Greater Functional ETB Receptor Antagonism With Bosentan Than Sitaxsentan in Healthy Men

Endothelin (ET)-1 is implicated in the development of hypertension and a role for endothelin receptor antagonists (ETRAs) in the management of hypertension is emerging. ETRAs are classified as selective or mixed depending on their degree of ETA:ETB receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ETB blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ETA selective ETRA, on plasma ET-1 concentrations and ETB-mediated vasodilatation to ET-3. In a randomized, double-blind, 3-way crossover study, 10 healthy subjects received 7 days of placebo, bosentan 250 mg, and sitaxsentan 100 mg daily. Plasma ET-1 concentrations were measured at baseline and 3 hours on day 1 and predose on day 7. Subjects also underwent forearm blood flow measurements on day 7 of each period with brachial artery infusion of ET-3 (60 pmol/min for 5 minutes). Bosentan, but not placebo or sitaxsentan, significantly increased plasma ET-1 concentrations at day 7 (+0.70 +/- 0.20 pg/mL; P<0.005). Maximal ET-3-mediated vasodilatation was seen at 2 minutes following placebo (30 +/- 6%) and sitaxsentan (21 +/- 11%); however, this was abolished by bosentan, with a reduction in forearm blood flow of 8 +/- 3% (P<0.01 versus placebo and sitaxsentan). Bosentan but not sitaxsentan increases circulating plasma ET-1 levels and abolishes acute ET-3-mediated vasodilatation, confirming that the mixed ETA/B antagonist bosentan, but not the selective ETA antagonist sitaxsentan, causes functional ETB blockade at clinically relevant doses in healthy human subjects. (Hypertension. 2010;55:1406-1411.)