SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts

There is debate concerning the involvement of p38 mitogen-activated protein kinase (MAPK) in ischemic preconditioning (PC). At the center of the controversy an data obtained after administration of SE 203580, a specific inhibitor of p38 MAPK. Whereas several studies have reported that SE 203580 abolishes the cardioprotective effect of PC, others claim that this compound is actually cardioprotective against ischemia. Many of these latter observations have been made in isolated myocardial cells. Accordingly the present study was designed to test the effect of SE 203580 in a model of preconditioning in intact rabbit hearts in which infarct size was the end-point. Isolated hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2 +/- 3.3 % of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion before the 30-min period of ischemia significantly reduced infarct size to 10.2 +/- 2.4 % (P < 0.05 vs. control). SE 203580 (2 <mu>M) added to the perfusate for 30 min starting 5 min before the index ischemia totally blocked the protection front PC (27.4 +/- 3.3 % infarction). SE 203580 alone had no effect on infarct size (28.6 +/- 4.6 % infarction). These results reveal that SE 203580 does not affect infarct size on its own,but selectively blocks preconditioning's anti-infarct effect in the intact rabbit heart.