Endothelins and their role in hypertension

Endothelin is a naturally occurring polypeptide substance with potent vasoconstrictive actions. It is produced from endothelial as well as non-endothelial cells. There are three closely related isoforms: endothelin-1, −2 and −3 (ET1, ET2 and ET3). The receptors for endothelin have been isolated and their genes cloned. Two receptors, called ET_A and ET_B, and having different affinities for the different endothelin isoforms, are well characterized. The different distribution of endothelin receptors in various tissues is responsible for the multiplicity of actions attributed to endothelin. Endothelin released from endothelial cells has local paracrine and autocrine effects on smooth muscle cells. It appears to be contributory to the pathophysiology of systemic hypertension, atherosclerosis, myocardial ischaemia, left ventricular dysfunction and congestive heart failure, ventricular hypertrophy, renal failure and pulmonary hypertension. Elevations of endothelin in the blod may also be markers of disease. Active research and drug development programmes are evaluating endothelin receptor inhibitors and endothelin-converting enzyme inhibitors for the treatment of patients with various cardiovascular, cerebrovascular, pulmonary vascular and renal diseases. Available agents such as potassium ion channel openers, calcium entry blockers and angiotensin-converting enzyme inhibitors also interfere with endothelin activity.