The nitric oxide-soluble guanylate cyclase-cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase.

Publisher: European Respiratory Society Country of Publication: England NLM ID: 9111391 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1600-0617 (Electronic) Linking ISSN: 09059180 NLM ISO Abbreviation: Eur Respir Rev Subsets: MEDLINE

Publication: Sheffield, United Kingdom : European Respiratory Society
Original Publication: Copenhagen K, Denmark : Published by the Society and distributed by Munksgaard International Publishers, 1991-

Hypertension, Pulmonary*/etiology ; Pulmonary Arterial Hypertension*; Humans ; Soluble Guanylyl Cyclase/metabolism ; Nitric Oxide/metabolism ; Signal Transduction ; Cyclic GMP/metabolism ; Guanylate Cyclase/metabolism

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO-sGC-cGMP pathway, with a focus on PH.
Competing Interests: Conflict of interest: R.L. Benza reports receiving grants from Actelion, Bayer AG, Bellerophon Therapeutics and Eiger Biopharmaceuticals. E. Grünig reports fees for lectures and/or consultations from Actelion, Bayer AG, GlaxoSmithKline, Merck Sharp & Dohme Corp., Pfizer and United Therapeutics outside the submitted work. P. Sandner and J.-P. Stasch are employees of Bayer AG, Wuppertal, Germany. G. Simonneau reports personal fees and nonfinancial support from Actelion, Bayer AG and Merck Sharp & Dohme outside the submitted work.
(Copyright ©The authors 2024.)

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EC 4.6.1.2 (Soluble Guanylyl Cyclase)
31C4KY9ESH (Nitric Oxide)
H2D2X058MU (Cyclic GMP)
EC 4.6.1.2 (Guanylate Cyclase)

Date Created: 20240320 Date Completed: 20240322 Latest Revision: 20240323

20240323

PMC10957071

10.1183/16000617.0183-2023

38508664