Abstract 737: IKACh Dominantly Increases under the Condition of Atrial Electrical Remodeling: Pharmacological Consideration Using the Selective IKACh Blockers in Canine Atrial Tachypacing Model

Abstract

Back ground and purpose: It is well-known that the increased vagal tone is a trigger of atrial fibrillation (AF). In dogs, vagal stimulation shortens atrial effective refractory period (ERP), increases ERP dispersion and promotes AF, possibly via the activation of the atrial acetylcholine-activated potassium channel. Recently, we have reported the blockers of the acetylcholine-activated potassium current (IKACh) terminated AF in canine paroxysmal AF model. However, the pathophysiological role of IKACh in the remodeled atrium seen in persistent AF patients remains unclear. The aim of this study is to evaluate the effects of the selective IKACh blockers, tertiapin and NIP-151 in the remodeled atrium induced by atrial-tachypacing (AT). Methods and results: The effects of tertiapin and NIP-151 on atrial ERP were investigated before and after 1 week of AT. Tertiapin (0.03 mg/kg, i.v.) and NIP-151 (0.3 mg/kg, i.v.) significantly prolonged the atrial ERP even before AT. The shortened atrial ERP which is associated with the electrical remodeling, was induced by AT (400 bpm) over 1 week. After AT for 1 week, the effects of tertiapin and NIP-151 significantly enhanced the prolongation of atrial ERP compared with those before AT. To evaluate whether a muscarinic M2 receptor and/or adenosine A1 receptor activates IKACh in remodeled atrium, we tested the effects of M2 receptor antagonist AF-DX116 (0.3 mg/kg, i.v.) and A1 receptor antagonist DPCPX (0.3 mg/kg, i.v.) in this model. Unlike the selective IKACh blockers, the effects of these drugs were not affected by AT for 1 week. Conclusion: Our results suggest that the constitutively activated IKACh, which is not associated with M2 receptor and/or A1 receptor, increases under the condition of atrial electrical remodeling. Therefore, the selective IKACh blockers such as tertiapin and NIP-151 might be useful for the treatment of persistent AF.