title: Ionic mechanism of delayed afterdepolarizations in ventricular cells isolated from human end-stage failing hearts.
abstract: BACKGROUND
  Animal studies have shown that the Ca(2+)-activated Cl(-) current (I(Cl(Ca))) and the Na(+)/Ca(2+) exchange current (I(Na/Ca)) contribute to the transient inward current (I(ti)). I(ti) is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of I(ti) and DADs in human cardiac cells.
  
  
  RESULTS
  Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology. I(ti)s were elicited in the presence of 1 micromol/L norepinephrine by trains of repetitive depolarizations from -80 to +50 mV. DADs were induced in the presence of 1 micromol/L norepinephrine at a stimulus frequency of 1 Hz. I(ti) currents were inwardly directed over the voltage range between -110 and + 50 mV. Neither the Cl(-) channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid nor changes in [Cl(-)](i) affected I(ti) or DAD amplitude. This excludes an important role for I(Cl(Ca)). Blockade of Na(+)/Ca(2+) exchange by substitution of all extracellular Na(+) by Li(+), conversely, completely inhibited I(ti). In rabbit, I(Cl(Ca)) density in ventricular cells isolated from control hearts did not differ significantly from that in ventricular cells isolated from failing hearts.
  
  
  CONCLUSIONS
  In contrast to many animal species, I(ti) and DADs in human ventricular cells from failing hearts consist only of I(Na/Ca). In rabbits, heart failure per se does not alter I(Cl(Ca)) density, suggesting that I(Cl(Ca)) may also be absent during DADs in nonfailing human ventricular cells.
authors.affiliation: Department of Physiology, Experimental and Molecular Cardiology Group, 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: A
authors.initials: A
authors.lastname: Baartscheer
authors.forename: C A
authors.initials: CA
authors.lastname: Schumacher
authors.forename: C
authors.initials: C
authors.lastname: Klöpping
authors.forename: A C
authors.initials: AC
authors.lastname: van Ginneken
authors.forename: J H
authors.initials: JH
authors.lastname: Ravesloot
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors
chemical_list: D018118:Chloride Channels; D019831:Sodium-Calcium Exchanger; D008094:Lithium; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002118:Calcium; D009638:Norepinephrine