Platelet GPIIb/IIIa receptor blockade reduces infarct size in a canine model of ischemia-reperfusion.
OBJECTIVE
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.
Kingma
J G
JG
Department of Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Quebec, Canada. john.kingma@med.ulaval.ca
Plante
S
S
Bogaty
P
P
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000503:physiopathology* / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D053778:Thiazolidines
D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D053778:Thiazolidines; C083231:MK 0852