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Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2016 Sep 01; Vol. 311 (3), pp. H604-12. Date of Electronic Publication: 2016 Jun 24. - Publication Year :
- 2016
-
Abstract
- BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload.<br /> (Copyright © 2016 the American Physiological Society.)
- Subjects :
- Animals
Atrial Natriuretic Factor drug effects
Atrial Natriuretic Factor metabolism
Blotting, Western
Disease Models, Animal
Echocardiography
Familial Primary Pulmonary Hypertension diagnostic imaging
Familial Primary Pulmonary Hypertension metabolism
Familial Primary Pulmonary Hypertension pathology
Heart Ventricles diagnostic imaging
Heart Ventricles metabolism
Heart Ventricles pathology
Male
Mitogen-Activated Protein Kinase 1 drug effects
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 drug effects
Mitogen-Activated Protein Kinase 3 metabolism
Proto-Oncogene Proteins c-akt drug effects
Proto-Oncogene Proteins c-akt metabolism
Pulmonary Artery surgery
Rats
Rats, Sprague-Dawley
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Receptors, Platelet-Derived Growth Factor antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors
Adaptation, Physiological drug effects
Heart Ventricles drug effects
Indoles pharmacology
Pressure
Protein Kinase Inhibitors pharmacology
Ventricular Function, Right drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 311
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 27342880
- Full Text :
- https://doi.org/10.1152/ajpheart.00656.2015