Myocardial and anti-inflammatory effects of chronic bosentan therapy in monocrotaline-induced pulmonary hypertension.
OBJECTIVE
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.
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
Dulce
D
Fontoura
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
José
J
Oliveira-Pinto
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiology, São João Hospital Centre, E.P.E., Porto, Portugal.
Marta
M
Tavares-Silva
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
Sara
S
Leite
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Internal Medicine, São João Hospital Centre, E.P.E., Porto, Portugal.
Francisco
F
Vasques-Nóvoa
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
Pedro
P
Mendes-Ferreira
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anaesthesiology, São João Hospital Centre, E.P.E., Porto, Portugal. Electronic address: aplourenco@yahoo.com.
André P
AP
Lourenço
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Department Cardiothoracic Surgery, São João Hospital Centre, E.P.E., Porto, Portugal.
Adelino F
AF
Leite-Moreira
D000818:Animals; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D016686:Monocrotaline; D000077300:Bosentan
Antagonistas da endotelina-1; Bosentan; Endothelin-1 antagonists; Função ventricular direita; Hipertensão pulmonar; Pulmonary hypertension; Right ventricular function