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Pharmacotherapy of Pulmonary Hypertension pp 229–255Cite as

Phosphodiesterase-5 Inhibitors

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Nitric oxide (NO) signaling plays a key role in modulating vascular tone and remodeling in the pulmonary circulation. The guanylate cyclase/cyclic guanylate monophosphate-signaling pathway primarily mediates nitric oxide signaling. This pathway is critical in normal regulation of the pulmonary vasculature, and is an important target for therapy in patients with pulmonary hypertension. In the pulmonary vasculature, degradation of cGMP is primarily regulated by PDE-5, and inhibition of this enzyme has important effects on pulmonary vasculature smooth muscle tone. Large randomized placebo-controlled trials of PDE-5 inhibitors demonstrated improved exercise capacity, hemodynamics and quality of life in adult patients with PAH. This chapter will discuss the mechanisms of NO signaling in the vasculature, characteristics of the PDE5-inhibitors approved for treatment of PH, and review available data on the use of phosphodiesterase inhibitors in PH.

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Abbreviations

6MWD:

6-min walk distance

ANP:

Atrial natriuretic peptide

BNP:

Brain-type natriuretic peptide

cAMP:

Cyclic adenosine monophosphate

cGK:

cGMP-dependent protein kinases

cGMP:

Cyclic guanosine monophosphate

CNP:

C-type natriuretic peptide

CrCL:

Creatinine clearance

EMA:

European Medicines Agency

eNOS:

Endothelial nitric oxide synthase

FDA:

United States Food and Drug Administration

GTP:

Guanosine triphosphate

HFpEF:

Heart failure preserved ejection fraction

HFrEF:

Heart failure reduced ejection fraction

NO:

Nitric oxide

PAH:

Pulmonary arterial hypertension

PAP:

Pulmonary artery pressure

PDE:

Phosphodiesterase

PH:

Pulmonary hypertension

PKG:

Protein kinase-G

QOL:

Quality of life

RHC:

Right heart catheterization

RV:

Right ventricle

sGC:

Soluble guanylate cyclase

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Authors and Affiliations

  1. Pulmonary Vascular Disease Program, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA

    Barbara A. Cockrill & Aaron B. Waxman

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  1. Barbara A. Cockrill
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Correspondence to Aaron B. Waxman .

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Editors and Affiliations

  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Cockrill, B.A., Waxman, A.B. (2013). Phosphodiesterase-5 Inhibitors. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_10

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