Effect of Carbenoxolone on Arrhythmogenesis in Rat Ventricular Muscle

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

doi:10.1253/circj.cj-15-0401

Cited by 7 publications

(10 citation statements)

References 47 publications

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“…Nevertheless, it has not yet been established whether the block of mitochondrial Cx43 is actually involved in the increase in arrhythmias because we cannot eliminate the possibility that carbenoxolone may block the other channels except for Cx43 in the previous study [21].…”

Section: Introductionmentioning

confidence: 83%

“…The minimal extracellular Ca 2+ concentration ([Ca 2+ ] o,min ), at which arrhythmias were induced by electrical stimulation (0.3-s stimulus intervals for 30 s, 0.1 μmol/L isoproterenol), was determined to estimate arrhythmia susceptibility, as previously described [21].…”

Section: Methodsmentioning

confidence: 99%

“…Measurements of 2',7'-dichloro uorescein (DCF) uorescence, tetramethylrhodamine methylester (TMRM) uorescence, and Ca 2+ sparks in isolated single mouse cardiomyocytes After mice had been adequately anesthetized, isolated single cardiomyocytes were obtained [30]. ROS production was estimated using DCF uorescence [22], and mitochondrial membrane potential was estimated using TMRM uorescence [21]. Ca 2+ sparks were measured by uo-4 and confocal microscopy (Figure S3AB) [21].…”

Section: Methodsmentioning

confidence: 99%

“…ROS production was estimated using DCF uorescence [22], and mitochondrial membrane potential was estimated using TMRM uorescence [21]. Ca 2+ sparks were measured by uo-4 and confocal microscopy (Figure S3AB) [21].…”

Section: Methodsmentioning

confidence: 99%

“…Actually, we have reported that in rat trabeculae, the reduction of GJ communication using octanol and heptanol decreased the velocity of Ca 2+ waves [47]. In contrast, we have previously reported that block of Cx43 using carbenoxolone increased the velocity of Ca 2+ waves, causing triggered arrhythmias in rat trabeculae [21]. In addition, we have further reported that the increase in arrhythmias by carbenoxolone was suppressed after the addition of diazoxide, suggesting that Cx43 plays important roles in the occurrence of trigged arrhythmias under modulation of mitochondrial K ATP channels [21].…”

Section: Introductionmentioning

confidence: 92%

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Mitochondrial connexin43 and mitochondrial KATP channels modulate triggered arrhythmias in mouse ventricular muscle

Sato

Nishiyama

Morita

et al. 2023

Pflugers Arch - Eur J Physiol

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Aim: Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias.Methods and Results: To generate cardiac-speci c Cx43-de cient (cCx43-/-) mice, Cx43 ox/ ox mice were crossed with α-MHC (Myh6)-cre+/-mice. The resulting offspring, Cx43 ox/ ox/ Myh6-cre+/mice (cCx43-/-mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2',7'-dichloro uorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methylester(TMRM), and Ca2+ spark frequency with uo-4 and confocal microscopy in cardiomyocytes. Mitochondrial Ca2+ was estimated with rhod-2 in trabeculae. Diazoxide was used to open mitochondrial KATP. Most of cCx43-/mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+mice, but not in cCx43-/-mice. In cCx43-/mice, the [Ca2+]o,min was lower, Ca2+ spark frequency and DCF oxidation rate were more increased, and TMRM uorescence was more decreased. These changes in cCx43-/-mice were suppressed by diazoxide. Besides, in cCx43-/mice, antioxidant peptide SS-31 increased the [Ca2+]o,min. Rhod-2 uorescence was increased at high [Ca2+]o only in Cx43-/mice.Conclusions: These results suggest that the de ciency of Cx43 activates Ca2+ leak from the SR probably due to an increase in ROS production, depolarization of mitochondrial membrane potential, and an increase in mitochondrial Ca2+, thereby causing triggered arrhythmias and that the de ciency of Cx43 hemichannels may be compensated by activation of mitochondrial KATP channels in mouse hearts.

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Section: Introductionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%