Journal
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
Volume 83, Issue 6, Pages 1000-1010Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/09168451.2019.1584520
Keywords
cAMP; cGMP; rat model of monocrotaline-induced pulmonary hypertension
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Funding
- Takeda Pharmaceutical Company
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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 1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, CC 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.
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