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Endothelin: setting the scene in PAH

CORRESPONDENCE: J. Dupuis, Dept of Medicine, Montreal Heart Institute and University of Montreal, Montreal, QC, Canada. E-mail: jocelyn.dupuis{at}bellnet.ca

Endothelin (ET), a 21-amino acid peptide secreted by the vascular endothelial cells, is frequently reported to be one of the most potent vasoconstrictors. ET induces endothelial cell, smooth muscle cell and fibroblast dysfunction and is now well recognised as a contributor to the complex pathogenesis of pulmonary arterial hypertension, a devastating chronic disease characterised by progressive vascular remodelling and occlusion of the pulmonary arterioles.

ET produces its effects through the stimulation of two receptor subtypes, ET_A and ET_B, both of which are expressed on smooth muscle cells of pulmonary arterioles. Only the ET_B receptor is expressed on vascular endothelial cells. In pre-clinical studies, dual blockade of both receptor subtypes was shown to produce greater inhibition of ET-induced contraction compared with blockade of either of the two receptor subtypes alone. There is also evidence that both the ET_A and ET_B receptors contribute to pulmonary artery smooth muscle cell proliferation. Pre-clinical research in various models of pulmonary arterial hypertension suggests that simultaneous blockade of the two receptor subtypes would be an effective therapeutic approach in the management of patients with pulmonary arterial hypertension. This has been shown to be the case in a number of randomised controlled clinical trials in pulmonary arterial hypertension due to a number of aetiologies.

KEYWORDS: Bosentan, endothelin, dual endothelin receptor antagonism, pulmonary arterial hypertension