Current and future strategies for targeting the endothelin pathway in cardiovascular disease

Abstract

The first endothelin (ET)-1 receptor antagonist was approved for clinical use over 20 years ago but to date, this class of compounds has been limited to treating pulmonary arterial hypertension, a rare disease. Translational research over the last 5 years has re-ignited interest in the endothelin system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-COVID-19 conditions. Significant developments include approval of a new ETA antagonist and, intriguingly, combining ETA and an angiotensin II type 1 receptor antagonist action within the same novel small molecule. Combinations of endothelin receptor blockers with other drugs, including phosphodiesterase-5 inhibitors and sodium-glucose co-transporter-2 antagonists, may drive synergistic benefits with the prospect of alleviating side effects. These new therapeutic strategies have the potential to dramatically widen the scope of indications targeting the ET-1 pathway.