PROTECTIVE EFFECTS OF L-659,989, A PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONIST, IN MYOCARDIAL-ISCHEMIA AND REPERFUSION IN RATS

The cardioprotective effects of L-659,989, a specific platelet-activat ing factor (PAF) receptor antagonist, were investigated in an ischemia /reperfusion model in rats. Pentobarbital-anesthetized rats were subje cted to left main coronary artery occlusion (1 h) followed by reperfus ion (1 h) (MI/R); Sham-operated rats were used as controls (Sham MI/R) . Rats receiving vehicle showed reduced survival rate (60%), marked my ocardial injury (necrotic area/total area=54.5+/-6%; necrotic area/are a at risk 76.6+/-6.7%), high serum creatine phosphokinase (CPK) activi ty (150+/-10 U/ml), and increased myocardial myeloperoxidase (MPO) act ivity in the area at risk (AR, 6.2+/-0.5 Ux10(-3)/g protein) and in th e necrotic area (6.6+/-0.7 Ux10(-3)/g protein). PAF plasma levels incr eased significantly during reperfusion and peaked at 15 min of reperfu sion. Administration of L-659,989 enhanced survival rate (80%), reduce d myocardial damage (necrotic area/total area 25.6+/-3.5%; necrotic ar ea/AR 34.6+/-5.4%), attenuated the increase in serum CPK (50+/-6 U/ml) and decreased MPO activity both in the AR (2.8+/-0.3 Ux10(-3)/g tissu e) and in the necrotic area(2.3+/-0.5 Ux10(-3)/g tissue). Our results suggest that PAF-inducing adhesion and activation of polymorphonuclear leukocytes (PMN) plays a significant role in the injury associated wi th ischemia/reperfusion.