Premium
IWP‐427, an sGC Stimulator, Has Cardioprotective Effects in the Monocrotaline Model of Pulmonary Hypertension
Author(s) -
Jacobson Sarah,
Tang Kim,
Long Kimberly,
Germano Peter,
Tobin Jenny,
Sheppeck James,
Nakai Takashi,
Masferrer Jaime
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1027.6
Subject(s) - ventricle , medicine , pulmonary hypertension , right ventricular hypertrophy , vascular resistance , stimulation , heart failure , cardiology , pulmonary artery , concomitant , pharmacology , endocrinology , hemodynamics
Pulmonary arterial hypertension (PAH) results in increased resistance of blood return to the pulmonary vasculature and concomitant hypertrophy of the right ventricle of the heart (RHH). Stimulation of the NO/sGC/cGMP pathway has been shown to reduce RHH in preclinical models of PAH and improves clinical outcomes in patients with PAH. We therefore hypothesized that prophylactic treatment with an sGC stimulator would prevent RHH in a preclinical model of PAH. IWP‐427 is a potent (HEK EC 50 =167nM), orally bioavailable sGC stimulator. In this study, a single subcutaneous injection of monocrotaline (MCT; 60mg/kg) induced significant RHH in male rats compared to naïve controls after 4 weeks as measured by the ratio of right heart weight to the left ventricle and septum (0.33±0.02 vs 0.22±0.01; p<0.001; n=9‐12). Prophylactic treatment with IWP‐427 prevented MCT‐induced RHH as compared to vehicle treated animals (0.21±0.03 vs 0.33±0.02; p<0.01; n=9‐12). Additionally, plasma levels of NT‐proBNP, a marker of right ventricular damage, were significantly lower in animals treated with IWP‐427 compared to vehicle (10913±1024 vs 15961±1993 ECL units; p<0.05; n=8). IWP‐427 is therefore a cardioprotective sGC stimulator in a monocrotaline model of PAH.