title: The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature.
abstract: OBJECTIVE
  The platelet ADP P2Y(12) receptor which is a target for the antithrombotic drug clopidogrel is also distributed on vascular smooth muscle cells and stimulate contraction. This study investigates whether AZD6140, in contrast to clopidogrel, can inhibit ADP-mediated arterial contractions.
  
  
  METHODS
  Mice were treated with clopidogrel, 50 mg/kg, 24 and 2 h before experiment. Thoracic aorta ring segments from both clopidogrel-treated (n=5) and untreated (n=4) mice were mounted in myograph baths. Contractions of human left internal mammary arteries (IMA) and small arteries were studied in an identical manner.
  
  
  RESULTS
  Clopidogrel treatment per os did not inhibit contractions by the stable ADP analogue 2-MeSADP (10 microM). However, addition of 1 microM AZD6140 in vitro inhibited ADP contraction (% of maximal contraction by 60 mM K(+)) both in the clopidogrel-treated, from 64% to 32% (P=0.002) and in the untreated group, from 59% to 33% (P=0.015). 2-MeSADP contractions in human IMA and small arteries were inhibited by AZD6140.
  
  
  CONCLUSIONS
  The antiplatelet drug AZD6140 blocks the contractile effects of ADP in both murine and human vasculature. These effects of AZD6140 could be beneficial in the management of conditions in which vasospasm may play a role.
authors.affiliation: Department of Cardiology, Lund University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Högberg
authors.forename: Helen
authors.initials: H
authors.lastname: Svensson
authors.forename: Ronny
authors.initials: R
authors.lastname: Gustafsson
authors.forename: Atli
authors.initials: A
authors.lastname: Eyjolfsson
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors* / Q000502:physiology; D000284:Administration, Oral; D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism* / Q000502:physiology; D013045:Species Specificity; D000077486:Ticagrelor; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12; D014662:Vasoconstrictor Agents; D000244:Adenosine Diphosphate; D000077486:Ticagrelor; D000241:Adenosine