Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K⁺ current blocker

Abstract

1Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2 The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3 Tedisamil (1-4mgkg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4 Tedisamil dose-dependently lengthened the effective refractory period and prevented electricallyinduced VF. In vivo, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5 Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA‐7, a furoquinoline alkaloid derivative, in rat heart

“…In rat heart this antiarrhythmic action is mediated mainly through blockade of the I to , I ss and Na + channels, although currents through the I K1 and L-type Ca 2+ channels are also altered somewhat. These actions are similar to those found for other class I and class III antiarrhythmic agents (Castle, 1990;Dukes et al, 1990;Beatch et al, 1991;Clark et al, 1995), but are unique in the relatively potent I to suppression, safety margin of I K1 suppression and minimal inhibition on I Ca .…”

“…I to is one of the predominant repolarizing currents in the action potential of several mammalian cardiac tissues, including human atrium and ventricle (Escande et al, 1987;NaÈ bauer et al, 1993) and in rat and rabbit ventricular myocytes (Josephson et al, 1984;Giles & Imaizumi, 1988). The potential importance of the I to in the origin of ventricular arrhythmias and as a target for class III antiarrhythmic drugs has also been suggested (Beatch et al, 1991;Sanguinetti, 1992;NaÈ bauer et al, 1993). An increase in the electrophysiological heterogeneity between the epicardium and endocardium has also been shown to be one of the prominent ischaemia and reperfusion-induced alterations (Ruy et al, 1979;Kimura et al, 1986).…”

“…The large epicardial I to may contribute to this electrical inhomogeneity and to the genesis of ventricular arrhythmias via phase 2 re-entry (Litovsky & Antzelevitch, 1988;Clark et al, 1993;Di Diego & Antzelevitch, 1994). The ®nding that blockers of this current (such as tedisamil) can reduce the incidence of ischaemia-induced extrasystolic activity suggests that compounds which block the I to could exert an antiarrhythmic eect (Beatch et al, 1991). In the present study, the fact that the extent of HA-7 induced prolongation of APD was attenuated by an I to channel blocker 4-AP together with the voltage clamp experiments which have demonstrated that HA-7 produced a signi®cant inhibition of I to , suggesting that the prolongation of APD by HA-7 could be attributed to the I to inhibition.…”

Pharmacology of a cloned potassium channel from mouse brain (MK‐1) expressed in CHO cells: effects of blockers and an ‘nactivation peptide’

“…Beatch et al, 1991), was a dramatic blocker of MK-1, producing a marked inactivation of the current in both peptidemodified and unmodified states. This action is consistent with tedisamil being an open-channel blocker, as previously suggested (Dukes et al, 1990).…”

Electrophysiological mechanisms for antiarrhythmic efficacy and positive inotropy of liriodenine, a natural aporphine alkaloid from Fissistigma glaucescens

“…The role of the transient outward current in the genesis of ventricular arrhythmia and as a target for Class III antiarrhythmic drugs has also been suggested (Beatch et al, 1991;Sanguinetti, 1992;Nabauer et al, 1993). An increase in the electrophysiological heterogeneity between the epicardium and endocardium has been well demonstrated as one of the prominent ischaemia and reperfusion-induced alterations (Ruffy et al, 1979;Kimura et al, 1986).…”