LU135252, an endothelin(A) receptor antagonist did not prevent pulmonary vascular remodelling or lung fibrosis in a rat model of myocardial infarction

1 The early intervention with endothelin(A) (ET,) receptor antagonists foll owing coronary artery ligation has been shown to reduce the development of pulmonary hypertension, despite a lack of improvement in left ventricular f unction. 2 The present study examined the contribution of pulmonary vascular remodel ling and the progression of lung fibrosis in the development of pulmonary h ypertension and the subsequent role of endothelin-1 in these processes in a rat model of myocardial infarction (MI). 3 The administration of 60 mg kg(-1) per day of the specific ETA receptor a ntagonist LU135253 ((+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy acid) 24 h f ollowing coronary artery ligation, failed to improve left ventricular contr actile indices, but reduced the extent of pulmonary hypertension, as reflec ted by the significant decrease in right ventricular systolic pressure. 4 The medial wall thickness of small pulmonary arteries (50 - 200 mu m) was significantly increased 4 weeks following MI, albeit LU135253 treatment di d not ameliorate this pattern of vascular remodelling. 5 The steady-state mRNA levels of collagen, fibronectin, transforming growt h 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 ex pression. 6 Thus, these data demonstrate pulmonary vascular remodelling and the incre ased expression of extracellular matrix proteins represent underlying mecha nisms implicated in the development of pulmonary hypertension in the MI rat . 7 Despite the amelioration of the pulmonary hypertensive state, ETA recepto r blockade was insufficient to reverse pulmonary vascular remodelling, or t he development of lung fibrosis in the MI rat.