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Vol. 285, Issue 1, 135-142, April 1998

Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers

Elizabeth P. Baskin and Joseph J. Lynch, Jr.

Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania

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 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°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 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.

0022-3565/98/2851-0135$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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