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 degreesC, the selective IKr blockers dofetilide, E-4031 and d-sotalol, as well as ibutilide, an IKr 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 IK1 and IKr, and tedisamil, primarily a blocker of Ito and IKr, 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 IKr and IKs, and indapamide, a blocker of IKs, 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 degrees 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 degrees C to 37 degrees C altered both magnitude and frequency dependence of response to K+ channel blockers. These findings support the potential to selectively modulate atrial versus 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.