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The Novel Class III Antiarrhythmic Agent MS-551 Blocks the Cardiac Inward Rectifier With Greater Potency Than Sotalol or E-4031: Possible Relevance to Reverse Use Dependence

Departments of Cardiology and Clinical Pharmacology, and the Victor Chang Cardiac Research Institute, St. Vincent's Hospital, Sydney, Australia

Donald K. Martin

Departments of Cardiology and Clinical Pharmacology, and the Victor Chang Cardiac Research Institute, St. Vincent's Hospital, Sydney, Australia

Terence J. Campbell

Departments of Cardiology and Clinical Pharmacology, and the Victor Chang Cardiac Research Institute, St. Vincent's Hospital, Sydney, Australia

Background: The tendency for the electrophysiologic effect of class III antiarrhythmic agents (action potential prolongation) to be diminished at faster heart rates represents a major drawback of this class of drug and is usually referred to as "reverse use dependence." A novel class III agent, MS-551, has recently been reported to exhibit less reverse use dependence than E-4031. We set out to investigate whether this observation may be due to differential blockade of the inward rectifier current (i_K1) by these drugs.

Methods and Results: We recorded i_K1 using single channel methods and cell attached patch configurations, with standard patch clamp technology. Neither E-4031 nor racemic sotalol in concentrations up to 100 µM had any significant effect on the open probability or kinetics of i_K1 channels. MS-551 produced a concentration-dependent reduction in the open probability of i _K1 without altering the single-channel conductance. Openings to subconductance levels were abolished in three of six patches in which they had been frequently present in the absence of drug. MS-551 had no effect on mean channel open time but increased the slower component of the closed time.

Conclusions: MS-551, unlike E-4031 and sotalol, appears to produce significant blockade of the inwardly rectifying potassium channel at clinically relevant concentrations. We propose that this might provide a partial explanation for the observed differences in their response to rate changes.

Key Words: MS-551 • E-4031 • sotalol • class III antiarrhythmic drugs • cardiac action poten tial • potassium channel • use dependence.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 2, No. 1, 39-46 (1997)
DOI: 10.1177/107424849700200105


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