title: Platelet P2Y₁₂ blockers confer direct postconditioning-like protection in reperfused rabbit hearts.
abstract: BACKGROUND
  Blockade of platelet activation during primary percutaneous intervention for acute myocardial infarction is standard care to minimize stent thrombosis. To determine whether antiplatelet agents offer any direct cardioprotective effect, we tested whether they could modify infarction in a rabbit model of ischemia/reperfusion caused by reversible ligation of a coronary artery.
  
  
  RESULTS
  The P2Y₁₂ (adenosine diphosphate) receptor blocker cangrelor administered shortly before reperfusion in rabbits undergoing 30-minute regional ischemia/3-hour reperfusion reduced infarction from 38% of ischemic zone in control hearts to only 19%. Protection was dose dependent and correlated with the degree of inhibition of platelet aggregation. Protection was comparable to that seen with ischemic postconditioning (IPOC). Cangrelor protection, but not its inhibition of platelet aggregation, was abolished by the same signaling inhibitors that block protection from IPOC suggesting protection resulted from protective signaling rather than anticoagulation. As with IPOC, protection was lost when cangrelor administration was delayed until 10 minutes after reperfusion and no added protection was seen when cangrelor and IPOC were combined. These findings suggest both IPOC and cangrelor may protect by the same mechanism. No protection was seen when cangrelor was used in crystalloid-perfused isolated hearts indicating some component in whole blood is required for protection. Clopidogrel had a very slow onset of action requiring 2 days of treatment before platelets were inhibited, and only then the hearts were protected. Signaling inhibitors given just prior to reperfusion blocked clopidogrel's protection. Neither aspirin nor heparin was protective.
  
  
  CONCLUSIONS
  Clopidogrel and cangrelor protected rabbit hearts against infarction. The mechanism appears to involve signal transduction during reperfusion rather than inhibition of intravascular coagulation. We hypothesize that both drugs protect by activating IPOC's protective signaling to prevent reperfusion injury. If true, patients receiving P2Y₁₂ inhibitors before percutaneous intervention may already be postconditioned thus explaining failure of recent clinical trials of postconditioning drugs.
authors.affiliation: Department of Physiology, University of South Alabama College of Medicine, Mobile, AL, USA.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Cui
authors.forename: Xiulan
authors.initials: X
authors.lastname: Yang
authors.forename: Yongge
authors.initials: Y
authors.lastname: Liu
authors.forename: Narendra
authors.initials: N
authors.lastname: Tandon
authors.forename: Junichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: James M
authors.initials: JM
authors.lastname: Downey
authors.forename: Michael V
authors.initials: MV
authors.lastname: Cohen
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077144:Clopidogrel; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D057775:Ischemic Postconditioning; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D013988:Ticlopidine