Inhibition of Phosphodiesterase 2 Augments cGMP and cAMP Signaling to Ameliorate Pulmonary Hypertension

Circulation. 2014 Aug 5;130(6):496-507. doi: 10.1161/CIRCULATIONAHA.114.009751. Epub 2014 Jun 4.

Abstract

Background: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH.

Methods and results: The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil.

Conclusions: PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.

Keywords: cyclic nucleotide; natriuretic peptide; nitric oxide; phosphodiesterase inhibitor; pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP / physiology*
  • Cyclic GMP / physiology*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / physiology
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / enzymology*
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Triazines / pharmacology
  • Triazines / therapeutic use

Substances

  • 2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one
  • Imidazoles
  • Phosphodiesterase Inhibitors
  • Triazines
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Cyclic GMP