Vascular Effects of Endothelin Receptor Antagonists Depends on Their Selectivity for ET(A) Versus ET(B) Receptors and on the Functionality of Endothelial ET(B) Receptors

The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ET(B)) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs). METHODS: The contribution of the ET(B) receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ET(B) receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ET(A)-selective and dual ET(A)/ET(B) ERAs on blood pressure in hypertensive rats equipped with telemetry. RESULTS: In healthy vessels, ET(B) receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ET(B)-mediated relaxation was lost while vasoconstriction on stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ET(A)/ET(B) ERA macitentan on top of a maximal effective dose of the ET(A)-selective ERA ambrisentan further reduced blood pressure, indicating that ET(B) receptors blockade provides additional benefit. CONCLUSIONS: Taken together, these data suggest that in pathology, dual ET(A)/ET(B) receptor antagonism can provide superior vascular effects compared with ET(A)-selective receptor blockade.