Endothelin: setting the scene in PAH

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.