Endothelin receptor antagonists and their developing role in cardiovascular therapeutics

Endothelin (ET)-1 is a potent vasoconstrictor and promitogenic peptide prod uced by the vascular endothelium. The ET system is activated in atheroscler osis and in most cardiovascular conditions associated with increased vascul ar tone and remodelling, There are two ET-receptor (ET-R) subtypes: the ETA -Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of cleara nce and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R ant agonists are entering the clinical development phase. These agents have sho wn their effectiveness in the therapy of various models of heart failure, p ulmonary hypertension, systemic hypertension and ischemia reperfusion and i n the prevention of restenosis. In patients with congestive heart failure, short term ET antagonist (ET-R) therapy provides hemodynamic and symptomati c improvement. Because of the dual role of the ETB-R, nonselective antagoni sts may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and FTB-R acti vity brought on by pathological conditions, the proportions of ETA versus E TB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB Versus the deleterious effects of th e smooth muscle ETB-R.