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)
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Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Weyrich
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Krantz
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Lefer
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AM
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D003402:Creatine Kinase / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C063964:bepafant; D003402:Creatine Kinase