Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence.

Abstract

In a perspective,' it was pointed out At present, class III antiarrhythmic agents2 are favored increasingly to treat patients with serious tachycardias. Although these agents could be very powerful antiarrhythmics, our investigation suggests that the currently available drugs have electrophysiologic features that render them relatively less effective than an ideal class III agent could be and may even render them proarrhythmic. We review briefly the kinetic effects on action potential duration of current class III agents. Desirable properties for lengthening of action potential duration are derived, and a simple model illustrating the time-and voltagedependent actions of a hypothetical compound is developed. Finally, we apply current knowledge of sodium and potassium channel blockade to illustrate how therapy combining class I and class III effects might prove to be especially effective.

The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. II. Closed state reverse use-dependent block by 4-aminopyridine.

“…We present data indicating that block by 4-AP displays strong reverse use-dependent characteristics (cf. Hondeghem and Snyders, 1990); i.e., block is relieved at depolarized potentials or by rapid rates of stimulation. Our measurements suggest that 4-AP does not interact strongly with either the open or inactivated state of the /to channel, but rather produces block through a closed state binding mechanism.…”

“…The simulations presented suggest that such a multiple closed state binding mechanism could serve as a useful general model for various compounds that appear to display reverse use-dependent blocking characteristics of cardiac K + channels (cf. Hondeghem and Snyders, 1990).…”

Density and Kinetics of I Kr and I Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

“…2,3 Therefore, these I Kr blockers may act in a proarrhythmic manner during bradycardia, with minimal therapeutic potency against tachyarrhythmias. 4,5 Chromanol 293B has recently been reported to selectively block I Ks . Moreover, it prolonged APD in a frequency-independent manner in guinea pig and human ventricular myocytes.…”

Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

“…In general, the selective blockade of a rapidly activating component of the delayed rectifier K ϩ current manifests as a prolongation of action potential duration in cardiac myocytes and its electrocardiographic surrogate, the QT interval (Hondeghem and Synders 1990). It is of importance to mention that the human ether-à-gogo -related gene ( HERG ) has also been found to be primarily responsible for this type of K ϩ current (Sanguinetti et al 1995) and that haloperidol can block HERG channel expressed in frog oocytes (Suessbrich et al 1997).…”