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 IKrblockers 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 Itoand 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 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.
Footnotes
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Send reprint requests to: Elizabeth P. Baskin, WP46–300, Merck Research Laboratories, West Point, PA 19486.
- Abbreviations:
- ERP
- effective refractory period
- IKr
- rapidly activating component of delayed rectifier K+ current
- IKs
- slowly activating component of delayed rectifier K+ current
- Ito
- transient outward K+ current
- IK1
- inward rectifier K+ current
- Isus or Iso
- sustained outward atrial K+ current
- Received September 17, 1997.
- Accepted December 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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