TY - JOUR A1 - Amirjanians, Matthieu A1 - Egemnazarov, Bakytbek A1 - Sydykov, Akylbek A1 - Kojonazarov, Baktybek A1 - Brandes, Ralf A1 - Luitel, Himal A1 - Pradhan, Kabita A1 - Stasch, Johannes-Peter A1 - Redlich, Gorden A1 - Weißmann, Norbert A1 - Grimminger, Friedrich A1 - Seeger, Werner A1 - Ghofrani, Hossein A1 - Schermuly, Ralph T1 - Chronic intratracheal application of the soluble guanylyl cyclase stimulator BAY 41-8543 ameliorates experimental pulmonary hypertension T2 - Oncotarget N2 - 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. KW - monocrotaline KW - cGMP KW - nitric oxide KW - pulmonary hypertension KW - remodelling KW - Pathology Section Y1 - 2017 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45833 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-458339 SN - 1949-2553 N1 - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. VL - 8 IS - 18 SP - 29613 EP - 29624 PB - Impact Journals LLC CY - [S.l.] ER -