Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias.
OBJECTIVE
The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations.


METHODS
Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of -73, -53, -33 or -13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling.


RESULTS
At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and "high-plateau" Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was -13 mV. Norepinephrine (1 microM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was -33 mV or more positive.


CONCLUSIONS
In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was -33 or -13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.
Verkerk
A O
AO
Department of Physiology, Cardiovascular Research Institute Amsterdam, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. a.o.verkerk@amc.uva.nl
Veldkamp
M W
MW
Coronel
R
R
Wilders
R
R
van Ginneken
A C
AC
D000200:Action Potentials / Q000187:drug effects*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002450:Cell Communication; D006352:Heart Ventricles / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000187:drug effects*; D012756:Sheep
D000316:Adrenergic alpha-Agonists; D009638:Norepinephrine