PK10453, a Nonselective Platelet‐Derived Growth Factor Receptor Inhibitor, Prevents the Progression of Pulmonary Arterial Hypertension. (1st March 2014)

• Record Type: Journal Article
• Authors: Medarametla, Venkatrao; Festin, Stephen; Sugarragchaa, Chuluunbaatar; Eng, Alexander; Naqwi, Amir; Wiedmann, Timothy; Zisman, Lawrence S.
• Is Part Of: Pulmonary circulation. Volume 4:Number 1(2014)
• Page Start: 82
• Page End: 102
• Publication Date: 2014-03-01
• Subjects: pulmonary arterial hypertension -- kinase inhibitors -- platelet‐derived growth factor (PDGF); Pulmonary circulation -- Periodicals; Pulmonary circulation; Electronic journals -- Sciences; Periodicals; 616.24005
• DOI: 10.1086/674881
• Languages: English
• ISSNs: 2045-8932

Abstract

Abstract : The platelet‐derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)‐ and 8 (D8)‐minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4 ± 2.6 mmHg in the vehicle MCT group ( n = 6), 44.4 ± 5.8 mmHg in the D4 MCT group ( n = 6), and 37.1 ± 4.5 mmHg in the D8 MCT group ( n = 5; P < 0.001 vs. vehicle); RVSP was 75.7 ± 7.1 mmHg in the vehicle MCT+PN group ( n = 9), 40.4 ± 2.7 mmHg in the D4 MCT+PN group ( n = 10), and 43.0 ± 3.0 mmHg in the D8 MCT+PN group ( n = 8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGFβ receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGFα receptor, whereas PK10453 has a lower half‐maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGFα and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGFα and PDGFβ receptors may have a therapeutic advantage over selective PDGFα receptor inhibition in PAH.