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

Abstract

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 microg/kg intravenous bolus followed by 3 microg/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.

• Authors: J G Kingma Jr, S Plante, P Bogaty
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 36 Issue 7 Pg. 2317-24 (Dec 2000) ISSN: 0735-1097 [Print] United States
• PMID: 11127479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligopeptides
• Peptides, Cyclic
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• Thiazolidines
• MK 0852

Topics

• Animals
• Coronary Circulation (drug effects)
• Disease Models, Animal
• Dogs
• Female
• Flow Cytometry
• Heart (drug effects)
• Hemodynamics (drug effects)
• Hyperemia (physiopathology)
• Male
• Myocardial Contraction (drug effects)
• Myocardial Infarction (physiopathology, prevention & control)
• Myocardial Reperfusion Injury (physiopathology, prevention & control)
• Oligopeptides (pharmacology, therapeutic use)
• Peptides, Cyclic (pharmacology, therapeutic use)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology, therapeutic use)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Thiazolidines