Endothelin and its antagonists in hypertension: can we foresee the future?

Endothelin-receptor antagonists may soon become a new therapeutic class of agents used to treat cardiovascular diseases. Although the first clinical trials are anxiously awaited to position this new family of compounds in the treatment of essential or secondary forms of hypertension, we dispose of an impressive amount of studies in which plasma endothelin levels have been measured, in addition to chronic preclinical studies that provide a general picture of what we can expect from these drugs. The experimental models that do respond to endothelin- receptor antagonists share vascular overexpression of endothelin, which seems directly linked with vascular hypertrophy of resistance arteries. In addition, salt sensitivity may represent an unbalanced condition between relaxing and constrictive properties of the renal endothelium that can respond favorably to endothelin blockade. Thus, African-American hypertensives may well be a responsive target population for the new drugs. In addition to blood pressure control, endothelin may also be involved in the evolution of end-organ damage by its potent vasoactive and vasoproliferative properties. The kidney, heart, large arteries and brain may therefore benefit from these drugs, but it is still unclear if this benefit goes beyond what can be attributed to the reduction of arterial pressure. Moreover, most studies performed so far have looked at prevention of end-organ damage, while very few have addressed the clinically relevant question of regression of lesions already installed by the disease process.