Effect of the antifibrillatory compound tedisamil (KC-8857) on transmembrane currents in mammalian ventricular myocytes

Jost, Norbert and Virág, László and Hála, O. and Varró, András and Thormahlen, D. and Papp, Gyula (2004) Effect of the antifibrillatory compound tedisamil (KC-8857) on transmembrane currents in mammalian ventricular myocytes. Current Medicinal Chemistry, 11 (24). pp. 3219-3228. ISSN 0929-8673

Text 1109502.pdf Restricted to Registered users only Download (423kB) | Request a copy

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 (I-Kr) was largely diminished by 1 muM TED (from 0.88 +/- 0.17 to 0.23 +/- 0.07 pA/pF, n=5, p<0.05), while its slow component (I-Kr) was reduced only by 5 muM TED (from 8.1 +/- 0.3 to 4.23 +/- 0.07 pA/pF, n=5, p<0.05). TED did not significantly change the I-Kr and I-Kr kinetics. In rabbit myocytes 1 muM TED decreased the amplitude of the transient outward current (I-to) 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 (I-KATP) from 38.2 +/- 11.8 to 18.4 +/- 4.7 pA/pF (activator: 50 muM cromakalim; n=5, p<0.05). In dog myocytes 2 muM TED blocked the fast sodium current (I-Na) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (I-K1), the inward calcium (I-Ca) and even the I-to currents were not affected by TED in concentration as high as 10 muM. The differences in I-to responsiveness between dog and rabbit are probably due to the different alpha-subunits of I-to in these species. It is concluded that inhibition of several transmembrane currents, including I-Kr, I-Ks, I-to, I-KATP and even I-Na, can contribute to the high antiarrhythmic/antifibrillatory potency of TED, underlying predominant Class III combined with I A/B type antiarrhythmic characteristics.

Actions (login required)

Edit Item