ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection.
Opioids have been previously shown to confer acute and delayed cardioprotection 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 cardioprotection. Therefore, we attempted to determine a role for ERK and the stress activated MAP kinase, p38, in opioid-induced delayed cardioprotection 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, injected 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 delta1-opioid receptor agonist, maximally reduced IS/AAR (31.2 +/- 6.5). The involvement of ERK was examined with PD 098059, a selective pharmacological antagonist which inhibits the upstream kinase, MEK-1, that phosphorylates and activates ERK. PD 098059 (0.3 mg/kg) did not alter IS/AAR when administered alone (60.7 +/- 4.9). However, PD 098059 (0.3 mg/kg) administration 30 min prior to TAN-67 (30 mg/kg) completely abolished cardioprotection (61.0 +/- 7.6). The selective p38 inhibitor, SB 203580 (1.0 mg/kg), had no effect on IS/AAR in the absence of TAN-67 (53.1 +/- 2.3). Additionally, SB 203580 (1.0 mg/kg) when administered prior to TAN-67 (30 mg/kg) partially abolished cardioprotection (51.3 +/- 6.4). These results suggest that both ERK and p38 are integral components of opioid-induced delayed cardioprotection and may act via parallel pathways.
Fryer
R M
RM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Hsu
A K
AK
Gross
G J
GJ
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006339:Heart Rate; D007093:Imidazoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000700:Analgesics; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D011957:Receptors, Opioid; C094142:TAN 67; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one