Effect of a cardioselective alpha-tocopherol analogue on reperfusion injury in rats induced by myocardial ischaemia.
Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion.
Petty
M A
MA
Merrell Dow Research Institute, Strasbourg, France.
Dow
J
J
Grisar
J M
JM
De Jong
W
W
D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003402:Creatine Kinase / Q000097:blood; D016166:Free Radical Scavengers; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D001578:Benzopyrans; D002250:Carbon Radioisotopes; D016166:Free Radical Scavengers; C064728:MDL 74270; C069478:MDL 74366; D014810:Vitamin E; D003402:Creatine Kinase