Related Experiment Videos
Frequency-dependent effects of E-4031, almokalant, dofetilide and tedisamil on action potential duration: no evidence
1Institut für Pharmakologie, Universität-Gesamthochschule Essen, Germany.
Insights
New antiarrhythmic drugs like E-4031 and dofetilide show reverse use dependency, requiring regular heartbeats for full effect. Almokalant and tedisamil, however, prolong action potential duration even at rest.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Class III antiarrhythmic drugs can exhibit "reverse use dependency," preferentially blocking channels when the heart is at rest.
- Understanding drug-channel interactions is crucial for developing effective antiarrhythmic therapies.
Purpose of the Study:
- To investigate the frequency dependence of four new antiarrhythmic compounds on action potential duration (APD).
- To scrutinize the concept of reverse use dependency and gather evidence for drug-channel interactions.
Main Methods:
- Assessed APD in guinea-pig papillary muscles and delayed rectifier currents in ventricular myocytes.
- Evaluated drug effects at various stimulation frequencies (0.2–1 Hz) and during periods of quiescence.
Main Results:
- E-4031, almokalant, dofetilide, and tedisamil prolonged APD concentration-dependently.
- E-4031 and dofetilide required regular pacing for full APD prolongation, indicating reverse use dependency.
- Almokalant and tedisamil prolonged APD even during rest, with almokalant showing partial recovery.
Conclusions:
- E-4031 and dofetilide exhibit reverse use dependency, impacting their therapeutic application.
- Almokalant and tedisamil demonstrate different interaction profiles, with almokalant showing less dependence on pacing frequency.
Abstract:
Antiarrhythmic drugs with class III action are incriminated by "reverse use dependency" which implies preferential block of resting channels (Hondeghem and Snyders 1990). The purpose of the present study was to investigate the frequency dependence of the effects of four new antiarrhythmic compounds on action potential duration (APD) in guinea-pig papillary muscle and on delayed rectifier in guinea-pig ventricular myocytes in order to scrutinize the concept of reverse use dependency and to obtain evidence for drug-channel interaction. In guinea-pig papillary muscles, E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4- (4-methylsulfonyl-aminobenzoyl)piperidine), almokalant, dofetilide and tedisamil prolonged APD in a concentration-dependent manner. Drug-induced APD prolongation was not affected significantly by low rates of stimulation (0.2 to 0.5 Hz. In order to investigate whether drug-channel interaction takes places during rest, regular stimulation (1 Hz) was interrupted by three 30-min periods of quiescence. Drug was added at the beginning of the second period of rest, the third period was interposed at steady state of drug action. With E-4031 and dofetilide no change in shape of the first AP after the initial 30 min of drug exposure was observed as compared with pre-drug control, but regular stimulation was required for the full effect to develop. APD did not recover to pre-drug values after the third period of quiescence. With almokalant and tedisamil, however, the first APD after wash-in was already prolonged and the effects increased further with regular pacing. Only with almokalant but not with tedisamil did APD recover during rest.(ABSTRACT TRUNCATED AT 250 WORDS)