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Biosci Biotechnol Biochem. 2019 Mar 5:1-11. doi: 10.1080/09168451.2019.1584520. [Epub ahead of print]

Improvement of pulmonary arterial hypertension, inflammatory response, and epithelium injury by dual activation of cAMP/cGMP pathway in a rat model of monocrotaline-induced pulmonary hypertension.

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1
a Pharmaceutical Research Division , Takeda Pharmaceutical Company Limited , Fujisawa , Kanagawa , Japan.

Abstract

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.

KEYWORDS:

cAMP; cGMP; rat model of monocrotaline-induced pulmonary hypertension

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