Antiarrhythmic therapy in general has a problem ‘especially in the treatmentof ventricular
arrhythmias’ that the compounds have proarrhythmic potentialwhich is due to the same
cellular mechanism that is responsible for theirantiarrhythmic properties. Drug-induced
arrhythmia can be attributed to eitherexcessive conduction slowing (e.g. with class
Ia or Ic Na+ channel blockers) orexcessive prolongation of ventricular action potential
duration (APD) (e.g. withclass III antiarrhythmic agents), or both. The aim of the
presents study was toinvestigate the antiarrhythmic and proarrhythmic potential of
somepharmacological agents. We therefore thoroughly investigated and compared thekinetics
of these Na+ channel blockers to provide further experimental data andto differentiate
between their antiarrhythmic and proarrhythmic properties. Inthe present study, conventional
microelectrode and patch clamp techniques wereused to measure the action potential
(AP) parameters and the transmembrane ioniccurrents underlying the AP, respectively.
The results show that GS967 inhibitsINaP similarly to the class Ib antiarrhythmic
drug mexiletine, but with higherpotency and three fold faster offset kinetics. Both
GS967 and mexiletinesignificantly depressed V+max at high stimulation rates. Flecainide
lengthenedAPD only at faster stimulation frequencies having cycle length (CL) shorter
than500 ms and increased the APDs of early extrasystoles noticeably. Moreover,flecainide
reduced V+max in the entire frequency range exhibiting much sloweroffset kinetics
than mexiletine. Similarly, quinidine depressed V+maxuse-dependently showing slower
offset kinetics than mexiletine. Although,quinidine slowed the restitution kinetics
of APD, however, it exhibited areverse rate-dependent prolongation on APD90. In addition,
acutedesethylamiodarone (DEA) administration exerted a mild but not reverserate-dependent
APD90 prolongation and significant V+max inhibition at short CLs.Furthermore, cannabidiol
lengthened APD90 significantly at the concentration of5 µM without changing any other
AP parameter significantly. These findingssuggest that the frequency dependence, restitution
kinetics and onset kineticsare important electrophysiological determinants which can
discriminate Na+channel blockers with proarrhythmic and antiarrhythmic potential.
Moreover, thecurrent data suggest that compounds which do not block impulse conduction
atnormal heart rate and have a fast recovery such as mexiletine and GS967, can bepromising
for future drug development. Also the interesting big APD lengtheningeffect on the
early extrasystole observed with flecainide would be probablyuseful but the effect
on sodium current at normal heart rate can be potentiallyproarrhythmic. Furthermore,
the absence of an increase in dispersion ofventricular repolarization with DEA correlates
with its clinically observedlower incidence of proarrhythmia. In addition, the physicians
should be aware inrecognizing of the deleterious effects of compounds that affect
therepolarization reserve in co-morbid or polypharmacy patient.
