ERK and p38 MAP kinase activation are components of opioid-induced delayedcardioprotection

Opioids have been previously shown to confer acute and delayed cardioprotec tion against a prolonged ischemic insult. We have extensively characterized the signal transduction pathway mediating acute cardioprotection and have suggested a role for extracellular signal regulated kinase (ERK) in this ca rdioprotection. Therefore, we attempted to determine a role for ERK and the stress activated MAP kinase, p38, in opioid-induced delayed cardioprotecti on by using selective inhibitors of these pathways. All rats were subjected to 30 min of ischemia and 2 h of reperfusion (I/R). Control animals, injec ted with Saline 48 h prior to I/R, had an infarct size/area at risk (IS/AAR ) of 61.6 +/- 1.6. 48-h pretreatment with TAN-67 (30 mg/kg), a delta (1)-op ioid receptor agonist, maximally reduced IS/AAR (31.2 +/- 6.5). The involve ment of ERK was examined with PD 098059, a selective pharmacological antago nist which inhibits the upstream kinase, MEK-1, that phosphorylates and act ivates ERK. PD 098059 (0.3 mg/kg) did not alter IS/AAR when administered al one (60.7 +/- 4.9). However, PD 098059 (0.3 mg/kg) administration 30 min pr ior to TAN-67 (30 mg/kg) completely abolished cardioprotection (61.0 +/- 7. 6). The selective p38 inhibitor, SE 203580 (1.0 mg/kg), had no effect on IS /AAR in the absence of TAN-67 (53.1 +/- 2.3). Additionally, SE 203580 (1.0 mg/kg) when administered prior to TAN-67 (30 mg/kg) partially abolished car dioprotection (51.3 +/- 6.4). These results suggest that both ERI( and p38 are integral components of opioid-induced delayed cardioprotection and may act via parallel pathways.