The role of transmembrane chloride current in afterdepolarisations in canine ventricular cardiomyocytes.
The physiological role of chloride currents (Icl) in cardiac cells is poorly understood. The aim of the present study was to reveal the role of Icl in the genesis of early and delayed afterdepolarisations (EADs and DADs, respectively). First we identified Icl under action potential voltage clamp conditions as the anthracene-9-carboxylic acid (ANTRA) (0.5 mmol/l)-sensitive current. The ANTRA-sensitive current was large and outwardly directed at the beginning, while it was moderate and inwardly directed at the end of the action potential. Application of ANTRA under current clamp conditions decreased the depth of the incisura, shifted the plateau upwards and lengthened the duration of action potentials. The effect of ANTRA was studied in three models of afterdepolarisations: the ouabain-induced DAD model, the caesium-induced EAD model, and in the presence of subthreshold concentration of isoproterenol. Preincubation of the cells with 0.5 mmol/l ANTRA failed to induce afterdepolarisations. Ouabain (200 nmol/l) alone caused DADs in 62.5% of the cells within 15 min. When ouabain was applied in the presence of ANTRA, 60% of the myocytes transiently displayed EADs before the development of DADs, and all cells developed DADs within 7 min. Isoproterenol (5 nmol/l) alone failed to induce afterdepolarisations. However, 75% of the cells produced DADs within 6 min when superfused with isoproterenol in the presence of ANTRA. Incubation of the myocytes with 3.6 mmol/l CsCl caused EADs in 71.4% of the cells within 30 min. Application of CsCl in the presence of ANTRA resulted in immediate depolarisation of the membrane from -79.6 +/- 0.4 to -54.2 +/- 3.5 mV. Summarizing our results we conclude that the ANTRA-sensitive current is an important mechanism of defence against afterdepolarisations. Suppression of Icl may thus increase the incidence and accelerate the rate of development of both EADs and DADs.
Department of Physiology, University Medical School of Debrecen, Debrecen, Hungary.
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Szentandrássy
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Magyar
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D002713:Chlorine / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010042:Ouabain / Q000494:pharmacology
D000873:Anthracenes; D018118:Chloride Channels; D002713:Chlorine; D010042:Ouabain; C010030:9-anthroic acid; D007545:Isoproterenol