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EXPERIMENTAL STUDY

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

John G. Kingma, Jr., PhD, FACC^*, Sylvain Plante, MD, FACC^* and Peter Bogaty, MD^*

^* Department of Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Quebec, Canada
Quebec Heart Institute, Laval Hospital, Sainte-Foy, Quebec, Canada

Manuscript received July 14, 1998; revised manuscript received August 9, 2000, accepted August 11, 2000.

Reprints requests and correspondence: Dr. J. G. Kingma, Jr., Research Center, Laval Hospital, 2725, Chemin Sainte-Foy, Sainte-Foy, Quebec, G1V 4G5, Canada
john.kingma{at}med.ulaval.ca

OBJECTIVES

We 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.

BACKGROUND

Platelet 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.

METHODS

Three 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).

RESULTS

Infarct 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.

CONCLUSIONS

Diminished 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.

Abbreviations and Acronyms   GPIIb/IIIa = platelet glycoprotein IIb/IIIa receptor   HEP = heparin   LV = left ventricle   MI = myocardial infarction   MK-0852 = N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate   PRISM-PLUS = Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial   PRP = platelet rich plasma   REP = coronary reperfusion

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