Modulation of cGMP Synthesis and Metabolism

  • Kristen J. Bubb
  • Adrian J. Hobbs
  • James R. Klinger
Part of the Respiratory Medicine book series (RM, volume 12)


The cyclic nucleotide cGMP acts as the secondary messenger for nitric oxide (NO) and natriuretic peptides (NP). It is synthesised by the activation of soluble or particulate guanylate cyclase by NO or NP, respectively. The primary downstream target of cGMP is cGMP-dependent kinase (PKG) which acts at a variety of intracellular sites to inhibit vasoconstriction, proliferation and hypertrophic responses and phosphodiesterases that are responsible for its metabolism. cGMP-mediated pulmonary vasodilation plays a critical role in maintaining normal pulmonary vascular pressure, and a growing body of evidence suggests that decreased cGMP synthesis or increased cGMP metabolism may contribute to the pathogenesis of pulmonary vascular disease. Several medications that target deficiencies in NO and cGMP signalling have recently been approved for the treatment of pulmonary arterial hypertension. This chapter will discuss the NO and NP/cGMP signalling pathways as they pertain to modulation of pulmonary vascular function and will review the efficacy and safety of the phosphodiesterase inhibitors and soluble guanylate cyclase stimulators that have been developed for the treatment of PAH. Alternative approaches to enhancing cGMP signalling that may be useful in developing new therapies for PAH will also be presented.


Cyclic guanosine monophosphate cGMP Nitric oxide Natriuretic peptide Guanylate cyclase Pulmonary arterial hypertension Nitric oxide synthase Phosphodiesterase 



Atrial natriuretic peptide




Brain natriuretic peptide


Cyclic adenosine-3′,5′-monophosphate


Cyclic guanosine-3′,5′-monophosphate


Congestive heart failure


C-type natriuretic peptide


Endothelial nitric oxide synthase




Guanosine triphosphate


Inducible nitric oxide synthase


Neutral endopeptidase


Neuronal nitric oxide synthase


Nitric oxide


Natriuretic peptide receptor-A


Natriuretic peptide receptor-B


Natriuretic peptide receptor-C




Phosphodiesterase type 5 inhibitor


Particulate guanylatecyclase


Pulmonary hypertension


cGMP-dependent protein kinase


Parts per million


Soluble guanylatecyclase




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Authors and Affiliations

  • Kristen J. Bubb
    • 1
  • Adrian J. Hobbs
    • 1
  • James R. Klinger
    • 2
  1. 1.William Harvey Research InstituteBarts and The London Medical SchoolLondonUK
  2. 2.Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island HospitalAlpert Medical School of Brown UniversityProvidenceUSA

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