Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels Terminates and Protects Against Atrial Fibrillation

Abstract

Inhibition of SK channels prolongs atrial effective refractory period without affecting QT interval and prevents and terminates AF ex vivo and in vivo, thus offering a promising new therapeutic opportunity in the treatment of AF.

Effects on Atrial Fibrillation in Aged Hypertensive Rats by Ca 2+ -Activated K + Channel Inhibition

“…9,29 Because the selectivity data include neuronal Na v 1.2, but not cardiac Na v 1.5, it cannot be ruled out that Na v 1.5 inhibition interferes with the recordings of AF durations in our experiments. However, two potent SK channel pore blockers, structurally unrelated to NS8593 and with a different mode of action than NS8593, exert antiarrhythmic effects comparable to those of NS8593, 9 and in combination with the selectivity data, this suggests that the antiarrhythmic effect of NS8593 is primarily a result of SK channel inhibition.…”

“…9 However, hypertension is the most prominent predisposing factor for the clinically encountered AF. Thus, the aging SHR constitutes a relevant preclinical model for addressing the potential antiarrhythmic properties of potential AF drugs, because it incorporates hypertension-induced atrial remodeling with atrial enlargement, interstitial fibrosis, and cellular electric remodeling.…”

“…9 Monophasic action potential recordings were obtained with a monophasic action potential electrode placed on the right atrium. The atrial effective refractory period (aERP) and the Wenckebach cycle length (WCL), as well as pacing-induced AF duration, were measured before and after IV injections of NS8593 (5 mg/kg), UCL1684 (3 mg/kg), or vehicle.…”

“…7,8 We have shown previously that inhibition of SK channels is antiarrhythmic in models of acutely induced AF. 9 These models, however, do not take into account that AF derives from a wide range of predisposing factors, the most prevalent being hypertension. 1,14,15 AF is secondary to underlying heart disease in 70% of patients, whereas lone AF patients with no detectable etiology constitute the remaining 30%.…”

Physiologie, pharmacologie et modélisation de canaux potassiques

“…Plus récemment, un composé d'une autre classe également accroître l'excitabilité des neurones dopaminergiques de la substance noire, ce qui pourrait être utile dans le traitement de certaines maladies liées à un dysfonctionnement de ces systèmes [1,24]. Des études plus récentes ont également présenté les canaux SK comme cibles potentielles dans d'autres pathologies sévères telles que le cancer du sein [4], la fibrillation auriculaire [25] ou encore les désordres cognitifs liés à la schizophrénie [26]. Ce large éventail de possibilités thérapeutiques justifie l'étude d'une telle cible.…”