Small conductance calcium activated K+ channel inhibitor decreases stretch induced vulnerability to atrial fibrillation

Abstract

Background: Atrial dilation is an important risk factor for atrial fibrillation (AF) and animal studies have found that acute atrial dilation shortens the atrial effective refractory period (AERP) and increases the risk of AF. Stretch activated ion channels (SACs) and calcium channels play a role in this. The expression profile and calcium dependent activation makes the small conductance calcium activated K+ channel (KCa2.x) a candidate for coupling stretch induced increases in intracellular calcium through K+-efflux and thereby shortening of atrial refractoriness. Objectives: We hypothesized that KCa2.x channel inhibitors can prevent the stretch induced shortening of AERP and protect the heart from AF. Methods: The effect of KCa2 channel inhibitor (N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) 1 µM) was investigated using the isolated perfused rabbit heart preparation. To stretch the left atrium (LA) a balloon was inserted and inflated. AERP and action potential duration (APD) were recorded before and after atrial stretch. AF was induced by burst pacing the LA at different degrees of atrial stretch. Results: Stretching of the LA by increasing the balloon pressure from 0 to 20 mmHg shortened the AERP by 8.6 ± 1 ms. In comparison, the KCa2 inhibitor ICA significantly attenuated the stretch induced shortening of AERP to 2.5 ± 1.1 ms. Total AF duration increased linearly with atrial balloon pressure. This relationship was not found in the presence of ICA. ICA lowered the incidence of AF induction and total AF duration. Conclusion: The KCa2 channel inhibitor ICA attenuates the acute stretch induced shortening of AERP and decreases stretch induced vulnerability to AF.

Keywords

• Ion channel
• Atrial fibrillation
• SK channel
• KCa2
• Stretch
• Pharmacology