PMID- 31170998
OWN - NLM
STAT- MEDLINE
DCOM- 20191226
LR  - 20200225
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 20
IP  - 1
DP  - 2019 Jun 6
TI  - Tyrosine kinase inhibitors relax pulmonary arteries in human and murine 
      precision-cut lung slices.
PG  - 111
LID - 10.1186/s12931-019-1074-2 [doi]
LID - 111
AB  - 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 muM) 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 muM 
      imatinib or nilotinib relaxed ET-1-pre-constricted PAs to 166% or 145% of IVA, 
      respectively, due to the activation of K(ATP)-, BK(Ca)(2+)- 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.
FAU - Rieg, Annette D
AU  - Rieg AD
AUID- ORCID: 0000-0002-7043-5494
AD  - Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, 
      Germany. arieg@ukaachen.de.
FAU - Bunting, Nina A
AU  - Bunting NA
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Cranen, Christian
AU  - Cranen C
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Suleiman, Said
AU  - Suleiman S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Spillner, Jan W
AU  - Spillner JW
AD  - Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Schnoring, Heike
AU  - Schnoring H
AD  - Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Schroder, Thomas
AU  - Schroder T
AD  - Department of Surgery, Luisenhospital Aachen, Aachen, Germany.
FAU - von Stillfried, Saskia
AU  - von Stillfried S
AD  - Institute of Pathology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
FAU - Braunschweig, Till
AU  - Braunschweig T
AD  - Institute of Pathology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
FAU - Manley, Paul W
AU  - Manley PW
AD  - Novartis Pharma AG, Basel, Switzerland.
FAU - Schalte, Gereon
AU  - Schalte G
AD  - Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, 
      Germany.
FAU - Rossaint, Rolf
AU  - Rossaint R
AD  - Department of Anaesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, 
      Germany.
FAU - Uhlig, Stefan
AU  - Uhlig S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Martin, Christian
AU  - Martin C
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
LA  - eng
GR  - 109/14 (691440)/RWTH Aachen University/
PT  - Journal Article
DEP - 20190606
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Lung/*blood supply/*drug effects/physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pulmonary Artery/*drug effects/physiology
MH  - Species Specificity
MH  - Vasodilation/*drug effects/physiology
PMC - PMC6555704
OTO - NOTNLM
OT  - Imatinib
OT  - Nilotinib
OT  - Pulmonary arterial hypertension
OT  - Pulmonary arteries
OT  - Tyrosine kinase inhibitors
COIS- The authors declare that they have no competing interests.
EDAT- 2019/06/07 06:00
MHDA- 2019/12/27 06:00
PMCR- 2019/06/06
CRDT- 2019/06/08 06:00
PHST- 2018/10/20 00:00 [received]
PHST- 2019/05/16 00:00 [accepted]
PHST- 2019/06/08 06:00 [entrez]
PHST- 2019/06/07 06:00 [pubmed]
PHST- 2019/12/27 06:00 [medline]
PHST- 2019/06/06 00:00 [pmc-release]
AID - 10.1186/s12931-019-1074-2 [pii]
AID - 1074 [pii]
AID - 10.1186/s12931-019-1074-2 [doi]
PST - epublish
SO  - Respir Res. 2019 Jun 6;20(1):111. doi: 10.1186/s12931-019-1074-2.