Abstract 15540: Effects of Broad Spectrum Tyrosine Kinase Inhibitor on Pulmonary Circulation Homeostasis
Rationale: The platelet derived growth factor (PDGF) pathway is altered in pulmonary hypertension (PH) and imatinib a tyrosine kinase inhibitor (TKI) of PDGF has shown encouraging results in animal models of PH. In the meantime, there is an increasing number of PH cases induced by dasatinib, a broad spectrum TKI.
Objectives: We studied the effects of dasatinib administration in rats: i) chronically and ii) as a pre-treatment before monocrotaline (MCT) injection; and secondary, the impact of dasatinib on cultured human pulmonary endothelial cells was examined by MTT and AnnexinV-PI assay.
Results: Forty rats, divided into three groups received daily intraperitoneal (IP) injections of: vehicle, dasatinib 1x and 10x the clinical dose/day, for maximum 8 weeks. Three rats developed mild PH with a normal cardiac output, but with pulmonary arterial remodeling. One-week pretreatment by dasatinib (same doses) before MCT administration was dose-dependently associated with a more severe hemodynamic profile, greater right ventricular hypertrophy and increased muscularization of distal pulmonary arteries, while imatinib (clinical dose) had a protective effect. In vitro, dasatinib had an important cytotoxic effect on cultured human pulmonary endothelial cells - MTT(50) between 100-200nM, effect due to a dose-dependent increase in apoptosis.
Conclusions: In conclusion, chronic dasatinib treatment in rats causes mild PH and as pretreatment aggravates the MCT-induced PH model. Pulmonary endothelial dysfunction may play a fundamental role in dasatinib-induced PH.
- © 2013 by American Heart Association, Inc.