Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage.
To determine the role of platelet-activating factor (1-O-hexa-decyl-2-acetyl-sn-glyceryl-phosphoryl-choline, PAF) in myocardial ischemic and reperfusion-induced injury, the effects of a PAF receptor antagonist (WEB 2086) were studied in an anesthetized canine model of ischemia (90 min) and reperfusion (6 h). Thirty minutes after onset of ischemia, WEB 2086 was administered as a bolus (20 mg/kg intravenously, i.v.) followed by a continuous 6-h infusion (10 mg/kg/h i.v.). Controls received vehicle alone (0.9% saline). Platelet aggregation was studied at baseline and at 1, 2, 4, and 6 h of drug administration and at the end of the reperfusion period. WEB 2086 treatment did not significantly affect platelet aggregation stimulated by ADP or arachidonic acid (AA). After 1 h of drug infusion, the ex vivo aggregatory response to exogenous (200 nM) PAF was ablated in WEB 2086-treated animals. WEB 2086 administration did not affect heart rate (HR) or mean arterial blood pressure (MAP) during the occlusion or reperfusion phases. During reperfusion of the ischemic tissue, left circumflex coronary artery (LCX) blood flow of WEB 2086-treated animals increased (p < 0.05) above control value. The area of the left ventricle at risk of infarct was not different between control and WEB 2086-treated groups. Infarct size was not significantly reduced in WEB 2086-treated animals. The results of our investigation using a 90-min ischemic period followed by 6-h reperfusion show that pharmacologic antagonism of PAF by WEB 2086 does not protect the heart against ischemia and reperfusion-induced injury.
D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D014230:Triazoles / Q000627:therapeutic use*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086