Triple Therapy Greatly Increases Myocardial Salvage During Ischemia/Reperfusion in the in situ Rat Heart
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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.
Open-chest rats underwent 30-min coronary occlusion/2-h reperfusion.
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.
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.
KeywordsCangrelor Cardioprotection Cariporide Hypothermia Myocardial infarction Platelet aggregation Ticagrelor
This study was supported in part by grant HL-20648 from the Heart, Lung and Blood Institute of the National Institutes of Health and by funds supplied by Otsuka Maryland Medicinal Labs., Inc., Rockville, MD. Cangrelor was kindly supplied by The Medicines Company, Parsippany, NJ.
Conflict of Interest
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