Effect of the Antifibrillatory Compound Tedisamil (KC-8857) on Transmembrane Currents in Mammalian Ventricular Myocytes
Abstract:The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic / antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique.
In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 μM TED (from 0.88±0.17 to 0.23±0.07 pA / pF, n=5, p<0.05), while its slow component (IKs) was reduced only by 5 μM TED (from 8.1±0.3 to 4.23±0.07 pA / pF, n=5, p<0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 μM TED decreased the amplitude of the transient outward current (Ito) from 20.3±4.9 to 13.9±2.8 pA / pF (n=5, p<0.05), accelerated its fast inactivation time constant from 8.3±0.6 to 3.5±0.5 ms (n=5, p<0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2±11.8 to 18.4±4.7 pA / pF (activator: 50 μM cromakalim; n=5, p<0.05). In dog myocytes 2 μM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the Ito currents were not affected by TED in concentration as high as 10 μM. The differences in Ito responsiveness between dog and rabbit are probably due to the different α-subunits of Ito in these species.
It is concluded that inhibition of several transmembrane currents, including IKr, IKs, Ito, IKATP and even INa, can contribute to the high antiarrhythmic / antifibrillatory potency of TED, underlying predominant Class III combined with I A / B type antiarrhythmic characteristics.
Document Type: Review Article
Affiliations: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Dom ter 12, P.O. Box 427, H-6701 Szeged, Hungary.
Publication date: December 1, 2004
More about this publication?
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.