Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.

Abstract

AIMS:

We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling.

METHODS AND RESULTS:

Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue.

CONCLUSIONS:

Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.

• Authors: Marc Iglarz, Kyle Landskroner, Yasmina Bauer, Magali Vercauteren, Markus Rey, Berengère Renault, Rolf Studer, Enrico Vezzali, Diego Freti, Hakim Hadana, Manuela Schläpfer, Christophe Cattaneo, Céline Bortolamiol, Edgar Weber, Brian R Whitby, Stéphane Delahaye, Daniel Wanner, Pauline Steiner, Oliver Nayler, Patrick Hess, Martine Clozel
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 66 Issue 5 Pg. 457-67 (Nov 2015) ISSN: 1533-4023 [Electronic] United States
• PMID: 26230396 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Pyrimidines
• Sulfonamides
• Bleomycin
• Bosentan
• macitentan

Topics

• Animals
• Bleomycin
• Bosentan
• Disease Models, Animal
• Endothelin Receptor Antagonists (pharmacology)
• Gene Expression Regulation
• Heart Ventricles (drug effects, metabolism, physiopathology)
• Hypertension, Pulmonary (chemically induced, drug therapy, genetics, metabolism, physiopathology)
• Hypertrophy, Right Ventricular (chemically induced, genetics, metabolism, physiopathology, prevention & control)
• Male
• Pulmonary Artery (drug effects, metabolism, physiopathology)
• Pyrimidines (pharmacology)
• Rats, Wistar
• Sulfonamides (pharmacology)
• Time Factors
• Vascular Remodeling (drug effects)
• Ventricular Function, Right (drug effects)
• Ventricular Remodeling (drug effects)