Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium

Abstract

SK channel inhibition modulates multiple parameters of AP. It prolongs the AP duration and shifts the RMP towards more depolarized potentials through direct ISK block. This indirectly leads to sodium channel inhibition through accumulation of state dependently inactivated channels, which ultimately slows conduction and decreases excitability. However, a contribution from a direct sodium channel inhibition cannot be ruled. We here propose that the primary antiarrhythmic mechanism of SK channel inhibition is through direct potassium channel block and through indirect sodium channel inhibition.

Refractoriness in human atria: Time and voltage dependence of sodium channel availability

“…More recent models of re-entry predict that changes, which prolong or cause heterogeneous ERP, do indeed increase source-to-sink mismatch in excitation, in this way slowing conduction velocity. As we recently reported [25], slowing of CV was mirrored by reversed changes in ERP, opposing wavelength shortening by actually prolonging the theoretical spatial wavelength. This concept could explain the relatively high efficiency of sodium channel blockers in the abolishment of re-entrant arrhythmias.…”

“…A clear relationship between refractory period, conduction velocity and functional wavelength exists [25]. According to the classical leading-circle theory [26], these two electrophysiological parameters are considered independent factors (WL = CV x ERP).…”

Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study

“…In addition to Na v 1.5 and K ir 2.1, previous studies have reported preferential localization of K V 1.5,(19) the voltage-gated, shaker-related potassium channel, small conductance calcium-activated potassium (SK) channels(26), and K ir 6.2, the ATP-sensitive potassium channel,(9) at the intercalated disc. Also, we have demonstrated that activation of the rapid (HERG)(14) and slow (KvLQT1)(33) delayed rectifier potassium channels as well as K ir 6.2 can modulate cardiac conduction.…”

Pharmacological gating modulation of small- and intermediate-conductance Ca2+-activated K+channels (KCa2.x and KCa3.1)

“…80 NS8593 as well as several small molecule blockers of K Ca 2 channels have shown efficacy in protecting against and terminating atrial fibrillation both ex vivo and in vivo across a number of different species. 81 Intriguingly, this concept also appears to be viable after hypertension induced cardiac remodeling.…”