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Updated: Mar 9, 2026

Measurement of Cyclic Guanosine Monophosphate (cGMP) in Solid Tissues using Competitive Enzyme-Linked Immunosorbent Assay (ELISA)
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Measurement of Cyclic Guanosine Monophosphate (cGMP) in Solid Tissues using Competitive Enzyme-Linked Immunosorbent Assay (ELISA)

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Differential modulation of the sGC-cGMP pathway by sGC stimulators and activators in human lung cells

Paula Montero1, María Amparo Bayarri2, Inés Roger3

  • 1Department of Pharmacology, Faculty of Medicine, University of Valencia 46010 Valencia, Spain; Research Foundation of the General University Hospital of Valencia (FIHGUV), 46014 Valencia, Spain; Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain.

Biochemical Pharmacology
|March 7, 2026
PubMed

Insights

Soluble guanylate cyclase (sGC) activators, unlike stimulators, maintain cyclic GMP (cGMP) production under oxidative stress in lung cells. Combining activators with PDE5 inhibitors shows promise for treating chronic lung diseases.

Area of Science:

  • Pulmonary Medicine
  • Pharmacology
  • Cell Biology

Background:

  • Chronic lung diseases involve oxidative stress, inflammation, and fibrosis, impairing nitric oxide-soluble guanylate cyclase-cyclic GMP (NO-sGC-cGMP) signaling.
  • Reduced sGC α1 and β1 expression is observed in COPD and asthma patients.
  • Cigarette smoke extract (CSE) causes oxidative damage to sGC, reducing its responsiveness.

Purpose of the Study:

  • To investigate the differential effects of an sGC stimulator (riociguat) and an sGC activator (cinaciguat) on pulmonary cells.
  • To evaluate the impact of combining these agents with a PDE5 inhibitor (sildenafil).
  • To assess their efficacy in mitigating CSE-induced cellular damage and dysfunction.

Main Methods:

  • Primary human pulmonary cells (epithelial cells, fibroblasts, neutrophils, endothelial monolayers) were exposed to CSE.
  • Cells were treated with riociguat, cinaciguat, sildenafil, or combinations thereof.
  • cGMP production, sGC heme oxidation, oxidative stress markers, inflammatory cell adhesion, and profibrotic gene expression were measured.

Main Results:

  • CSE oxidized the sGC heme group, diminishing responsiveness to NO and riociguat.
  • Cinaciguat, but not riociguat, preserved cGMP production under oxidizing conditions.
  • Co-treatment with sildenafil enhanced cGMP levels for both drugs.
  • Both drugs attenuated CSE-induced oxidative stress, inflammation, and fibrosis; cinaciguat with sildenafil showed more potent effects.

Conclusions:

  • sGC activators exhibit distinct pharmacodynamic profiles compared to stimulators under oxidative conditions.
  • Cinaciguat, especially combined with sildenafil, demonstrates robust therapeutic potential.
  • sGC modulation represents a promising strategy for treating oxidative chronic lung diseases.
Keywords:
Cigarette smokeOxidative stressPulmonary cellssGC modulators

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