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.