Effect of carbenoxolone on arrhythmogenesis in rat ventricular muscle

Masahito Miura, Tsuyoshi Nagano, Naomi Murai, Yuhto Taguchi, Tetsuya Handoh, Minami Satoh, Satoshi Miyata, Lawson Miller, Chiyohiko Shindoh, Bruno D. Stuyvers

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2 Citations (Scopus)

Abstract

Background: Connexin43 (Cx43) is a major connexin that forms gap junction (GJ) channels in the heart and is also present in the cell membrane as unopposed/non-junctional hemichannels and in the inner mitochondrial membrane. By using carbenoxolone (CBX), a blocker of Cx43, the effect of the blockade of Cx43 on Ca2+ waves and triggered arrhythmias in the myocardium with non-uniform contraction was examined. Methods and Results: Trabeculae were obtained from rat hearts. Force, [Ca2+]i, and the diffusion coefficient were measured. Non-uniform contraction was produced with a 2,3-butanedione monoxime jet. Ca2+ waves were induced by electrical stimulation. Inducibility of arrhythmias was estimated based on the minimal [Ca2+]o at which arrhythmias were induced. The Ca2+spark rate was measured in isolated single rat ventricular myocytes. CBX reduced the GJ permeability, whereas it did not change force and [Ca2+]i transients. CBX increased the Ca2+ leak from the sarcoplasmic reticulum in trabeculae and increased the Ca2+ spark rate in isolated single myocytes. CBX increased the velocity of Ca2+ waves and further increased the inducibility of arrhythmias. Modulation of mitochondrial KATP channels by diazoxide, cromakalim and 5-hydroxydecanoic acid affected the inducibility of arrhythmias increased by CBX. Conclusions: These results suggest that in diseased hearts, Cx43 plays an important role in the occurrence of triggered arrhythmias, probably under the modulation of mitochondrial KATP channels.

Original languageEnglish
Pages (from-to)76-84
Number of pages9
JournalCirculation Journal
Volume80
Issue number1
DOIs
Publication statusPublished - 2015 Dec 25

Keywords

  • Calcium
  • Carbenoxolone
  • Connexin43
  • Diazoxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Miura, M., Nagano, T., Murai, N., Taguchi, Y., Handoh, T., Satoh, M., Miyata, S., Miller, L., Shindoh, C., & Stuyvers, B. D. (2015). Effect of carbenoxolone on arrhythmogenesis in rat ventricular muscle. Circulation Journal, 80(1), 76-84. https://doi.org/10.1253/circj.CJ-15-0401