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- Title
Platelet P2Y12 Blockers Confer Direct Postconditioning-Like Protection in Reperfused Rabbit Hearts.
- Authors
Yang, Xi-Ming; Liu, Yanping; Cui, Lin; Yang, Xiulan; Liu, Yongge; Tandon, Narendra; Kambayashi, Junichi; Downey, James M.; Cohen, Michael V.
- Abstract
Background: Blockade of platelet activation during primary percutaneous intervention for acute myocardial infarction is standardcare to minimize stent thrombosis. To determine whether antiplatelet agents offer any direct cardioprotective effect, we testedwhether they could modify infarction in a rabbit model of ischemia/reperfusion caused by reversible ligation of a coronary artery.Methods and Results: The P2Y12 (adenosine diphosphate) receptor blocker cangrelor administered shortly before reperfusion inrabbits undergoing 30-minute regional ischemia/3-hour reperfusion reduced infarction from 38% of ischemic zone in control heartsto only 19%. Protection was dose dependent and correlated with the degree of inhibition of platelet aggregation. Protection wascomparable 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 signalingrather than anticoagulation. As with IPOC, protection was lost when cangrelor administration was delayed until 10 minutesafter reperfusion and no added protection was seen when cangrelor and IPOC were combined. These findings suggest both IPOCand cangrelor may protect by the same mechanism. No protection was seen when cangrelor was used in crystalloid-perfused isolatedhearts indicating some component in whole blood is required for protection. Clopidogrel had a very slow onset of actionrequiring 2 days of treatment before platelets were inhibited, and only then the hearts were protected. Signaling inhibitors givenjust prior to reperfusion blocked clopidogrel's protection. Neither aspirin nor heparin was protective. Conclusions: Clopidogreland cangrelor protected rabbit hearts against infarction. The mechanism appears to involve signal transduction during reperfusionrather than inhibition of intravascular coagulation.We hypothesize that both drugs protect by activating IPOC's protective signalingto prevent reperfusion injury. If true, patients receiving P2Y12 inhibitors before percutaneous intervention may already be postconditionedthus explaining failure of recent clinical trials of postconditioning drugs.
- Subjects
CLOPIDOGREL; MYOCARDIAL infarction; BLOOD platelets; REPERFUSION; LABORATORY rabbits
- Publication
Journal of Cardiovascular Pharmacology & Therapeutics, 2013, Vol 18, Issue 3, p251
- ISSN
1074-2484
- Publication type
Article
- DOI
10.1177/1074248412467692