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

  • 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.

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Author:Matthieu Amirjanians, Bakytbek Egemnazarov, Akylbek Sydykov, Baktybek Kojonazarov, Ralf Peter Louis BrandesORCiDGND, Himal Luitel, Kabita Pradhan, Johannes-Peter Stasch, Gorden Redlich, Norbert Weißmann, Friedrich GrimmingerORCiDGND, Werner SeegerORCiDGND, Hossein Ghofrani, Ralph Schermuly
Pubmed Id:
Parent Title (English):Oncotarget
Publisher:Impact Journals LLC
Place of publication:[S.l.]
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/03/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/03/08
Tag:Pathology Section; cGMP; monocrotaline; nitric oxide; pulmonary hypertension; remodelling
Page Number:12
First Page:29613
Last Page:29624
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Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 3.0