Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling.

Abstract

BACKGROUND:

Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling.

METHODS:

We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1mg/kg, 5mg/kg and 10mg/kg/day) or sorafenib (10mg/kg/day). PAB rats were treated with vehicle, sunitinib (10mg/kg/day) or sorafenib (10mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry.

RESULTS:

Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function.

CONCLUSION:

We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.

• Authors: Baktybek Kojonazarov, Akylbek Sydykov, Soni Savai Pullamsetti, Himal Luitel, Bhola K Dahal, Djuro Kosanovic, Xia Tian, Matthaeus Majewski, Christin Baumann, Steve Evans, Peter Phillips, David Fairman, Neil Davie, Chris Wayman, Iain Kilty, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Hossein Ardeschir Ghofrani, Ralph Theo Schermuly
• Journal: International journal of cardiology (Int J Cardiol) Vol. 167 Issue 6 Pg. 2630-7 (Sep 10 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 22854298 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Indoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyrroles
• Niacinamide
• Sorafenib
• Sunitinib

Topics

• Animals
• Dose-Response Relationship, Drug
• Familial Primary Pulmonary Hypertension
• Hypertension, Pulmonary (drug therapy, enzymology)
• Indoles (pharmacology, therapeutic use)
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Sorafenib
• Sunitinib
• Ventricular Function, Right (drug effects, physiology)
• Ventricular Remodeling (drug effects, physiology)