Kabita Pradhan1, Akylbek Sydykov1, Xia Tian1, Argen Mamazhakypov1, Balram Neupane1, Himal Luitel1, Norbert Weissmann1, Werner Seeger2, Friedrich Grimminger1, Axel Kretschmer3, Johannes-Peter Stasch3, Hossein Ardeschir Ghofrani1, Ralph Theo Schermuly4. 1. Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany. 2. Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany; Max-Planck-Institute for Heart and Lung Research, Parkstraße 1, 61231 Bad Nauheim, Germany. 3. Bayer HealthCare, Aprather Weg 18a, 42096, Wuppertal, Germany. 4. Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany. Electronic address: ralph.schermuly@innere.med.uni-giessen.de.
Abstract
BACKGROUND: Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO-sGC-cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction. METHODS: C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks. RESULTS: Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function. CONCLUSIONS: Thus, modulation of the NO-sGC-cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.
BACKGROUND: Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO-sGC-cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction. METHODS: C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks. RESULTS: Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function. CONCLUSIONS: Thus, modulation of the NO-sGC-cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.
Authors: Jennifer L Philip; Thomas M Murphy; David A Schreier; Sydney Stevens; Diana M Tabima; Margie Albrecht; Andrea L Frump; Timothy A Hacker; Tim Lahm; Naomi C Chesler Journal: Am J Physiol Heart Circ Physiol Date: 2019-02-15 Impact factor: 4.733
Authors: Kálmán Benke; Balázs Tamás Németh; Alex Ali Sayour; Klára Aliz Stark; Attila Oláh; Mihály Ruppert; Gábor Szabó; Sevil Korkmaz-Icöz; Eszter Mária Horváth; Rita Benkő; István Hartyánszky; Zoltán Szabolcs; Béla Merkely; Tamás Radovits Journal: Sci Rep Date: 2020-03-24 Impact factor: 4.379