Cardioprotection via activation of protein kinase C-δ depends on modulation of the reverse mode of the Na+/Ca2+ exchanger

R. Arthur Bouwman, Kanita Salic, F. Gieneke Padding, Etto C. Eringa, Brechje J. Van Beek-Harmsen, Toshio Matsuda, Akemichi Baba, René J.P. Musters, Walter J. Paulus, Jaap J. De Lange, Christa Boer

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Abstract

BACKGROUND - Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-δ mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca handling, and because Ca also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na/Ca exchanger (NCX) in relation with PKC-δ in sevoflurane-induced cardioprotection was investigated. METHODS AND RESULTS - Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83±7% [sevo] versus 57±2% [SI/R];n=8; P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 μmol/L) or SEA0400 (1 μmol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-δ translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-δ phosphorylation at serine as determined by western blot analysis was not affected by sevoflurane. CONCLUSIONS - Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-δ translocation presumably via increased NCX-mediated Ca influx. This may suggest that increased myocardial Ca load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.

Original languageEnglish
JournalCirculation
Volume114
Issue numberSUPPL. 1
DOIs
Publication statusPublished - 1 Jul 2006

Keywords

  • Anesthesia
  • Calcium
  • Ion channels
  • Preconditioning
  • Signal transduction

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