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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers

Elizabeth P. Baskin and Joseph J. Lynch Jr.
Journal of Pharmacology and Experimental Therapeutics April 1998, 285 (1) 135-142;
Elizabeth P. Baskin
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Joseph J. Lynch Jr.
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 1
1 Apr 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers

Elizabeth P. Baskin and Joseph J. Lynch
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 135-142;

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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers

Elizabeth P. Baskin and Joseph J. Lynch
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 135-142;
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