title: Calcium-activated Cl(-) current contributes to delayed afterdepolarizations in single Purkinje and ventricular myocytes.
abstract: BACKGROUND
  The ionic mechanism underlying the transient inward current (I(ti)), the current responsible for delayed afterdepolarizations (DADs), appears to be different in ventricular myocytes and Purkinje fibers. In ventricular myocytes, I(ti) was ascribed to a Na(+)-Ca(2+) exchange current, whereas in Purkinje fibers, it was additionally ascribed to a Cl(-) current and a nonselective cation current. If Cl(-) current contributes to I(ti) and thus to DADs, Cl(-) current blockade may be potentially antiarrhythmogenic. In this study, we investigated the ionic nature of I(ti) in single sheep Purkinje and ventricular myocytes and the effects of Cl(-) current blockade on DADs.
  
  
  RESULTS
  In whole-cell patch-clamp experiments, I(ti) was induced by repetitive depolarizations from -93 to +37 mV in the presence of 1 micromol/L norepinephrine. In both Purkinje and ventricular myocytes, I(ti) was inward at negative potentials and outward at positive potentials. The anion blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) blocked outward I(ti) completely but inward I(ti) only slightly. The DIDS-sensitive component of I(ti) was outwardly rectifying, with a reversal close to the reversal potential of Cl(-) currents. Blockade of Na(+)-Ca(2+) exchange by substitution of extracellular Na(+) by equimolar Li(+) abolished the DIDS-insensitive component of I(ti). DIDS reduced both DAD amplitude and triggered activity based on DADs. Conclusions-In both Purkinje and ventricular myocytes, I(ti) consists of 2 ionic mechanisms: a Cl(-) current and a Na(+)-Ca(2+) exchange current. Blockade of the Cl(-) current may be potentially antiarrhythmogenic by lowering DAD amplitude and triggered activity based on DADs.
authors.affiliation: Department of Physiology, Academic Medical Center, University of Amsterdam, The Netherlands. a.o.verkerk@amc.uva.nl
authors.forename: A O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: M W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: L N
authors.initials: LN
authors.lastname: Bouman
authors.forename: A C
authors.initials: AC
authors.lastname: van Ginneken
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D015640:Ion Channel Gating / Q000502:physiology; D008094:Lithium / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D009206:Myocardium / Q000166:cytology; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D012756:Sheep; D012964:Sodium / Q000493:pharmacokinetics; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D019831:Sodium-Calcium Exchanger; D013566:Sympathomimetics; D008094:Lithium; D012964:Sodium; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002118:Calcium; D009638:Norepinephrine