title: Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation.
abstract: Opioids introduced at reperfusion (R) following ischemia (I) reduce infarct size much like postconditioning, suggesting the hypothesis that postconditioning increases cardiac opioids and activates local opioid receptors. Anesthetized male rats subjected to 30 min regional I and 3 h R were postconditioned with three cycles of 10 s R and 10 s reocclusion at onset of R. Naloxone (NL), its peripherally restricted analog naloxone methiodide, delta-opioid receptor (DOR) antagonist naltrindole (NTI), kappa-opioid receptor antagonist norbinaltorphimine (NorBNI), and mu-opioid receptor (MOR) antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) were administered intravenously 5 min before R. The area at risk (AAR) was comparable among groups, and postconditioning reduced infarct size from 57 +/- 2 to 42 +/- 2% (P < 0.05). None of the antagonists alone altered infarct size. All antagonists abrogated postconditioning protection at higher doses. However, blockade of infarct sparing by postconditioning was lost, since tested doses of NL, NTI, NorBNI, and CTAP were lowered. The efficacy of NorBNI declined first at 3.4 micromol/kg, followed sequentially by NTI (1.1), NL (0.37), and CTAP (0.09), suggesting likely MOR and perhaps DOR participation. Representative small, intermediate, and large enkephalins in the AAR were quantified (fmol/mg protein; mean +/- SE). I/R reduced proenkephalin (58 +/- 9 vs. 33 +/- 4; P < 0.05) and sum total of measured enkephalins, including proenkephalin, peptide B, methionine-enkephalin, and methionine-enkephalin-arginine-phenylalanine (139 +/- 17 vs. 104 +/- 7; P < 0.05) compared with shams. Postconditioning increased total enkephalins (89 +/- 8 vs. 135 +/- 5; P < 0.05) largely by increasing proenkephalin (33 +/- 4 vs. 96 +/- 7; P < 0.05). Thus the infarct-sparing effect of postconditioning appeared to involve endogenously activated MORs and possibly DORs, and preservation of enkephalin precursor synthesis in the AAR.
authors.affiliation: Department of Cardiothoracic Surgery, Carlyle Fraser Heart Center/Crawford Long Hospital, Emory University School of Medicine, Atlanta, Georgia 30308-2225, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Zatta
authors.forename: Hajime
authors.initials: H
authors.lastname: Kin
authors.forename: Darice
authors.initials: D
authors.lastname: Yoshishige
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Ningping
authors.initials: N
authors.lastname: Wang
authors.forename: James G
authors.initials: JG
authors.lastname: Reeves
authors.forename: James
authors.initials: J
authors.lastname: Mykytenko
authors.forename: Robert A
authors.initials: RA
authors.lastname: Guyton
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: James L
authors.initials: JL
authors.lastname: Caffrey
authors.forename: Jakob
authors.initials: J
authors.lastname: Vinten-Johansen
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D004723:Endorphins / Q000378:metabolism*; D004745:Enkephalins / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010446:Peptide Fragments; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000502:physiology; D013004:Somatostatin
chemical_list: D000701:Analgesics, Opioid; C529311:CTAP octapeptide; D004723:Endorphins; D004745:Enkephalins; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C029992:proenkephalin; C051844:norbinaltorphimine; D013004:Somatostatin; D009271:Naltrexone; D009638:Norepinephrine