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Modulation of cGMP Synthesis and Metabolism

  • Chapter
Diagnosis and Management of Pulmonary Hypertension

Part of the book series: Respiratory Medicine ((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.

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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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Authors and Affiliations

  1. William Harvey Research Institute, Barts and The London Medical School, London, UK

    Kristen J. Bubb & Adrian J. Hobbs

  2. Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI, 02903, USA

    James R. Klinger M.D.

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  1. Kristen J. Bubb
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  2. Adrian J. Hobbs
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  3. James R. Klinger M.D.
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Correspondence to James R. Klinger M.D. .

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Editors and Affiliations

  1. Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, USA

    James R. Klinger

  2. Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Robert P. Frantz

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Bubb, K.J., Hobbs, A.J., Klinger, J.R. (2015). Modulation of cGMP Synthesis and Metabolism. In: Klinger, J., Frantz, R. (eds) Diagnosis and Management of Pulmonary Hypertension. Respiratory Medicine, vol 12. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2636-7_15

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  • DOI: https://doi.org/10.1007/978-1-4939-2636-7_15

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