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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1425    most recent 01115.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miura, T. Articles by Shimamoto, K. Search for Related Content PubMed PubMed Citation Articles by Miura, T. Articles by Shimamoto, K.

-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC--mediated phosphorylation of connexin 43

¹Second Department of Internal Medicine and ²Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan

Submitted 12 October 2006 ; accepted in final form 14 May 2007

The aim of this study was to examine the hypothesis that -opioid receptor activation before ischemia suppresses gap junction (GJ) permeability by PKC-mediated connexin 43 (Cx43) modulation, which contributes to infarct size limitation afforded by the -opioid receptor activation. A -opioid receptor agonist, [D-Ala²,D-Leu⁵]-enkephalin acetate (DADLE, 300 nM), was used in place of preconditioning (PC) ischemia to trigger PC mechanisms in rat hearts. GJ permeability during ischemia, which was assessed by Lucifer yellow, was reduced by DADLE to 47% of the control level, and this effect of DADLE was almost abolished by a PKC- inhibitor [PKC- translocation inhibitory peptide (PKC--TIP)] but was not affected by a PKC- inhibitor (rottlerin). After DADLE infusion, PKC-, but not PKC-, was coimmunoprecipitated with Cx43, and the level of phosphorylation of Cx43 at a PKC-dependent site (Ser³⁶⁸) was significantly elevated during ischemia. DADLE reduced infarct size after 35 min of ischemia followed by 2 h of reperfusion by 69%, and PKC--TIP and rottlerin eliminated 48% and 63%, respectively, of the infarct size-limiting effect of DADLE. Infusion of a GJ blocker, heptanol, before reperfusion reduced infarct size by 36%, and this protection was not enhanced by preischemic infusion of rottlerin + DADLE, which allows PKC- activation by DADLE. These results suggest that phosphorylation of Cx43 by PKC- plays a crucial role in -opioid-induced suppression of GJ permeability in ischemic myocardium and that this modulation of the GJ is possibly an adjunct mechanism of infarct size limitation afforded by preischemic -opioid receptor activation.

infarct size; preconditioning