Enhanced sodium-calcium exchange enabled by an increase in the calcium transient in the presence of an abbreviated action potential: A new arrhythmia mechanism

Abstract

Early afterdepolarizations (EADs) are observed in superfused canine pulmonary vein sleeves following norepinephrine (NE) (3.2 x 10−8 M) administration and tachycardia-pause pacing, interventions increasing the magnitude of the calcium transient. Further shortening of the already abbreviated pulmonary vein action potential by acetylcholine (10−7 M) enables the EADs to trigger arrhythmia formation. We examined the hypothesis that an increased calcium transient enhances an inward Na-Ca exchange current during late systole, and in the presence of an abbreviated action potential, serves as a basis for EADs and triggered arrhythmia. Using intracellular microelectrode recordings in superfused canine pulmonary vein sleeves, EADs were observed following NE administration (N= 18 of 23). EAD formation was pause-enhanced, following a single premature beat or a 5-20 beat (5.0 Hz) pacing train. Both EAD formation and triggered arrhythmia were suppressed by ryanodine administration (10 μM for 10 min), an intervention suppressing the calcium transient. EAD formation with pacing was enhanced by facilitation of Na-Ca exchange (forward mode)(reintroduction of 140 mM Nao following superfusion with 30 mM NaCl substituted with LiCl) and was suppressed by an acute increase in Cao from 1.35 to 5 mM, an intervention decreasing inward Na-Ca exchange. Triggering of rapid (¾800 bpm) sustained (¾1 sec in duration) arrhythmia was observed following acetylcholine administration in the presence of NE (N= 18 of 23).