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.

scholarly journals Novel Therapeutic Approaches of Pulmonary Arterial Hypertension

2019 ◽  
Vol 28 (02) ◽  
pp. 112-117
Author(s):  
Sanjay Tyagi ◽  
Vishal Batra
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptors ◽  
Pulmonary Vasculature ◽  
Therapeutic Approaches ◽  
Uncommon Disease ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

AbstractPulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

scholarly journals Ion channels as convergence points in the pathology of pulmonary arterial hypertension

2021 ◽  
Author(s):  
Thibault R. H. Jouen-Tachoire ◽  
Stephen J. Tucker ◽  
Paolo Tammaro
Keyword(s):  
Smooth Muscle ◽  
Ion Channels ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Muscle Tone ◽  
Pulmonary Vasculature ◽  
Extrinsic Factors ◽  
Pulmonary Arterial ◽  
Vascular Smooth Muscle Tone

Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

scholarly journals Combination Therapy in Pulmonary Arterial Hypertension—Targeting the Nitric Oxide and Prostacyclin Pathways

2021 ◽  
pp. 107424842110065
Author(s):  
Stacy Mandras ◽  
Gabor Kovacs ◽  
Horst Olschewski ◽  
Meredith Broderick ◽  
Andrew Nelsen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Signaling Pathways ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Secondary Data ◽  
Current Treatment ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I2) (PGI2) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI2 pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI2 signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.

scholarly journals Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat

2021 ◽  
Vol 93 (9) ◽  
pp. 1117-1124
Author(s):  
Tamila V. Martynyuk ◽  
Anton A. Shmalts ◽  
Sergey V. Gorbachevsky ◽  
Irina E. Chazova
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Fatal Outcome ◽  
Controlled Study ◽  
Specific Therapy ◽  
Level Of Evidence ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

scholarly journals Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities

2017 ◽  
Vol 8 (2-3) ◽  
pp. 47-64 ◽  
Author(s):  
Jessica B. Badlam ◽  
Todd M. Bull
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response To Treatment ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Efficacy Parameters

Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more ‘personalized’ therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.

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.

Disease-specific platelet signaling defects in idiopathic pulmonary arterial hypertension

2021 ◽  
Vol 320 (5) ◽  
pp. L739-L749
Author(s):  
Kulwant S. Aulak ◽  
Sami Al Abdi ◽  
Ling Li ◽  
Jack S. Crabb ◽  
Arnab Ghosh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Specific Activity ◽  
Ex Vivo ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Therapeutic Decisions ◽  
Pulmonary Arterial ◽  
Disease Specific

Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with several treatment options. Long-term mortality remains high with great heterogeneity in treatment response. Even though most of the pathology of IPAH is observed in the lung, there is systemic involvement. Platelets from patients with IPAH have characteristic metabolic shifts and defects in activation; therefore, we investigated whether they could be used to identify other disease-specific abnormalities. We used proteomics to investigate protein expression changes in platelets from patients with IPAH compared with healthy controls. Key abnormalities of nitric oxide pathway were tested in platelets from a larger cohort of unique patients with IPAH. Platelets showed abnormalities in the prostacyclin and nitric oxide pathways, which are dysregulated in IPAH and hence targets of therapy. We detected reduced expression of G protein αs and increased expression of the regulatory subunits of the cAMP-dependent protein kinase (PKA) type II isoforms, supporting an overall decrease in the activation of the prostacyclin pathway. We noted reduced levels of the soluble guanylate cyclase (sGC) subunits and increased expression of the phosphodiesterase type 5 A (PDE5A), conditions that affect the response to nitric oxide. Ensuing analysis of 38 unique patients with IPAH demonstrated considerable variation in the levels and specific activity of sGC, a finding with novel implications for personalized therapy. Platelets have some of the characteristic vasoactive signal abnormalities seen in IPAH and may provide comprehensive ex vivo mechanistic information to direct therapeutic decisions.

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.

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