title: Big endothelin-3 constricts forearm resistance vessels but not hand veins in humans.
abstract: BACKGROUND
  Endothelin-3 (ET-3) and its inactive precursor, big endothelin-3 (big ET-3), are both found in human plasma. We investigated whether big ET-3 is converted to ET-3 in the human forearm resistance vessels and dorsal hand veins in vivo.
  
  
  METHODS
  In a 4-phase study, 6 subjects received 90 minute intrabrachial artery infusions of big ET-3 (50 and 100 pmol x min(-1)) and ET-3 (5 and 10 pmol x min(-1)) in random order. Forearm blood flow was measured by venous occlusion plethysmography. In a second 3-phase study, 6 subjects received 90-minute dorsal hand vein infusions of saline solution, big ET-3 (50 pmol x min(-1)) and ET-3 (5 pmol x min(-1)) in random order. In a third 2-phase study, 6 subjects received 90-minute dorsal hand vein infusions of big ET-3 (100 pmol x min(-1)) and ET-3 (10 pmol x min(-1)). In the dorsal hand vein studies, vessel diameter was measured by the Aellig technique.
  
  
  RESULTS
  Intra-arterial ET-3 caused local forearm vasoconstriction of 20%+/-9% (P = .009) at 5 pmol x min(-1) and 20%+/-10% (P = .001) at 10 pmol x min(-1) after 90 minutes, with no difference between doses (P = .69). Intra-arterial big ET-3 also caused local forearm vasoconstriction of 22%+/-6% at 50 pmol x min(-1) (P = .004) and 18%+/-3% at 100 pmol x min(-1) (P<.0001) after 90 minutes, with no difference between doses (P = .44). There were no significant differences between the responses to intra-arterial big ET-3 and ET-3 at these doses. Local intravenous ET-3 caused a constriction of 9%+/-2% at 5 pmol x min(-1) (P = .04) and 22%+/-8% at 10 pmol x min(-1) (P = .002) after 90 minutes. Big ET-3 at 50 pmol x min(-1) and 100 pmol x min(-1) did not affect hand vein tone. All responses were slowly progressive.
  
  
  CONCLUSIONS
  Based on vasoconstriction, measurable conversion of big ET-3 to ET-3 occurs in forearm resistance vessels but not in dorsal hand veins in vivo. An endothelin-converting enzyme, capable of converting exogenously administered big ET-3 to ET-3, appears to be present in upper limb resistance arteries but not in capacitance vessels in humans.
authors.affiliation: Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Scotland.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ferro
authors.forename: F E
authors.initials: FE
authors.lastname: Strachan
authors.forename: E
authors.initials: E
authors.lastname: Shepherd
authors.forename: W G
authors.initials: WG
authors.lastname: Haynes
authors.forename: D J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000328:Adult; D019334:Endothelin-3 / Q000378:metabolism; D016232:Endothelins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply*; D006225:Hand / Q000098:blood supply*; D006801:Humans; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014680:Veins / Q000187:drug effects
chemical_list: D019334:Endothelin-3; D016232:Endothelins; D011498:Protein Precursors; D014662:Vasoconstrictor Agents