Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices

Respiratory Research

Gereon Schälte¹  Annette D. Rieg¹  Rolf Rossaint¹  Heike Schnöring²  Jan W. Spillner²  Thomas Schröder³  Till Braunschweig⁴  Saskia von Stillfried⁴  Nina A. Bünting⁵  Christian Martin⁵  Christian Cranen⁵  Stefan Uhlig⁵  Said Suleiman⁵  Paul W. Manley⁶ 

[1] Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen;Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-Aachen;Department of Surgery, Luisenhospital Aachen;Institute of Pathology, Medical Faculty Aachen, RWTH-Aachen;Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen;Novartis Pharma AG;

关键词: Tyrosine kinase inhibitors;    Imatinib;    Nilotinib;    Pulmonary arteries;    Pulmonary arterial hypertension;   

DOI  :  10.1186/s12931-019-1074-2

来源: DOAJ

【 摘 要 】

Abstract Background Tyrosine kinase inhibitors (TKIs) inhibit the platelet derived growth factor receptor (PDGFR) and gain increasing significance in the therapy of proliferative diseases, e.g. pulmonary arterial hypertension (PAH). Moreover, TKIs relax pulmonary vessels of rats and guinea pigs. So far, it is unknown, whether TKIs exert relaxation in human and murine pulmonary vessels. Thus, we studied the effects of TKIs and the PDGFR-agonist PDGF-BB in precision-cut lung slices (PCLS) from both species. Methods The vascular effects of imatinib (mice/human) or nilotinib (human) were studied in Endothelin-1 (ET-1) pre-constricted pulmonary arteries (PAs) or veins (PVs) by videomicroscopy. Baseline initial vessel area (IVA) was defined as 100%. With regard to TKI-induced relaxation, K+-channel activation was studied in human PAs (PCLS) and imatinib/nilotinib-related changes of cAMP and cGMP were analysed in human PAs/PVs (ELISA). Finally, the contractile potency of PDGF-BB was explored in PCLS (mice/human). Results Murine PCLS: Imatinib (10 μM) relaxed ET-1-pre-constricted PAs to 167% of IVA. Vice versa, 100 nM PDGF-BB contracted PAs to 60% of IVA and pre-treatment with imatinib or amlodipine prevented PDGF-BB-induced contraction. Murine PVs reacted only slightly to imatinib or PDGF-BB. Human PCLS: 100 μM imatinib or nilotinib relaxed ET-1-pre-constricted PAs to 166% or 145% of IVA, respectively, due to the activation of KATP-, BKCa 2+- or Kv-channels. In PVs, imatinib exerted only slight relaxation and nilotinib had no effect. Imatinib and nilotinib increased cAMP in human PAs, but not in PVs. In addition, PDGF-BB contracted human PAs/PVs, which was prevented by imatinib. Conclusions TKIs relax pre-constricted PAs/PVs from both, mice and humans. In human PAs, the activation of K+-channels and the generation of cAMP are relevant for TKI-induced relaxation. Vice versa, PDGF-BB contracts PAs/PVs (human/mice) due to PDGFR. In murine PAs, PDGF-BB-induced contraction depends on intracellular calcium. So, PDGFR regulates the tone of PAs/PVs. Since TKIs combine relaxant and antiproliferative effects, they may be promising in therapy of PAH.

【 授权许可】

Unknown