Current and future strategies for targeting the endothelin pathway in cardiovascular disease
George Abraham, Thomas Williams, Janet J. Maguire, Peter J. Greasley, Phil Ambery, Anthony P. Davenport
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 reignited interest in the ET system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-coronavirus disease 2019 conditions. Notable developments include approval of a new ETA receptor antagonist and, intriguingly, combining the actions of ETA and an angiotensin II type 1 receptor antagonist within the same novel small molecule. Combinations of ET 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. Abraham and colleagues review the recent developments and future strategies to therapeutically target the endothelin pathway for a broad spectrum of cardiovascular diseases.