riociguat mechanism of action include endogen NO independence in cGMP synthesis and its independence from other phosphodiesterase isoferments (other than PDE5). Clinical options, safety and effectiveness of iPDE5 - riociguat transition in patients with PAH were for the first time shown in non-controlled study RESPITE and the assessment is continued in randomized placebo-controlled trial REPLACE.

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 Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

2020 ◽  
Vol 29 (155) ◽  
pp. 190089 ◽  
Author(s):  
Daniela Knafl ◽  
Christian Gerges ◽  
Charles H. King ◽  
Marc Humbert ◽  
Amaya L. Bustinduy
Keyword(s):  
Systematic Review ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Signalling Pathway ◽  
Pathophysiological Mechanisms ◽  
Clinical Registries ◽  
Life Threatening ◽  
Pulmonary Arterial

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is a life-threatening complication of chronic hepatosplenic schistosomiasis. It is suggested to be the leading cause of pulmonary arterial hypertension (PAH) worldwide. However, pathophysiological data on Sch-PAH are scarce. We examined the hypothesis that there are pronounced similarities in pathophysiology, haemodynamics, and survival of Sch-PAH and idiopathic PAH (iPAH).This systematic review and meta-analysis was registered in the PROSPERO database (identifier CRD42018104066). A systematic search and review of the literature was performed according to PRISMA guidelines for studies published between 01 January 1990 and 29 June 2018.For Sch-PAH, 18 studies evaluating pathophysiological mechanisms, eight studies on haemodynamics (n=277), and three studies on survival (n=191) were identified. 16 clinical registries reporting data on haemodynamics and survival including a total of 5792 patients with iPAH were included for comparison. Proinflammatory molecular pathways are involved in both Sch-PAH and iPAH. The transforming growth factor (TGF)-β signalling pathway is upregulated in Sch-PAH and iPAH. While there was no difference in mean pulmonary artery pressure (54±17 mmHg versus 55±15 mmHg, p=0.29), cardiac output (4.4±1.3 L·min−1versus 4.1±1.4 L·min−1, p=0.046), and cardiac index (2.6±0.7 L·min−1·m−2versus 2.3±0.8 L·min−1·m−2, p<0.001) were significantly higher in Sch-PAH compared to iPAH, resulting in a lower pulmonary vascular resistance in Sch-PAH (10±6 Woods units versus 13±7 Woods units, p<0.001). 1- and 3-year survival were significantly better in the Sch-PAH group (p<0.001).Sch-PAH and iPAH share common pathophysiological mechanisms related to inflammation and the TGF-β signalling pathway. Patients with Sch-PAH show a significantly better haemodynamic profile and survival than patients with iPAH.

scholarly journals Treating pulmonary arterial hypertension: current treatments and future prospects

2011 ◽  
Vol 2 (6) ◽  
pp. 359-370 ◽  
Author(s):  
Shahzad G. Raja ◽  
Shahbaz M. Raja
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Tyrosine Kinases ◽  
Serotonin Receptor ◽  
Therapeutic Targets ◽  
Soluble Guanylyl Cyclase ◽  
Guanosine Monophosphate ◽  
Therapeutic Options ◽  
Activated T Cells ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) consists of a group of heterogeneous but distinct disorders characterized by complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling that leads to right ventricular failure and death. Over the past two decades, significant advances in our understanding of the pathobiology of PAH have led to the development of several therapeutic targets in this disease. Besides conservative therapeutic strategies such as anticoagulation and diuretics, the current treatment paradigm for PAH targets the mediators of the three main biologic pathways that are critical for its pathogenesis and progression: endothelin receptor antagonists inhibit the upregulated endothelin pathway by blocking the biologic activity of endothelin-1; phosphodiesterase-5 inhibitors prevent breakdown and increase the endogenous availability of cyclic guanosine monophosphate, which signals the vasorelaxing effects of the downregulated mediator nitric oxide; and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin. In addition to these established current therapeutic options, a large number of potential therapeutic targets are being investigated. These novel therapeutic targets include soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-hydroxytryptamine (serotonin) receptor 2B, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. This review provides an overview of the current therapeutic options and potential therapeutic targets for PAH.

scholarly journals Exploring the binding mechanisms of PDE5 with chromeno[2,3-c]pyrrol-9(2H)-one by theoretical approaches

RSC Advances ◽  
2018 ◽  
Vol 8 (53) ◽  
pp. 30481-30490 ◽  
Author(s):  
Xianfeng Huang ◽  
Peng Xu ◽  
Yijing Cao ◽  
Li Liu ◽  
Guoqiang Song ◽  
...  
Keyword(s):  
Erectile Dysfunction ◽  
Pulmonary Arterial Hypertension ◽  
Drug Target ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Theoretical Approaches ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type ◽  
Binding Mechanisms ◽  
Important Drug

Cyclic nucleotide phosphodiesterase type 5 (PDE5) is exclusively specific for the cyclic guanosine monophosphate (cGMP), and PDE5 is an important drug target for the treatment of erectile dysfunction and pulmonary arterial hypertension (PAH).

The Nitric Oxide Pathway in Pulmonary Arterial Hypertension: Pathomechanism, Biomarkers and Drug Targets

2020 ◽  
Vol 27 (42) ◽  
pp. 7168-7188
Author(s):  
Zsófia Lázár ◽  
Martina Mészáros ◽  
Andras Bikov
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Current Knowledge ◽  
Muscle Tone ◽  
Degradation Products ◽  
Guanosine Monophosphate ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial

The altered Nitric Oxide (NO) pathway in the pulmonary endothelium leads to increased vascular smooth muscle tone and vascular remodelling, and thus contributes to the development and progression of pulmonary arterial hypertension (PAH). The pulmonary NO signalling is abrogated by the decreased expression and dysfunction of the endothelial NO synthase (eNOS) and the accumulation of factors blocking eNOS functionality. The NO deficiency of the pulmonary vasculature can be assessed by detecting nitric oxide in the exhaled breath or measuring the degradation products of NO (nitrite, nitrate, S-nitrosothiol) in blood or urine. These non-invasive biomarkers might show the potential to correlate with changes in pulmonary haemodynamics and predict response to therapies. Current pharmacological therapies aim to stimulate pulmonary NO signalling by suppressing the degradation of NO (phosphodiesterase- 5 inhibitors) or increasing the formation of the endothelial cyclic guanosine monophosphate, which mediates the downstream effects of the pathway (soluble guanylate cyclase sensitizers). Recent data support that nitrite compounds and dietary supplements rich in nitrate might increase pulmonary NO availability and lessen vascular resistance. This review summarizes current knowledge on the involvement of the NO pathway in the pathomechanism of PAH, explores novel and easy-to-detect biomarkers of the pulmonary NO.

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