The new antiarrhythmic substance AWD 23-111 inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.
The effects of N-(dicyclohexyl-carbamoylmethyl)-N-(3-diethylamino-propyl)-4-nitro -benzamide hydrochloride (AWD 23-111), a novel antiarrhythmic compound, were studied in isolated cardiomyocytes of guinea pigs. Using whole-cell configuration of the patch-clamp technique AWD 23-111 was tested for its ability to block the delayed rectifier potassium channel (IK). In guinea pig ventricular myocytes the current is composed of two components: IKr, a rapidly activating current and IKs, a slowly activating component which were discriminated by their different activation and deactivation behaviour. In this preparation AWD 23-111 displayed concentration dependent inhibitory effects on IKr as well as on IKs in the tested concentration range between 1 and 100 mumol/l. This blocking effect was independent of the stimulation frequency (0.2, 1 and 2 Hz). There was no influence of AWD 23-111 on the amplitude of L-type calcium whole-cell currents. The compound significantly prolonged action potential duration (APD) at a stimulation frequency of 2 Hz (1 and 10 mumol/l). At 0.2 Hz there was no effect on APD. Our results suggest that AWD 23-111 blocks both components of IK without a reverse use-dependent effect on APD which limits the therapeutic potential of most other class III agents.
Klapperstück
M
M
Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle Wittenberg, Saale, Germany.
Markwardt
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated