Frequency-dependent effects of E-4031, almokalant, dofetilide and tedisamil on action potential duration: no evidence for “reverse use dependent” block

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)

Dofetilide

“…1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval.…”

Effects of the antiarrhythmic drug dofetilide on myocardial electrical activity: a computer modelling study

“…It has been recently suggested that dofetilide interacts with the channels in both the open and the inactivated states [17]. The interaction between dofetilide and receptor presents a very slow kinetics [11,13] and exhibits reverse use-dependence [2,16]. The increment in the dofetilide dose enhances the reverse-use dependence [2].…”

“…Experimental evidences suggest that the interaction between the drug and the receptor in the channel is produced in the open state (open channel block) rather than in the closed state [3,13,16]. Once the block has been produced, the effect persists during a long period at rest, suggesting that the drug does not dissociate when the channel is closed; the drug seems to be trapped within the channel [3,16].…”

“…An IC 50 in the nanomolar range has been experimentally measured in guinea pig ventricular myocytes, namely 8. [3,13,16]. Once the block has been produced, the effect persists during a long period at rest, suggesting that the drug does not dissociate when the channel is closed; the drug seems to be trapped within the channel [3,16].…”

“…[3,13,16]. Once the block has been produced, the effect persists during a long period at rest, suggesting that the drug does not dissociate when the channel is closed; the drug seems to be trapped within the channel [3,16]. It has been recently suggested that dofetilide interacts with the channels in both the open and the inactivated states [17].…”