title: Soluble guanylate cyclase stimulator riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice.
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.
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Kabita
authors.initials: K
authors.lastname: Pradhan
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Argen
authors.initials: A
authors.lastname: Mamazhakypov
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Balram
authors.initials: B
authors.lastname: Neupane
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Himal
authors.initials: H
authors.lastname: Luitel
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: 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.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Bayer HealthCare, Aprather Weg 18a, 42096, Wuppertal, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Kretschmer
authors.affiliation: Bayer HealthCare, Aprather Weg 18a, 42096, Wuppertal, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: 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.
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction; D000068677:Sildenafil Citrate / Q000008:administration & dosage* / Q000494:pharmacology; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C542595:riociguat
keywords: Heart failure; Pulmonary hypertension; Riociguat; Sildenafil; Transverse aortic constriction