LU135252, an endothelin(A) receptor antagonist did not prevent pulmonary vascular remodelling or lung fibrosis in a rat model of myocardial infarction.
The early intervention with endothelin(A) (ET(A)) receptor antagonists following coronary artery ligation has been shown to reduce the development of pulmonary hypertension, despite a lack of improvement in left ventricular function. The present study examined the contribution of pulmonary vascular remodelling and the progression of lung fibrosis in the development of pulmonary hypertension and the subsequent role of endothelin-1 in these processes in a rat model of myocardial infarction (MI). The administration of 60 mg kg(-1) per day of the specific ET(A) receptor antagonist LU135253 ((+)-(S)-2-(4, 6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid) 24 h following coronary artery ligation, failed to improve left ventricular contractile indices, but reduced the extent of pulmonary hypertension, as reflected by the significant decrease in right ventricular systolic pressure. The medial wall thickness of small pulmonary arteries (50 - 200 microm) was significantly increased 4 weeks following MI, albeit LU135253 treatment did not ameliorate this pattern of vascular remodelling. The steady-state mRNA levels of collagen, fibronectin, transforming growth factor-beta(1), and -beta(3) were significantly increased in the lungs of MI rats. The treatment with LU135252 did not alter this pattern of gene expression. Thus, these data demonstrate pulmonary vascular remodelling and the increased expression of extracellular matrix proteins represent underlying mechanisms implicated in the development of pulmonary hypertension in the MI rat. Despite the amelioration of the pulmonary hypertensive state, ET(A) receptor blockade was insufficient to reverse pulmonary vascular remodelling, or the development of lung fibrosis in the MI rat.
Département de Physiologie, Université de Montréal and L'Institut de Cardiologie de Montréal, Montréal, Quebec, Canada.
Q T
QT
Nguyen
F
F
Colombo
J L
JL
Rouleau
J
J
Dupuis
A
A
Calderone
D000818:Animals; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D010641:Phenotype; D010666:Phenylpropionates / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000517:prevention & control*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan