Differential effects of antiarrhythmic agents on post-pause repolarization in cardiac Purkinje fibres.
1. Marked action potential duration (APD) prolongation with agents such quinidine is often a precursor of early after-depolarizations and triggered activity, thought to be underlying mechanism of torsade de pointes. Episodes of torsade de pointes commonly occur following a pause. 2. We recently demonstrated that quinidine, but not disopyramide, produced marked further prolongation of APD immediately following pauses of 2-10s interpolated into a basic drive train in canine Purkinje fibres. 3. We report here experiments aimed at further elucidating the mechanisms of this phenomenon. 4. We used standard microelectrode techniques to record action potentials from canine Purkinje fibres driven at a baseline interstimulus interval (ISI) of 1000 ms. 5. We were able to reproduce the phenomenon of post-pause prolongation of APD with amitriptyline, which blocks both sodium and potassium channels, as does quinidine. Furthermore, we showed that the kinetics of interaction of amitriptyline, with the sodium channel, are similar to those known to exist for quinidine (time constant of recovery from blockade 2.3 +/- 0.6s). 6. In contrast, we were unable to reproduce post-pause prolongation of APD with three pure class III antiarrhythmic agents, D-sotalol, clofilium and dofetilide. 7. We propose that quinidine and amitriptyline behave similarly, in that they both produce two separate, opposing effects on APD. During a pause, the sodium channel-blocking action of these compounds diminishes exponentially, allowing the potassium channel blocking effect to become manifest as post-pause prolongation of APD. None of D-sotalol, clofilium or dofetilide exhibits significant sodium channel blockade and, thus, these agents do not manifest post-pause prolongation of repolarization. Disopyramide does produce sodium channel blockade, but recovery from this effect is much slower than for quinidine or amitriptyline (time constant 12-50s). Thus, we propose insufficient recovery occurs during the intervals under study to uncover the action potential-prolonging effect of the unopposed potassium channel blockade for disopyramide.
Wyse
K R
KR
Department of Cardiology, St. Vincent's Hospital, Sydney, Australia.
Bursill
J A
JA
Campbell
T J
TJ
D000200:Action Potentials; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004206:Disopyramide / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D010627:Phenethylamines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D015222:Sodium Channels; D013449:Sulfonamides; D000639:Amitriptyline; C022799:clofilium; D013015:Sotalol; D004206:Disopyramide; D011802:Quinidine; C063533:dofetilide