Imatinib relaxes the pulmonary venous bed of guinea pigs

Abstract

BackgroundRecently, 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.MethodsPrecision-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.ResultsIn 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, -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.ConclusionsImatinib-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.

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

“…imatinib relaxes the pulmonary arterial bed of healthy and pulmonary hypertensive rats [ 5 , 6 ]. Within this context, the relaxant effects of TKIs appear to be not limited to the pulmonary arterial bed, as imatinib, just as the PDGFR-β-inhibitors SU6668 or DMPQ also relax pulmonary veins (PVs) [ 7 ]. With regard to imatinib, it even exerts pulmonary venous relaxation if it is inhaled [ 7 ].…”

“…Within this context, the relaxant effects of TKIs appear to be not limited to the pulmonary arterial bed, as imatinib, just as the PDGFR-β-inhibitors SU6668 or DMPQ also relax pulmonary veins (PVs) [ 7 ]. With regard to imatinib, it even exerts pulmonary venous relaxation if it is inhaled [ 7 ]. The dual action of imatinib on pulmonary vascular remodelling and vessel tone [ 2 , 5 – 7 ] is still more remarkable, as PDGF-BB also contracts PVs [ 7 ].…”

“…With regard to imatinib, it even exerts pulmonary venous relaxation if it is inhaled [ 7 ]. The dual action of imatinib on pulmonary vascular remodelling and vessel tone [ 2 , 5 – 7 ] is still more remarkable, as PDGF-BB also contracts PVs [ 7 ]. Consecutively, aside the involvement in vascular remodelling [ 2 , 3 ], PDGF-BB and PDGFR appear to regulate the tone of pulmonary vessels.…”

“…We designed this study to evaluate the contractile effects of PDGF-BB on the pulmonary arterial and venous bed in isolated perfused lungs (IPL) of guinea pigs (GPs) [ 7 , 13 , 14 ]. Further, we analysed the PDGF-BB-induced release of the prostaglandins TXA 2 and PGI 2 in supernatants of IPL-perfusate samples.…”

Pulmonary hypertension: Molecular aspects of current therapeutic intervention and future direction

“…Platelet‐derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase (Andrae, Gallini, & Betsholtz, ). Thus, treatment with Imatinib, (PDGF receptor antagonist) have considered reducing right ventricular pressure, pulmonary proliferation by suppressing activation of downstream signaling pathways in guinea pigs (Maihöfer et al, ). Furthermore, the clinical investigations reported that treatment with Imatinib has shown significant improvement in 6 min walk test and hemodynamics in pulmonary hypertensive patients through vasodilation potential (Minami et al, ).…”