Chronic intratracheal application of the soluble guanylyl cyclase stimulator BAY 41-8543 ameliorates experimental pulmonary hypertension

// Matthieu Amirjanians 1 , Bakytbek Egemnazarov 1 , Akylbek Sydykov 1 , Baktybek Kojonazarov 1 , Ralf Brandes 3 , Himal Luitel 1 , Kabita Pradhan 1 , Johannes-Peter Stasch 4,5 , Gorden Redlich 6 , Norbert Weissmann 1 , Friedrich Grimminger 1 , Werner Seeger 1,2 , Hossein Ghofrani 1 and Ralph Schermuly 1,2 1 University of Giessen Lung Center, Giessen, Germany 2 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany 3 Institute for Cardiovascular Physiology, J.W. Goethe University, Frankfurt, Germany 4 Cardiology Research, Pharmaceuticals, Bayer AG, Wuppertal, Germany 5 Institute of Pharmacy, Martin Luther University of Halle Wittenberg, Halle, Germany 6 Research Pharmacokinetics, Pharmaceuticals, Bayer AG, Wuppertal, Germany Correspondence to: Ralph Schermuly, email: // Keywords : monocrotaline; cGMP; nitric oxide; pulmonary hypertension; remodelling; Pathology Section Received : August 19, 2016 Accepted : March 08, 2017 Published : March 31, 2017 Abstract Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect. Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg). Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed pulmonary hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of pulmonary vascular remodeling was largely reversed in all treatment groups. Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.