Role of platelet activating factor in propagation of cardiac damage during myocardial ischemia.

The role of platelet activating factor (PAF) in acute myocardial ischemia (MI), produced by the ligation of the left main coronary artery, was studied in anesthetized rats. A significant loss of cardiac amino-nitrogen concentration and cathepsin D activity was observed 6 hr after permanent occlusion MI or 10 min of MI followed by 6 hr of reperfusion in rats. A novel, potent, PAF antagonist, CV-6209 (160 nmol/kg or 1.6 mumol/kg) injected after the ligation, significantly retarded the loss of amino-nitrogen and cathepsin D activity in a dose-related manner. In another group of rats, CV-6209 (1.6 mumol/kg) significantly blocked the hypotension induced by repetitive injections of PAF (570 pmol/kg) with an apparent half-life of approximately 180 min. In isolated rat hearts perfused with Krebs-Henseleit solution, PAF (25 nmol/l) significantly increased coronary perfusion pressure by 15 +/- 2 mmHg and induced an increase in cardiac permeability using fluorescein isothiocyanate bovine albumin as a marker. Furthermore, the increase in cardiac permeability induced in isolated perfused rat hearts undergoing 15 min global ischemia followed by reperfusion was significantly attenuated by CV-6209 (250 nmol/l). These data indicate that PAF is an important mediator of ischemic damage in rat MI. Moreover, the extension of ischemic damage may be enhanced by the increase in cardiac permeability induced by PAF.