Abstract
Connexin43 (Cx43), a gap junction protein, mediates cell-cell communication via electrical and chemical coupling. Ischemic stress of the cardiac muscle interrupts intercellular communication by changing the distribution and phosphorylation status of Cx43. This may be a factor contributing to reentrant arrhythmia. The calcium channel blocker diltiazem is known for its protective and anti-arrhythmogenic effect in ischemic heart disease. In this study, we assess the effect of diltiazem pretreatment upon ischemia-induced phosphorylation change of Cx43. Langendorff preparations of isolated Wistar rat hearts were performed. After stabilization, hearts were treated with (D+) or without diltiazem (D⁻), then subjected to hypoxia-reoxygenation. After perfusion, the left ventricle was prepared for immunocytochemistry and immunoblot analysis. During perfusion, left ventricular function was better in the D+ group than the D⁻ group. Immunostaining of the heart indicated that dephosphorylated Cx43 (dpCx43) signal was increased after hypoxic perfusion, and this finding was confirmed by immunoblot data. The quantitative area analysis of dpCx43 using the immunohistochemical approach showed that the dpCx43-positive area was enlarged, as the hypoxic perfusion time was longer, and it was reduced by pretreatment of diltiazem. There was a negative correlation between the dpCx43 area and %RPP (rate-pressure product), calculated by heart rate and contraction force. Pretreatment of diltiazem could protect the heart against hypoxia-reoxygenation injury by attenuation of dephosphorylation of Cx43. The anti-arrhythmic mechanism of diltiazem may include the preservation of phosphorylation status of Cx43 after hypoxia-reoxygenation injury.
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