Myocardial and anti-inflammatory effects of chronic bosentan therapy in monocrotaline-induced pulmonary hypertension.

Abstract

INTRODUCTION AND OBJECTIVES:

Endothelin-1 antagonists are increasingly used in the treatment of pulmonary hypertension despite the lack of knowledge of their myocardial and systemic effects. We assessed the right ventricular myocardial and systemic effects of endothelin-1 antagonists in monocrotaline-induced pulmonary hypertension.

METHODS:

Male Wistar rats (180-200 g, n=57) randomly received 60 mg/kg monocrotaline or vehicle subcutaneously. Two days later, bosentan was randomly started (300 mg/kg/day) by oral route in a subgroup of monocrotaline-injected rats, while the other monocrotaline-injected and control rats received vehicle. At 25-30 days, invasive hemodynamic assessment was performed under anesthesia, arterial blood samples were collected for gas analysis and plasma was extracted for quantification of endothelin-1, cytokines, nitrates and 6-keto-prostaglandin F1α. Right ventricular myocardium was collected for assessment of cyclooxygenase and nitric oxide synthase activity and gene expression.

RESULTS:

The monocrotaline group developed pulmonary hypertension, low cardiac output, right ventricular hypertrophy and dilation, changes in gene expression and inflammatory activation that were attenuated in the group treated with bosentan. From a functional point of view, this group had improved right ventricular function and preserved ventriculo-vascular coupling, without deterioration in arterial gas parameters or systemic hypotension. In molecular terms, they showed reduced endothelin-1 and cytokine levels, decreased right ventricular inducible nitric oxide synthase and cyclooxygenase-2 activity and increased nitrate plasma levels compared with the non-treated group.

CONCLUSIONS:

In this study we demonstrate that besides attenuating pulmonary hypertension, bosentan has beneficial hemodynamic, myocardial and anti-inflammatory effects.

• Authors: Dulce Fontoura, José Oliveira-Pinto, Marta Tavares-Silva, Sara Leite, Francisco Vasques-Nóvoa, Pedro Mendes-Ferreira, André P Lourenço, Adelino F Leite-Moreira
• Journal: Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology (Rev Port Cardiol) Vol. 33 Issue 4 Pg. 213-22 (Apr 2014) ISSN: 2174-2030 [Electronic] Portugal
• PMID: 24780128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Chemical References

• Endothelin Receptor Antagonists
• Sulfonamides
• Monocrotaline
• Bosentan

Topics

• Animals
• Bosentan
• Disease Models, Animal
• Endothelin Receptor Antagonists (therapeutic use)
• Heart Ventricles (drug effects)
• Hypertension, Pulmonary (chemically induced, drug therapy)
• Inflammation (drug therapy)
• Male
• Monocrotaline (administration & dosage)
• Rats
• Rats, Wistar
• Sulfonamides (therapeutic use)