DIFFERENTIAL ATRIAL VERSUS VENTRICULAR ACTIVITIES OF CLASS-III POTASSIUM CHANNEL BLOCKERS

The atrial versus ventricular activities of Class III agents with diff ering K+ channel blocking profiles were assessed in vitro in ferret at rial and right ventricular papillary muscles. In concentration-effecti ve refractory period (ERP) response studies at 2 Hz and 32 degrees C, the selective I-Kr blockers dofetilide, E-4031 and d-sotalol, as well as ibutilide, an I-Kr blocker also reported to enhance inward Na+ curr ent, 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-to and I-Kr, increas ed atrial ERP with approximately 10-fold greater potencies than ventri cular 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 ''balanc ed'' activities, increasing atrial and ventricular ERP with equivalent potencies and efficacies (+40-60% increases for both tissues). Freque ncy-dependence profiles at 32 degrees C varied between atrial and vent ricular tissues, and there was no general correspondence between atria l versus ventricular selectivity and frequency-dependence profiles. In the papillary muscle preparation, increasing temperature from 32 degr ees C to 37 degrees C altered both magnitude and frequency dependence of response to Kt channel blockers. These findings support the potenti al to selectively modulate atrial versus ventricular refractoriness wi th the targeting of appropriate K+ channel subtypes, and further demon strate the differential frequency and temperature dependence of varyin g K+ channel subtype blockade. Ultimately, the identification and targ eting of an appropriate K+ channel subtype or mix of subtypes may resu lt in the achievement of optimal atrial-selective activity for the tre atment of supraventricular arrhythmias.