In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions.

Abstract

OBJECTIVES:

This study evaluated the in vivo electrophysiological effects of a highly selective slow delayed-rectifier K+-current blocker, HMR 1556, to gain insights into the consequences of selectively inhibiting the slow delayed-rectifier current in vivo.

METHODS:

Atrial and ventricular effective refractory periods, sinus node recovery time, Wenckebach cycle-length, atrial fibrillation duration and electrocardiographic intervals were measured before and after intravenous HMR 1556.

RESULTS:

HMR 1556 increased atrial and ventricular refractory periods (e.g. by 6 +/- 4% and 27 +/- 6% at cycle lengths of 360 and 400 ms, respectively), QT intervals and sinus-node recovery times. Beta-adrenoceptor blockade with nadolol abolished all effects except those on ventricular refractoriness and changed positive use-dependent effects on refractoriness to reverse use-dependent ones. In the presence of dofetilide to block rapid delayed-rectifier current, HMR 1556 effects were potentiated (e.g. atrial and ventricular refractory periods increased by 26 +/- 3% and 34 +/- 3% at cycle lengths of 360 and 400 ms, respectively). HMR 1556 reduced vagal atrial fibrillation duration from 1077 +/- 81 to 471 +/- 38 s, an effect abolished by nadolol and greatly potentiated by dofetilide (duration 77 +/- 30 s). HMR 1556 increased Wenckebach cycle length only in the presence of dofetilide.

CONCLUSIONS:

Slowed delayed-rectifier current inhibition affects atrial repolarization, sinus node function and atrial fibrillation in vivo, but only in the presence of intact beta-adrenergic tone, and delays ventricular repolarization even when beta-adrenoceptors are blocked. The slow delayed-rectifier current is particularly important when rapid delayed-rectifier current is suppressed, illustrating the importance of repolarization reserve.

• Authors: Hideko Nakashima, Uwe Gerlach, Dietmar Schmidt, Stanley Nattel
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 61 Issue 4 Pg. 705-14 (Mar 01 2004) ISSN: 0008-6363 [Print] England
• PMID: 14985067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Chromans
• HMR 1556
• Phenethylamines
• Potassium Channel Blockers
• Potassium Channels, Inwardly Rectifying
• Sulfonamides
• Nadolol
• dofetilide

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Arrhythmias, Cardiac (drug therapy, metabolism)
• Chromans (pharmacology, therapeutic use)
• Dogs
• Electrocardiography
• Electrophysiology
• Female
• Male
• Myocardium (metabolism)
• Nadolol (pharmacology)
• Phenethylamines (pharmacology)
• Potassium Channel Blockers (pharmacology, therapeutic use)
• Potassium Channels, Inwardly Rectifying (drug effects, metabolism)
• Sulfonamides (pharmacology, therapeutic use)