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

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...

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Main Authors: 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
Format: Article
Language:English
Published: BMC 2019-06-01
Series:Respiratory Research
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Online Access:http://link.springer.com/article/10.1186/s12931-019-1074-2
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author 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
author_facet 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
author_sort Annette D. Rieg
collection DOAJ
description 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.
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spelling doaj.art-b1524b2b48c34a6682b9f82cc9cc36d92022-12-21T18:55:19ZengBMCRespiratory Research1465-993X2019-06-0120111410.1186/s12931-019-1074-2Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slicesAnnette D. Rieg0Nina A. Bünting1Christian Cranen2Said Suleiman3Jan W. Spillner4Heike Schnöring5Thomas Schröder6Saskia von Stillfried7Till Braunschweig8Paul W. Manley9Gereon Schälte10Rolf Rossaint11Stefan Uhlig12Christian Martin13Department of Anaesthesiology, Medical Faculty Aachen, RWTH-AachenInstitute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-AachenInstitute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-AachenInstitute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-AachenDepartment of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-AachenDepartment of Cardiac and Thoracic Surgery, Medical Faculty Aachen, RWTH-AachenDepartment of Surgery, Luisenhospital AachenInstitute of Pathology, Medical Faculty Aachen, RWTH-AachenInstitute of Pathology, Medical Faculty Aachen, RWTH-AachenNovartis Pharma AGDepartment of Anaesthesiology, Medical Faculty Aachen, RWTH-AachenDepartment of Anaesthesiology, Medical Faculty Aachen, RWTH-AachenInstitute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-AachenInstitute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-AachenAbstract 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.http://link.springer.com/article/10.1186/s12931-019-1074-2Tyrosine kinase inhibitorsImatinibNilotinibPulmonary arteriesPulmonary arterial hypertension
spellingShingle 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
Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
Respiratory Research
Tyrosine kinase inhibitors
Imatinib
Nilotinib
Pulmonary arteries
Pulmonary arterial hypertension
title Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
title_full Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
title_fullStr Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
title_full_unstemmed Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
title_short Tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision-cut lung slices
title_sort tyrosine kinase inhibitors relax pulmonary arteries in human and murine precision cut lung slices
topic Tyrosine kinase inhibitors
Imatinib
Nilotinib
Pulmonary arteries
Pulmonary arterial hypertension
url http://link.springer.com/article/10.1186/s12931-019-1074-2
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