Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers

Abstract

The atrial versus ventricular activities of Class III agents with differing K⁺ channel blocking profiles were assessed in vitro in ferret atrial and right ventricular papillary muscles. In concentration-effective refractory period (ERP) response studies at 2 Hz and 32°C, the selective I_Krblockers dofetilide, E-4031 and d-sotalol, as well as ibutilide, an I_Kr blocker also reported to enhance inward Na⁺ current, displayed markedly greater efficacies in increasing atrial ERP (+90–110%) versus ventricular ERP (+10–20%). RP58866, a blocker of I_K1 and I_Kr, and tedisamil, primarily a blocker of I_toand I_Kr, increased atrial ERP with approximately 10-fold greater potencies than ventricular ERP, but with similar efficacies for both tissues (+60–80% with RP58866; +150–160% with tedisamil). Azimilide, a blocker of I_Kr and I_Ks, and indapamide, a blocker of I_Ks, displayed essentially “balanced” activities, increasing atrial and ventricular ERP with equivalent potencies and efficacies (+40–60% increases for both tissues). Frequency-dependence profiles at 32°C varied between atrial and ventricular tissues, and there was no general correspondence between atrial versus ventricular selectivity and frequency-dependence profiles. In the papillary muscle preparation, increasing temperature from 32°C to 37°C altered both magnitude and frequency dependence of response to K⁺ channel blockers. These findings support the potential to selectively modulate atrialversus ventricular refractoriness with the targeting of appropriate K⁺ channel subtypes, and further demonstrate the differential frequency and temperature dependence of varying K⁺ channel subtype blockade. Ultimately, the identification and targeting of an appropriate K⁺ channel subtype or mix of subtypes may result in the achievement of optimal atrial-selective activity for the treatment of supraventricular arrhythmias.