title: Greater functional ETB receptor antagonism with bosentan than sitaxsentan in healthy men.
abstract: 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 ET(A):ET(B) receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ET(B) blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ET(A) selective ETRA, on plasma ET-1 concentrations and ET(B)-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 ET(A/B) antagonist bosentan, but not the selective ET(A) antagonist sitaxsentan, causes functional ET(B) blockade at clinically relevant doses in healthy human subjects.
authors.affiliation: Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK. imacint2@staffmail.ed.ac.uk
authors.forename: Iain M
authors.initials: IM
authors.lastname: MacIntyre
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.forename: Pajaree
authors.initials: P
authors.lastname: Lilitkarntakul
authors.forename: Vanessa
authors.initials: V
authors.lastname: Melville
authors.forename: Jane
authors.initials: J
authors.lastname: Goddard
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D001795:Blood Pressure Determination; D000077300:Bosentan; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010991:Plethysmography; D011336:Probability; D044022:Receptor, Endothelin A / Q000378:metabolism; D012016:Reference Values; D013449:Sulfonamides / Q000008:administration & dosage*; D013876:Thiophenes / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013876:Thiophenes; C106276:sitaxsentan; D000077300:Bosentan