title: Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart.
abstract: BACKGROUND
  Cangrelor, a P2Y12 receptor blocker, administered just prior to reperfusion reduced but did not eliminate myocardial infarction in rabbits. Combining cangrelor with ischemic postconditioning offered no additional protection suggesting they protected by a similar mechanism. To determine if cangrelor's protection might be additive to other cardioprotective interventions we tested cangrelor in combination with ischemic preconditioning, cariporide, a sodium-hydrogen exchange blocker, and mild hypothermia.
  
  
  METHODS
  Open-chest rats underwent 30-min coronary occlusion/2-h reperfusion.
  
  
  RESULTS
  Cangrelor, administered as a bolus (60 μg/kg) 10 min before reperfusion and continued as an infusion (6 μg/kg/min) for the duration of the experiment, decreased infarction from 45.3 % of risk zone in control hearts to 25.0 %. Combining cangrelor and ischemic preconditioning offered no additional protection. Mild hypothermia (32-33 °C) instituted by peritoneal lavage with cold saline just prior to coronary occlusion resulted in 25.2 % infarction, and combining cangrelor and hypothermia nearly halved infarction to 14.1 % of risk zone. Cariporide (0.5 mg/kg) just prior to occlusion resulted in 27.2 % infarction and 15.8 % when combined with cangrelor. Combining cangrelor, hypothermia and cariporide further halved infarction to only 6.3 %. We also tested another P2Y12 inhibitor ticagrelor which is chemically similar to cangrelor. Ticagrelor (20 mg/kg) fed 1 h prior to surgery reduced infarct size by an amount similar to that obtained with cangrelor (25.6 % infarction), and this protective effect was abolished by chelerythrine and wortmannin, thus implicating participation of PKC and PI3-kinase, resp., in signaling.
  
  
  CONCLUSIONS
  Cardioprotection from a P2Y12 receptor antagonist can be combined with at least 2 other strategies to magnify the protection. Combining multiple interventions that use different cardioprotective mechanisms could provide powerful protection against infarction in patients with acute coronary thrombosis.
authors.affiliation: Department of Physiology, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Cui
authors.forename: Ahmad
authors.initials: A
authors.lastname: Alhammouri
authors.forename: James M
authors.initials: JM
authors.lastname: Downey
authors.forename: Michael V
authors.initials: MV
authors.lastname: Cohen
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D006146:Guanidines / Q000008:administration & dosage; D007036:Hypothermia, Induced; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000628:therapy*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage; D000077486:Ticagrelor
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D006146:Guanidines; D058921:Purinergic P2Y Receptor Antagonists; D013450:Sulfones; D000249:Adenosine Monophosphate; C117446:cangrelor; C093373:cariporide; D000077486:Ticagrelor; D000241:Adenosine