Effect of the antifibrillatory compound tedisamil (KC-8857) on transmembrane currents in mammalian ventricular myocytes.
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 microM 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 microM 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 microM 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 (IKATP) from 38.2+/-11.8 to 18.4+/-4.7 pA/pF (activator: 50 microM cromakalim; n=5, p<0.05). In dog myocytes 2 microM 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 I(to) currents were not affected by TED in concentration as high as 10 microM. 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 IKr, IKs, I(to), 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.
Jost
N
N
Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, Albert Szent-Györgyi Medical Center, University of Szeged, Hungary. papp@phcol.szote.u-szeged.hu
Virág
L
L
Hála
O
O
Varró
A
A
Thormählen
D
D
Papp
J Gy
JG
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D007473:Ion Channels; C059921:tedisamil