title: The peptide endothelin receptor antagonist, TAK-044, produces sustained inhibition of endothelin-1 mediated arteriolar vasoconstriction.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK-044, abolishes the forearm vasoconstriction caused by intrabrachial ET-1 infusion for at least 3 h. In this study we investigated whether TAK-044 can inhibit ET-1 mediated forearm vasoconstriction for longer periods.
  
  
  METHODS
  Eighteen subjects were recruited to a randomized, placebo-controlled, single-blind, three-way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK-044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET-1 (5 pmol min(-1)). On a third occasion subjects received only placebo before intra-arterial ET-1 infusion. Forearm vasoconstriction to ET-1 was measured by venous occlusion plethysmography.
  
  
  RESULTS
  In the placebo phase, ET-1 caused significant, slowly-progressive local forearm vasoconstriction of approximately 30% (P<0.01) in all three groups. All three doses of TAK-044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET-1. When the responses from all three groups were combined, TAK-044 significantly reduced ET-1 mediated vasoconstriction compared with placebo -9% (95% CI -15 to -3; P=0.01) at 8 h and by -9% (95% CI -17 to -2; P=0.01) 12 h after dosing.
  
  
  CONCLUSIONS
  TAK-044 attenuated, but did not abolish, local ET-1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra-arterial administration of ET-1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.
authors.affiliation: Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ferro
authors.forename: W G
authors.initials: WG
authors.lastname: Haynes
authors.forename: N R
authors.initials: NR
authors.lastname: Johnston
authors.forename: C C
authors.initials: CC
authors.lastname: Lomax
authors.forename: D E
authors.initials: DE
authors.lastname: Newby
authors.forename: D J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000328:Adult; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology*; D005542:Forearm; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C088196:TAK 044