The endothelin system and its role in pulmonary arterial hypertension (PAH)

The endothelin system is emerging as an important mediator in pulmonary arterial hypertension (PAH) and the endothelin receptor antagonists represent a major advance in the treatment of this condition. PAH results from a massive proliferation of myofibroblast cells in the intima of small pulmonary arteries. Thickening of the media is also observed and abnormal proliferation of endothelial cells may result in plexiform lesions.

The endothelin system has been extensively studied over the 15 years since its initial discovery by Yanagisawa and co-workers in 1988. It is clear that endothelin 1 (ET-1) is a key mediator of pulmonary vascular biology and pathophysiology. It is a powerful vasoconstrictor and proliferative cytokine. In the early 1990s ET-1 was identified as an important mediator of PAH. Plasma ET-1 levels were found to be elevated in patients with pulmonary hypertension and correlated with the raised pulmonary vascular resistance.¹ Furthermore, expression of ET-1 mRNA and protein was increased in endothelial cells comprising vascular lesions in primary pulmonary hypertension.²

The availability of ET-1 receptor antagonists allowed testing of these compounds in experimental models. In rat models of experimental pulmonary hypertension—including pulmonary hypertension induced by chronic (2–3 weeks) hypoxia³ and by the alkaloid monocrotaline—ET-1 antagonists prevent the development of PAH. More compelling is the finding that ET-1 antagonists can partly reverse established PAH in experimental models.⁴ These observations suggest that ET-1 antagonists can potentially reverse established pulmonary vascular remodelling rather than simply prevent vasoconstriction.⁵ In clinical PAH the main component of the increased pulmonary vascular resistance is remodelling rather than vasoconstriction. However, in animal models the predominant lesion is medial hypertrophy rather than intimal thickening, and …