title: Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation.
abstract: The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Jun
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Hironori
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ohori
authors.forename: Akari
authors.initials: A
authors.lastname: Takahashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065095:Calcineurin Inhibitors; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D017465:Receptors, Opioid, delta; D016308:Enkephalin, Leucine-2-Alanine; D048049:Extracellular Signal-Regulated MAP Kinases; D016559:Tacrolimus