Effects of the antiarrhythmic agent EGIS-7229 (S 21407) on calcium and potassium currents in canine ventricular cardiomyocytes.
Based on earlier pharmacological studies performed using conventional microelectrodes EGIS-7229 (S 21407), the novel antiarrhythmic candidate, was suggested to have a combined mode of action in cardiac tissues isolated from various mammalian species. In order to characterize the electrophysiological effects of the compound, its effects on calcium and potassium currents of isolated canine ventricular cardiomyocytes were studied in the present work using the whole cell configuration of the patch clamp technique. L-type Ca current (ICa) was significantly depressed by EGIS-7229 at concentrations of 3 microM or higher with no concomitant changes in the voltage-dependence of activation and time course of inactivation of ICa. The drug reversibly suppressed the rapid component of the delayed rectifier K current (IKr) in a concentration-dependent manner, having a K0.5 value of 1.1+/-0.1 microM and a slope factor of close to unity (1.23+/-0.16), indicating that probably one single binding site of high affinity may be involved in binding of EGIS-7229 to the IKr channel. In contrast, no changes in the slow component of the delayed rectifier K current (IKs) was observed with the compound up to the concentration of 100 microM, even if the current was fully activated by 8-bromo-cAMP. At a concentration of 10 microM or higher, EGIS-7229 caused also a moderate but significant reduction in the inward rectifier K current (IK1) and the transient outward K current (Ito) with no change in the voltage-dependence of activation and steady-state inactivation of Ito. Present results indicate that EGIS-7229 can be considered as a selective IKr blocker at low (1 microM) concentration; however, its combined (class III + IV) mechanism of action is evident at concentrations of 3 microM or higher. Suppression of ICa may explain the lack of development of early afterdepolarizations in the presence of EGIS-7229, predicting a relatively safe clinical application in contrast to pure class III compounds.
Magyar
J
J
Department of Physiology, University Medical School of Debrecen, Hungary.
Bányász
T
T
Fülöp
L
L
Szentandrássy
N
N
Körtvély
A
A
Kovács
A
A
Szénási
G
G
Nánási
P P
PP
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; C106729:EGIS 7229; D015221:Potassium Channels; D011724:Pyridazines