title: Effects of endothelium/leukocytes/platelet interaction on myocardial ischemia--reperfusion injury.
abstract: Platelet fibrinogen receptor (GPIIb/IIIa) antagonists clinically improve the effectiveness of thrombolysis or PTCA in treatment of acute myocardial infarction. 7E3Fab, the chimeric Fab fragment of a monoclonal GPIIb/IIIa antibody, reduces the incidence of death, reinfarction or restenosis in patients and may improve blood flow and regional wall motion in reperfused myocardium. Besides inhibition of platelet aggregation, 7E3Fab may block fibrinogen bridging between the polymorphonuclear neutrophil (PMN) adhesion molecule MAC-1 and platelet GP IIb/IIIa, thus attenuating interaction of platelets with PMN. Experimentally, the interaction of platelets with PMN exacerbated postischemic myocardial stunning. In our own studies in isolated guinea pig hearts, human PMN, platelets and fibrinogen where simultaneously infused during the initial reperfusion period after 15 min of global ischemia. FACS analysis of cells in the coronary effluant revealed that 7E3Fab reduced platelet GP IIb/IIIa expression to 10% of baseline. PMN-platelet aggregate formation in the coronary effluate was markedly reduced by 7E3Fab, parallel to a decrease of PMN-platelet aggregates found by in situ double fluorescence microscopy in the postischemic coronary vasculature. The inhibition of PMN-platelet aggregate formation by 7E3Fab treatment coincided with a significant improvement of external heart work, which suffered a 50% reduction after ischemia, reperfusion, and exposure to PMN, platelets and fibrinogen. Obviously, application of 7E3Fab inhibits formation and coronary retention of PMN-platelet aggregates in the postischemic, reperfused myocardium. This effect may contribute to the clinically observed beneficial effects of this adjuvant treatment after myocardial ischemia.
authors.affiliation: Deutsches Herzzentrum Berlin and Institute for Physiology, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Habazettl
authors.forename: P
authors.initials: P
authors.lastname: Hanusch
authors.forename: C
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007962:Leukocytes / Q000502:physiology*; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000628:therapy*; D015425:Myocardial Reperfusion; D009504:Neutrophils / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000077284:Abciximab