Abstract 2896: Negative Modulation of SK Channels Terminates and Protects Against Atrial Fibrillation in Rat and Guinea Pig Ex Vivo and in vivo Models
Introduction Recently, small conductance Ca2+-activated K+-channels (SK-channels) have been shown to exist in human and mouse hearts. There is biochemical evidence that SK2-channels are predominantly expressed in the atria of human and mouse hearts, and that SK1-channels are predominantly expressed in the atria of mouse hearts, making SK-channels an interesting target in AF. We assessed the hypothesis that pharmacological inhibition of SK-channels with two structurally unrelated compounds, UCL1684 and NS8593, is antiarrhythmic in rat and guinea pig in ex vivo and in vivo models of AF.
Methods Ex vivo experiments were conducted in isolated, perfused guinea pig hearts, continuously paced on the right atrium (5 Hz). AF was induced by 1 μM acetylcholine combined with extrastimuli 1–3 ms after the end of atrial refractoriness. When sustained AF was obtained, either no drug, Amiodarone (10 μM), UCL1684 (0.3 μM), or NS8593 (1 μM, 3 μM, or 10 μM) was added to the perfusate. In vivo experiments were conducted in a novel AF model; in mebumal-anaesthetized rats (50mg/kg, i.p.), short episodes of AF were induced every 2 minutes by open-chest burst pacing (83 Hz) of the right atrium for 30 s with concomitant asphyxia. Animals were divided into two groups receiving i.v. injections of either SK-inhibitor or vehicle subsequent to 30 minutes of baseline recordings. After injection, the total duration of AF was measured over a period of 30 minutes.
Results Ex vivo: In all of the time matched control experiments AF was sustained (n=7). AF was reverted and non-reinducible in 33% (p<0.19, n=6), 83% (p<0.01, n=6), and 100% (p<0.001, n=6) of hearts perfused with increasing concentrations of NS8593 (1 μM, 3μM, and 10μM, respectively). AF was reverted and non-reinducible in 100% of the hearts perfused with UCL1684 or Amiodarone (p<0.01, n=4 in both groups). In vivo: Duration of AF normalized to baseline recordings was significantly shorter (26.5%±19.2%, p<0.001, n=5) in the SK-inhibitor treated group compared to the vehicle treated group (99.5%±27.2%, n=5).
Conclusion Pharmacological inhibition of SK channels shows strong antiarrhythmic effects in both ex vivo and in vivo models of AF in two different species.