In a limited number of cells, I(to) in human ventricular myocytes shows no dramatic differences between cells derived from failing and non-failing hearts. The characteristics of I(to) in human cells were similar though not identical to I(to) in rat heart cells. This current may be a potential target for antiarrhythmic drug action.

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)

H 345/52 blocks I(Kr) with high potency and I(Ca) with somewhat lower potency and was found to delay ventricular repolarisation without substantially increasing temporal or spatial dispersion and without inducing early after-depolarisations or TdP.

No abstract

1 Tedisamil is a new antiarrhythmic drug with predominant class III action. The aim of the present study was to investigate the blocking pattern of the compound on the transient outward current (I to ) in human subepicardial myocytes isolated from explanted left ventricles. Using the single electrode whole cell voltage clamp technique, I to was analysed after appropriate voltage inactivation of sodium current and block of calcium current. 2 Tedisamil reduced the amplitude of peak I to , but did not a ect the amplitude of non-inactivating outward current. The drug accelerated the apparent rate of I to inactivation. The reduction in time constant of I to inactivation depended on drug concentration, the apparent IC 50 value was 4.4 mM. 3 Tedisamil a ected I to amplitude in a use-dependent manner. After 2 min at 780 mV, maximum block of I to was reached after 4 ± 5 clamp steps either at the frequency of 0.2 or 2 Hz, indicating that the block was not frequency-dependent in an experimentally relevant range. Recovery from block was very slow and proceeded with a time constant of 12.1+1.8 s. Also in the presence of drug, a fraction of channels recovered from inactivation with a similar time constant as in control myocytes (i.e. 81+40 ms and 51+8 ms, respectively, n.s.). 4 From the onset of fractional block of I to by tedisamil during the initial 60 ms of a clamp step, we calculated k 1 =9610 6 mol 71 s 71 for the association rate constant, and k 2 =23 s 71 for the dissociation rate constant. The resulting apparent K D was 2.6 mM and is similar to the IC 50 value.5 The e ects of tedisamil on I to could be simulated by assuming a four state channel model where the drug binds to the channel in an open (activated) conformation. It is concluded that in human subepicardial myocytes tedisamil is an open channel blocker of I to and that this e ect probably contributes to the antiarrhythmic potential of this drug.