Connexin-43 Redistribution and Gap Junction Activation During Forced Restraint Protects Against Sudden Arrhythmic Death in Rats

Abstract

Background: Connexin-43 (Cx43) expression is reduced or redistributed in heart disease. Restraint or other emotional stressors might cause sudden death in persons with such diseases, but the mechanism of death and its connection to Cx43 during restraint remain unknown. Whether Cx43 distribution or gap junction (GJ) function during restraint is involved in sudden arrhythmic death in rats is addressed in this study. Methods and Results:Male Sprague -Dawley rats underwent immobilization (IMO), and individual electrocardiographic responses were monitored by telemetry. Heart sections were used to examine ventricular Cx43 distribution, and GJ intercellular communication (GJIC) activity was assessed using a dye-transfer assay. IMO induced the translocation of Cx43 into to the GJ-rich fraction, with a peak at 60 min. During IMO, Cx43 immunofluorescence was enhanced at intercalated discs, in association with GJIC activation, and premature ventricular contractions (PVCs) increased. In the presence of the GJ inhibitor, carbenoxolone (0.25 mg·kg -1 ·h -1 ), IMO induced lethal ventricular tachycardia or fibrillation in 21.7% of rats, in association with QRS prolongation and increased PVCs.Conclusions: IMO causes Cx43 translocation to intercalated discs, thereby reducing vulnerability to lethal arrhythmias via enhancing GJ coupling. (Circ J 2010; 74: 1087 - 1095

Immobilization Stress With <i>α</i>₂-Adrenergic Stimulation Induces Regional and Transient Reduction of Cardiac Contraction Through Gi Coupling in Rats

“…Previously, we demonstrated that IMO induced arrhythmic death when coupled with the GJ inhibition that frequently results from heart diseases. 9,10) This study has provided additional support for the hypothesis on the role of cardiogenic death in restraint.…”

“…8) We also showed that whereas IMO induced enhanced gap-junction (GJ) coupling through α-AR, it triggered lethal ventricular arrhythmias when GJ was inhibited. 9,10) Stress (takotsubo) cardiomyopathy is typically induced by psychological stress in postmenopausal women, and is characterized by apical myocardial akinesis and preserved basal movement, which is reflected by a takotsubo (Japanese octopus trap)-like ventriculogram.…”

Acute restraint stress provokes sudden cardiac death in normotensive rats and enhances susceptibility to arrhythmogenic effects of adrenaline in spontaneously hypertensive rats

“…The physical restraint induced SCD in young males without structural heart disease [41]. Rats underwent immobilization showed the increased premature ventricular contractions [42]. Furthermore, SCD in individuals with underlying cardiac disease can be caused by arrhythmic episodes precipitated by emotional stresses [43,44].…”

“…Clusters of gap junctions appear at the intercalated discs and to a lesser extent along the lateral membranes of the heart cells [51]. The disturbances in Cx43 expression and distribution [51], including the enhanced Cx43 immunofluorescence at intercalated discs [42] were used to evaluate the gap junction remodeling. Immobilization stress induced the enhanced Cx43 immunofluorescence at intercalated discs, in association with gap junction intercellular communication activation in male Sprague -Dawley rats [42].…”

“…The disturbances in Cx43 expression and distribution [51], including the enhanced Cx43 immunofluorescence at intercalated discs [42] were used to evaluate the gap junction remodeling. Immobilization stress induced the enhanced Cx43 immunofluorescence at intercalated discs, in association with gap junction intercellular communication activation in male Sprague -Dawley rats [42]. In the present study, Cx43 mRNA expression was used to assess the gap junction remod- eling.…”