Effect of carbenoxolone on arrhythmogenesis in rat ventricular muscle

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 K_ATP 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 K_ATP channels.