Effects of a reduction in the number of gap junction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mouse hearts

Jose A. Sánchez, Antonio Rodríguez-Sinovas, Celia Fernández-Sanz, Marisol Ruiz-Meana, David García-Dorado

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18 Citations (Scopus)

Abstract

A transient reduction of cell coupling during reperfusion limits myocardial necrosis, but little is known about its arrhythmogenic effects during ischemia-reperfusion. Thus, we analyzed the effect of an extreme reduction in the number of gap junction channels or in their unitary conductance on ventricular arrhythmias during myocardial ischemia-reperfusion. Available gap junction uncouplers have electrophysiological effects independent from their uncoupling actions. Thus, isolated hearts from Cx43Cre-ER(T)/fl mice treated with 4-hydroxytamoxifen (4-OHT), from Cx43KI32 mice [in which connexin (Cx)43 was replaced with Cx32], and from control animals were submitted to regional ischemia and reperfusion, and spontaneous and induced ventricular arrhythmias were monitored. In additional hearts, changes in activation time and electrical impedance during global ischemia-reperfusion were assessed. In contrast to treatment with 4-OHT, replacement of Cx43 with Cx32 did not modify baseline activation time or electrical impedance. However, the number of extrasistole and ventricular tachyarrhytmias was higher in isolated hearts from Cx43KI32 and 4-OHT-treated Cx43Cre-ER(T)/fl animals versus wild-type animals during normoxia, ischemia (12.29±3.26 and 52.17 ± 22.51 vs. 3.00 ± 1.46 spontaneous tachyarrhythmias, P ± 0.05), and reperfusion. The impairment in conduction during ischemia was steeper in isolated hearts from Cx43KI32 animals, whereas changes in myocardial impedance were attenuated during ischemia in both transgenic models, suggesting altered cell-to-cell coupling at baseline. In conclusion, both reduction of Cx43 with 4-OHT and replacement of Cx43 by less-conductive Cx32 were arrhythmogenic under normoxia and ischemia-reperfusion, despite no major effects on baseline electrical properties. These results suggest that modifications in gap junction communication silent under normal conditions may be arrhythmogenic during ischemia-reperfusion. © 2011 the American Physiological Society.
Original languageEnglish
Pages (from-to)2442-2453
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number6
DOIs
Publication statusPublished - 1 Dec 2011

Keywords

  • Connexin43
  • Electrical impedance

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