Platelet GPIIb/IIIa receptor blockade reduces infarct size in a canine model of ischemia-reperfusion

Abstract

OBJECTIVESWe studied the effects of N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate (MK-0852) (platelet GPIIb/IIIa receptor blocker) on peak reactive hyperemia, distribution of blood flow, regional contractile function and infarct size in a canine model of acute ischemia-reperfusion injury.BACKGROUNDPlatelet activation and formation of platelet microaggregates in coronary vessels could contribute to ischemia-induced myocyte injury. Inhibition of platelet aggregation could reduce ischemia-reperfusion injury.METHODSThree groups of dogs (n = 10/group) were studied; group 1—heparin (HEP) (100 U/kg/h intravenously), group 2—MK-0852 (300 μg/kg intravenous bolus followed by 3 μg/kg/min for 3 h) and group 3—MK-0852 plus HEP. Infarct size after 60 min regional ischemia and 3 h reperfusion was evaluated by tetrazolium staining and normalized to risk area (Monastral blue dye).RESULTSInfarct size in HEP-treated controls was 32.4 ± 2.8%; in MK-0852 without or with HEP groups, infarct size was 17.4 ± 1.9% (p = 0.001) and 23.4 ± 3.0% (p = 0.04), respectively. Cardiac hemodynamics and rate-pressure product were comparable between groups. Multivariate analysis using collateral blood flow as the independent variable confirmed the cytoprotective actions of MK-0852. Postischemic peak reactive hyperemia in the infarct-related artery was depressed in all groups; during reperfusion, transmural distribution of myocardial blood flow returned to near control levels, but severe regional hypokinesia persisted.CONCLUSIONSDiminished infarct size with MK-0852 treatment suggests an additional mechanism of benefit for GPIIb/IIIa blockers beyond stabilization of a “culprit” acute coronary lesion. This cytoprotective effect was unrelated to preservation of coronary vasoreactivity (assessed by reactive hyperemia), restoration of blood flow across the myocardium or acute improvement in contractility.