Figure 3.

Late I_Ca,L antiarrhythmic modifications. Class IV antiarrhythmics block the L-type channels indiscriminately reducing peak and late I_Ca,L, suppressing EC-coupling. I_Ca,L gating modifications identified by dynamic clamp studies (Madhvani et al., 2011, 2015) specifically reduce late I_Ca,L, potently abolishing EADs without affecting maximum Cav1.2 open probability; therefore peak I_Ca,L remains largely preserved. These maneuvers include: (1) pedestal reduction from 10 to 4%; (2) a 5 mV depolarizing shift of steady-state activation; (3) a 5 mV hyperpolarizing shift of SS-inactivation. Roscovitine enantiomers can reduce late I_Ca,L (pedestal).