Rationale for Promising Novel Therapeutic Approach Focused On Endothelin Pathway for Peripheral Arterial Disease

Abstract

There is evidence to suggest that endothelin (ET-1) is involved in the pathophysiology of peripheral arterial disease (PAD), contributing to atherosclerotic narrowing of the lower limb arteries as well as microvascular dysfunction. This paper summarises the evidence and discusses the potential role of a promising novel therapeutic strategy for PAD focused on ET-1 pathway modification. ET-1 pathway is involved in PAD with raised plasma levels and local sources of ET-1. More recent evidence of a potential role of ET-1 in ischaemia- induced skeletal muscle damage suggests that this may be a useful target for treatment. ET antagonism may play an adjunctive role in improving endothelial function and reducing oxidative tissue damage within the affected vessels. However, in patients with advanced atherosclerotic lesions, manipulation of the ET-1 pathway is unlikely to be of a significant benefit in terms of lesion regression and improving blood flow. Results from small clinical studies support data from promising initial pilot and basic research. Considering the potentially important role of ET-1 in the development of vascular dysfunction reviewed in the present article – conditions with increased inflammatory activity, oxidative stress, and vascular tone such as atherosclerosis, and PAD – larger clinical trials using ET receptor antagonists are encouraged and needed.