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

Basic Res Cardiol. 2001 Apr;96(2):136-42. doi: 10.1007/s003950170063.

Abstract

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.

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Blood Pressure
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Heart Rate
  • Imidazoles / pharmacology
  • Ischemic Preconditioning, Myocardial*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myocardial Ischemia / drug therapy
  • Myocardial Ischemia / metabolism*
  • Myocardium / enzymology
  • Pyridines / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Opioid / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Analgesics
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Pyridines
  • Quinolines
  • Receptors, Opioid
  • TAN 67
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one