Imatinib relaxes the pulmonary venous bed of guinea pigs.
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.



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.



In PCLS, imatinib (100 μM) 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 KATP-channels, [Formula: see text]-channels or Kv-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-β kinase inhibitor SU6668, whereas inhibition of PDGFR-α (ponatinib) had no significant effect. Conversely, PDGFR-β kinase inhibitors (SU6668/DMPQ) relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-α kinase inhibitor ponatinib did not.



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-β suggesting that imatinib-induced relaxation depends on PDGFR-β-antagonism. Imatinib combines short-term relaxant and long-term antiproliferative effects. Thus, imatinib might be a promising therapy for PH due to LHD.
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Nina A
NA
Maihöfer
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Said
S
Suleiman
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Daniela
D
Dreymüller
Novartis Pharma, AG, Basel, Switzerland.
Paul W
PW
Manley
Department of Anesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Rolf
R
Rossaint
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Stefan
S
Uhlig
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany.
Christian
C
Martin
Institute of Pharmacology and Toxicology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany. arieg@ukaachen.de.|Department of Anesthesiology, Medical Faculty Aachen, RWTH-Aachen, Aachen, Germany. arieg@ukaachen.de.
Annette D
AD
Rieg
D000818:Animals; D000077214:Becaplermin; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D011667:Pulmonary Veins / Q000187:drug effects* / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage
D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D014665:Vasodilator Agents; D000077214:Becaplermin; D000068877:Imatinib Mesylate
Imatinib; PDGFR; Postcapillary resistance; Pulmonary hypertension due to left heart disease; Pulmonary veins; Tyrosine kinase inhibitors