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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)

Abstract

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.

Keywords

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

Abbreviations

ANP

Atrial natriuretic peptide

BH4

Tetrahydrobiopterin

BNP

Brain natriuretic peptide

cAMP

Cyclic adenosine-3′,5′-monophosphate

cGMP

Cyclic guanosine-3′,5′-monophosphate

CHF

Congestive heart failure

CNP

C-type natriuretic peptide

eNOS

Endothelial nitric oxide synthase

GC

Guanylatecyclase

GTP

Guanosine triphosphate

iNOS

Inducible nitric oxide synthase

NEP

Neutral endopeptidase

nNOS

Neuronal nitric oxide synthase

NO

Nitric oxide

NPR-A

Natriuretic peptide receptor-A

NPR-B

Natriuretic peptide receptor-B

NPR-C

Natriuretic peptide receptor-C

PDE

Phosphodiesterase

PDE5i

Phosphodiesterase type 5 inhibitor

pGC

Particulate guanylatecyclase

PH

Pulmonary hypertension

PKG

cGMP-dependent protein kinase

Ppm

Parts per million

sGC

Soluble guanylatecyclase

V/Q

Ventilation/perfusion

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Copyright information

© Springer Science+Business Media New York 2015

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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