Therapeutic effects of trans-3-methoxy-β-nitrostyrene in rat model of monocrotaline-induced pulmonary hypertension.

PURPOSE: We examined the therapeutic effects of the soluble guanylate cyclase stimulator, trans-3-methoxy-β-nitrostyrene (T3MN), on monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. EXPERIMENTAL APPROACH: Four weeks following subcutaneous MCT (60 mg/kg) injection, Male Wistar rats were orally treated for two weeks with sildenafil (10 mg/kg/day, MCT-SILD group), T3MN at 25, 50, and 75 mg/kg/day (MCT-T3MN75 group) or with its vehicle (MCT-V group). Control (CNT) rats received only MCT vehicle at Day 0 (D0). All experimental procedures were performed on D43, except for the echodopplercardiography analysis which was performed in D42 in rats from the CNT, MCT-V, MCT-T3MN75 and MCT-SILD groups. KEY RESULTS: Compared to CNT rats, MCT-V rats showed significant (1) increase in right ventricle (RV) free wall thickness and Fulton index, (2) decreases of RV stroke volume, pulmonary artery acceleration time (PAAT), PAAT/time of ejection ratio, tricuspid annular plane systolic excursion and velocity-time integral, (3) increase in RV systolic pressure, (4) increase in both pulmonary fibrosis and wall thickness of pulmonary arterioles, and (5) endothelial dysfunction. All these morphometric, invasive hemodynamic, vascular reactivity and pulmonary remodeling changes were significantly and dose-dependently reduced by T3MN. Indeed, changes in hemodynamic parameters recorded by echodopplercardiography were reversed in the MCT-T3MN75 group. CONCLUSION: T3MN treatment reversed dose-dependently the established PH in rats, as evidenced by its inhibitory effects on MCT-induced RV hypertrophy, lung congestion, RV systolic dysfunction, RV pressure overload, pulmonary artery stiffness, endothelial dysfunction, pulmonary artery remodeling and collagen deposition. Further mechanistic studies of these therapeutic effects of T3MN are warranted.