Protection of infarcted, chronically reperfused hearts by an alpha-tocopherol analogue.
Free radicals may cause part of the irreversible injury which occurs during myocardial infarction and reperfusion. In the present study MDL 73404, a hydrophilic, cardioselective, free radical scavenger analogue of alpha-tocopherol, was evaluated for its effects on infarct size as well as on indicators of reperfusion injury. A pentobarbitone-anaesthetised rat model of coronary artery ligation (60 min; followed by 8 days of reperfusion) was used. Intravenous infusion of MDL 73404 (3 mg/kg per h) began 10 min before occlusion until 30 min after the onset of reperfusion. MDL 73404 reduced (P < 0.02) the elevated serum levels of thiobarbituric acid reactive substances and plasma levels of creatine phosphokinase (P < 0.01). An increase in cardiac output and heart rate together with a decrease (P < 0.01) in infarct size was evident in rats that had received MDL 73404, 8 days previously. Isolated infarcted hearts obtained from rats after 8 days of reperfusion had greater (P < 0.01) + dP/dt max, -dP/dt max, left ventricular systolic pressure and coronary flow after MDL 73404 compared to saline-treated controls. Infusion of [14C]MDL 73404, during the time of occlusion resulted in a concentration of 14.5 +/- 2.2 mg eq/g in the non-ischaemic ventricular tissue and a concentration of 3.0 +/- 0.4 mg eq/g in the area at risk. After infusion for the 30 min of reperfusion, 6.4 +/- 0.2 mg eq/g was detected in the non-ischaemic ventricular tissue but only 3.1 +/- 0.5 mg eq/g in the area at risk.(ABSTRACT TRUNCATED AT 250 WORDS)
Lukovic
L
L
Marion Merrell Dow Research Institute, Strasbourg, France.
Petty
M A
MA
Bolkenius
F N
FN
Grisar
J M
JM
Dow
J
J
De Jong
W
W
D000818:Animals; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002395:Catecholamines / Q000097:blood; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood / Q000378:metabolism; D004837:Epinephrine / Q000097:blood; D016166:Free Radical Scavengers; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D002317:Cardiovascular Agents; D002395:Catecholamines; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; C067190:MDL 73404; D014810:Vitamin E; D003402:Creatine Kinase; D009638:Norepinephrine; D004837:Epinephrine