Trimetazidine protects isolated rat hearts against ischemia-reperfusion injury in an experimental timing-dependent manner.
The present study investigated the tolerance of the isolated rat heart to ischemia-reperfusion after administration of trimetazidine (TMZ) at different experimental phases, as well as the possible involvement of p38 MAPK and JNKs in this response. Isolated rat hearts were perfused in Langendorff mode. Untreated hearts after stabilization (S) were subjected to 20 min of zero-flow global ischemia (I) and 45 min of reperfusion (R), (NORM), n = 9. TMZ (10(-5) M) was administered (in the perfusate): a) only at S phase, (TMZ-STAB), n = 8, b) only at R, (TMZ-REP), n = 8 and c) during both S and R, (TMZ-STAB+REP), n = 8. Recovery of left ventricular developed pressure at 45 min of R (Rec) was significantly higher in TMZ-STAB and TMZ-STAB+REP and LDH release was lower in TMZ-STAB+REP and TMZ-STAB than NORM, [1153.2 (121.0) and 1152.1 (86.8) vs 1573.5 (138.2), P < 0.05]. TMZ induced cardioprotection did not involve p38 MAPK and JNKs. Phospho-p38 MAPK and JNKs levels after I/R were not changed with TMZ treatment. In TMZ-REP, Rec and LDH release were similar to NORM, but the rate of functional recovery (ratio of Rec at 10 min of R to Rec) was 86.7% (13.3) for TMZ-REP vs 53.8% (7.7) for NORM, P < 0.05. This effect was associated with decreased myocardial lactate content early at reperfusion. In conclusion, preischemic administration of TMZ protects against I/R injury while TMZ given only at reperfusion accelerates recovery of function without reducing the extent of injury.
Pantos
Costantinos
C
Department of Pharmacology, University of Athens, Athens, Greece. cpantos@cc.uoa.gr
Bescond-Jacquet
Anne
A
Tzeis
Stylianos
S
Paizis
Ioannis
I
Mourouzis
Iordanis
I
Moraitis
Panagiotis
P
Malliopoulou
Vassiliki
V
Politi
Eustathia D
ED
Karageorgiou
Hariklia
H
Varonos
Dennis
D
Cokkinos
Dennis V
DV
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D010477:Perfusion; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014292:Trimetazidine / Q000008:administration & dosage / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014292:Trimetazidine