Mechanisms of the cardioprotective actions of WEB-2170, bepafant, a platelet activating factor antagonist, in myocardial ischemia and reperfusion.

The cardioprotective effects of WEB-2170, a specific platelet activating factor (PAF) receptor antagonist, were investigated in a feline model of myocardial ischemia (MI) and reperfusion. Either WEB-2170 (1-mg/kg bolus plus 2 mg/kg/hr) or its vehicle (0.9% NaCl) was administered 1 hr after left anterior descending coronary artery occlusion (i.e., 30 min before reperfusion). The cardiac area-at-risk (AAR) was similar in MI-reperfused (MI + R) cats given either WEB-2170 (31.5 +/- 3.6%) or vehicle (27.8 +/- 2.8%). However, in cats receiving only the vehicle, 1.5 hr of ischemia plus 4.5 hr of reperfusion resulted in significant myocardial injury (necrotic tissue/AAR, 37.7 +/- 4.5%), high plasma creatine kinase activity (29.4 +/- 4.1 I.U./micrograms of protein) and a marked decrease in endothelium-dependent relaxation in isolated left anterior descending coronary arteries to acetylcholine (33 +/- 4% of U-46619-induced vasocontraction) with no change in endothelium-independent relaxation to NaNO2 (91 +/- 1%). In contrast, MI + R cats treated with WEB-2170 developed significantly less myocardial necrosis (necrotic tissue/AAR, 12.0 +/- 2.8%, P less than .001), lower plasma creatine kinase activity (16.5 +/- 4.1 I.U./micrograms of protein, P less than .01) and enhanced vascular relaxation to acetylcholine (53 +/- 4.1%, P less than .01) compared to MI + R cats given only the vehicle. Furthermore, the addition of WEB-2170 to PMN suspensions in vitro significantly inhibited (P less than .01) PAF-induced polymorphonuclear leukocyte (PMN) adherence to endothelial cells (12 +/- 2.4 cells/field vs. 27 +/- 2.6 in the control group).(ABSTRACT TRUNCATED AT 250 WORDS)