title: Effects of different pulmonary vasodilators on arterial saturation in a model of pulmonary hypertension.
abstract: BACKGROUND
  Approved therapies for pulmonary arterial hypertension can induce oxygen desaturation when administered to patients with secondary forms of pulmonary hypertension (PH), probably due to an increase in ventilation/perfusion mismatch. Thus, so far these treatments have largely failed in secondary forms of PH.
  
  
  METHODS
  We established an animal model of heterogeneous lung ventilation to evaluate the desaturation potential of mechanistically distinct vasoactive drugs launched or currently in clinical development for the treatment of PH. Single-lung ventilation was induced in five groups (N = 6) of anesthetized minipigs (7 weeks, 4 to 5 kg BW), and their hemodynamic parameters were monitored before and after intravenous injection of control (vehicle only), endothelin antagonist (bosentan; 0.3, 1, 3, 10 mg/kg), phosphodiesterase type 5 inhibitor (sildenafil; 3, 10, 30, 100 µg/kg), and soluble guanylate cyclase stimulators (BAY 41-8543 and riociguat; 1, 3, 10, 30 µg/kg). Cumulative doses were administered before successive unilateral ventilation cycles. The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.
  
  
  RESULTS
  Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation. In contrast to control, all drugs dose-dependently decreased hypoxic mPAP (a positive treatment effect) and increased area under the arterial hemoglobin saturation curve (unwanted desaturation effect). Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41-8543 lowered arterial oxygen saturation of hemoglobin the least.
  
  
  CONCLUSIONS
  Future investigations will be required to confirm these findings in clinical settings.
authors.affiliation: Bayer Pharma AG, Cardiology Research, Wuppertal, Germany ; University Witten/Herdecke, Fakultät für Gesundheit, Witten, Germany.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Becker
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Martin
authors.initials: M
authors.lastname: Bechem
authors.forename: Jörg
authors.initials: J
authors.lastname: Keldenich
authors.forename: Alexandra
authors.initials: A
authors.lastname: Klipp
authors.forename: Katja
authors.initials: K
authors.lastname: Schaefer
authors.forename: Hannes-Friedrich
authors.initials: HF
authors.lastname: Ulbrich
authors.forename: Hubert
authors.initials: H
authors.lastname: Truebel
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013552:Swine; D013556:Swine, Miniature; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D014665:Vasodilator Agents