BACKGROUND: Early afterdepolarizations (EADs) are triggers of @entity943 driven by L-type @entity141 current (ICaL) reactivation or sarcoplasmic reticulum @entity141 release and Na(+)/ @entity141 exchange. In large mammals the positive action potential plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K(+) currents. However, EADs are also frequent in the rapidly repolarizing @entity19 action potential, which should not readily permit ICaL reactivation. This suggests that @entity19 EADs exhibit unique dynamics, which are key for interpreting @entity943 mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from @entity943 -susceptible @entity460 calmodulin-dependent protein kinase II delta C (CaMKII  C)-overexpressing @entity19 (Tg), and via computational simulations. METHODS AND RESULTS: In Tg myocytes, b-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum @entity141 release, and initiated EADs below the ICaL activation range (-47  0.7 mV). These EADs were abolished by @entity5834 and @entity1022 (but not @entity16590 ), suggesting that sarcoplasmic reticulum @entity141 release and Na(+) current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum @entity141 release and Na(+)/ @entity141 exchange shape late action potential repolarization to favor nonequilibrium reactivation of INa and thereby drive the @entity27732 . Action potential clamp experiments suggest that @entity3303 eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60  mol/L) for which @entity3303 remains specific for inactivated Na(+) channels. This strongly suggests that previously inactive channels are recruited during the @entity27732 , and that nonequilibrium INa dynamics underlie @entity19 EADs. CONCLUSIONS: Nonequilibrium reactivation of INa drives @entity19 EADs.

Nonequilibrium reactivation of na+ current drives early afterdepolarizations in XXXX ventricle.

@entity27732 :: ('MESH:C566415', 'Disease') :: ['EAD upstroke'] @entity16590 :: ('MESH:C055512', 'Chemical') :: ['ranolazine'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse', 'murine'] @entity1022 :: ('MESH:D013779', 'Chemical') :: ['tetrodotoxin'] @entity5834 :: ('MESH:D002110', 'Chemical') :: ['caffeine'] @entity3303 :: ('MESH:D008012', 'Chemical') :: ['lidocaine'] @entity460 :: ('MESH:D002118', 'Chemical') :: ['calcium'] @entity141 :: ('CHEBI:29108', 'Chemical') :: ['Ca(2+)'] @entity943 :: ('MESH:D001145', 'Disease') :: ['cardiac arrhythmia', 'arrhythmia']
@entity19 :: (10090,Species) :: ['mouse']
