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

Annette D Rieg; Nina A Bünting; Christian Cranen; Said Suleiman; Jan W Spillner; Heike Schnöring; Thomas Schröder; Saskia von Stillfried; Till Braunschweig; Paul W Manley; Gereon Schälte; Rolf Rossaint; Stefan Uhlig; Christian Martin

doi:10.1186/s12931-019-1074-2

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

Respir Res. 2019 Jun 6;20(1):111. doi: 10.1186/s12931-019-1074-2.

Affiliations

¹ Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany. arieg@ukaachen.de.
² Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
³ Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
⁴ Department of Surgery, Luisenhospital Aachen, Aachen, Germany.
⁵ Institute of Pathology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
⁶ Novartis Pharma AG, Basel, Switzerland.
⁷ Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.

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 K_ATP-, BK_Ca²⁺- or K_v-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.

Keywords: Imatinib; Nilotinib; Pulmonary arterial hypertension; Pulmonary arteries; Tyrosine kinase inhibitors.

MeSH terms

Animals
Dose-Response Relationship, Drug
Female
Humans
Lung / blood supply*
Lung / drug effects*
Lung / physiology
Mice
Mice, Inbred BALB C
Protein Kinase Inhibitors / pharmacology*
Pulmonary Artery / drug effects*
Pulmonary Artery / physiology
Species Specificity
Vasodilation / drug effects*
Vasodilation / physiology

Substances

Protein Kinase Inhibitors

Grants and funding

109/14 (691440)/RWTH Aachen University