Myocardial protection by a cardioselective free radical scavenger.
Oxygen-derived free radicals are involved in myocardial reperfusion injury. In the present study MDL 74,405 (S-(-)-3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzo pyran-2-ethanaminium 4-methylbenzenesulfonate), a hydrophilic derivative of alpha-tocopherol, has been shown to inhibit lipid peroxidation in rat brain homogenate, ex vivo lipid peroxidation in mouse heart and to accumulate in myocardial tissue. Infused i.v. MDL 74,405 induced a dose-related reduction of myocardial infarct size in pentobarbitone-anaesthetised rats subjected to 60 min coronary artery ligation followed by 30 min reperfusion. Similarly i.v. infusion of MDL 74,405 beginning 10 min before coronary artery occlusion (60 min) until 30 min after the onset of reperfusion (8 days) caused a decrease of infarct size associated with an increase in aortic flow. Plasma levels of creatine phosphokinase were significantly reduced. In isolated infarcted hearts, obtained from MDL 74,405-treated rats after 8 days of reperfusion and perfused according to the Langendorff technique, an increase in the contractility index (+) and (-) dP/dtmax was apparent. In isolated non-infarcted rat hearts subjected to 30 min no-flow global ischaemia, perfusion with MDL 74,405 resulted in an increase in heart rate and the contractility indices (+) dP/dtmax, and left ventricular systolic pressure during reperfusion. In conclusion MDL 74,405, is a cardioselective free radical scavenger, that reduces myocardial infarct size and attenuates post-ischaemic dysfunction.
Marion Merell Dow, Strasbourg, France.
M A
MA
Petty
L
L
Lukovic
J M
JM
Grisar
J
J
Dow
F N
FN
Bolkenius
W
W
De Jong
D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000378:metabolism; D016166:Free Radical Scavengers; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D002317:Cardiovascular Agents; D016166:Free Radical Scavengers; C067190:MDL 73404; D014810:Vitamin E; D003402:Creatine Kinase