PMID- 28178968
OWN - NLM
STAT- MEDLINE
DCOM- 20171201
LR  - 20181202
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 18
IP  - 1
DP  - 2017 Feb 8
TI  - Imatinib relaxes the pulmonary venous bed of guinea pigs.
PG  - 32
LID - 10.1186/s12931-017-0514-0 [doi]
LID - 32
AB  - BACKGROUND: Recently, the IMPRES study revealed that systemic imatinib improves 
      exercise capacity in patients with advanced pulmonary arterial hypertension. 
      Imatinib blocks the tyrosine kinase activity of the platelet-derived growth 
      factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary 
      arteries. However so far, the relaxant effects of imatinib on pulmonary veins 
      (PVs) and on the postcapillary resistance are unknown, although pulmonary 
      hypertension (PH) due to left heart disease (LHD) is most common and primarily 
      affects PVs. Next, it is unknown whether activation of PDGFR alters the pulmonary 
      venous tone. Due to the reported adverse effects of systemic imatinib, we 
      evaluated the effects of nebulized imatinib on the postcapillary resistance. 
      METHODS: Precision-cut lung slices (PCLS) were prepared from guinea pigs. PVs 
      were pre-constricted with Endothelin-1 (ET-1) and the imatinib-induced relaxation 
      was studied by videomicroscopy; PDGF-BB-related vascular properties were 
      evaluated as well. The effects of perfused/nebulized imatinib on the 
      postcapillary resistance were studied in cavine isolated perfused lungs (IPL). 
      Intracellular cAMP/cGMP was measured by ELISA in PVs. RESULTS: In PCLS, imatinib 
      (100 muM) relaxed pre-constricted PVs (126%). In PVs, imatinib increased cAMP, but 
      not cGMP and inhibition of adenyl cyclase or protein kinase A reduced the 
      imatinib-induced relaxation. Further, inhibition of K(ATP)-channels, [Formula: 
      see text]-channels or K(v)-channels diminished the imatinib-induced relaxation, 
      whereas inhibition of NO-signaling was without effect. In the IPL, perfusion or 
      nebulization of imatinib reduced the ET-1-induced increase of the postcapillary 
      resistance. In PCLS, PDGF-BB contracted PVs, which was blocked by imatinib and by 
      the PDGFR-beta kinase inhibitor SU6668, whereas inhibition of PDGFR-alpha (ponatinib) 
      had no significant effect. Conversely, PDGFR-beta kinase inhibitors (SU6668/DMPQ) 
      relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-alpha 
      kinase inhibitor ponatinib did not. CONCLUSIONS: Imatinib-induced relaxation 
      depends on cAMP and on the activation of K(+)-channels. Perfused or nebulized 
      imatinib significantly reduces the postcapillary resistance in the 
      pre-constricted (ET-1) pulmonary venous bed. Hence, nebulization of imatinib is 
      feasible and might reduce systemic side effects. Conversely, PDGF-BB contracts 
      PVs by activation of PDGFR-beta suggesting that imatinib-induced relaxation depends 
      on PDGFR-beta-antagonism. Imatinib combines short-term relaxant and long-term 
      antiproliferative effects. Thus, imatinib might be a promising therapy for PH due 
      to LHD.
FAU - Maihofer, Nina A
AU  - Maihofer NA
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 - Dreymuller, Daniela
AU  - Dreymuller D
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany.
FAU - Manley, Paul W
AU  - Manley PW
AD  - Novartis Pharma, AG, Basel, Switzerland.
FAU - Rossaint, Rolf
AU  - Rossaint R
AD  - Department of Anesthesiology, 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.
FAU - Rieg, Annette D
AU  - Rieg AD
AD  - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, 
      Aachen, Germany. arieg@ukaachen.de.
AD  - Department of Anesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, 
      Germany. arieg@ukaachen.de.
LA  - eng
PT  - Journal Article
DEP - 20170208
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (Vasodilator Agents)
RN  - 1B56C968OA (Becaplermin)
RN  - 8A1O1M485B (Imatinib Mesylate)
SB  - IM
EIN - Respir Res. 2017 Jun 19;18(1):121. PMID: 28629421
MH  - Animals
MH  - Becaplermin
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Guinea Pigs
MH  - Imatinib Mesylate/*administration & dosage
MH  - Protein Kinase Inhibitors/administration & dosage
MH  - Proto-Oncogene Proteins c-sis/*metabolism
MH  - Pulmonary Veins/*drug effects/*physiology
MH  - Vascular Resistance/drug effects/*physiology
MH  - Vasodilation/drug effects/*physiology
MH  - Vasodilator Agents/administration & dosage
PMC - PMC5299687
OTO - NOTNLM
OT  - Imatinib
OT  - PDGFR
OT  - Postcapillary resistance
OT  - Pulmonary hypertension due to left heart disease
OT  - Pulmonary veins
OT  - Tyrosine kinase inhibitors
EDAT- 2017/02/10 06:00
MHDA- 2017/12/02 06:00
PMCR- 2017/02/08
CRDT- 2017/02/10 06:00
PHST- 2016/09/30 00:00 [received]
PHST- 2017/01/19 00:00 [accepted]
PHST- 2017/02/10 06:00 [entrez]
PHST- 2017/02/10 06:00 [pubmed]
PHST- 2017/12/02 06:00 [medline]
PHST- 2017/02/08 00:00 [pmc-release]
AID - 10.1186/s12931-017-0514-0 [pii]
AID - 514 [pii]
AID - 10.1186/s12931-017-0514-0 [doi]
PST - epublish
SO  - Respir Res. 2017 Feb 8;18(1):32. doi: 10.1186/s12931-017-0514-0.