Effect of the Antifibrillatory Compound Tedisamil (KC-8857) on Transmembrane Currents in Mammalian Ventricular Myocytes

N.      Jost; L.      Virag; O.      Hala; A.      Varro; D.      Thormahlen; J.   Gy.   Papp

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.

Keywords: tedisamil (kc-8857), cellular mechanism of action, transmembrane ion currents, cardiomyocytes

« Previous Next »