Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations.
OBJECTIVE
The aim was to study factors contributing to torsade de pointes in the acquired long QT syndrome.


METHODS
Anaesthetised rabbits or cats were given a continuous infusion of methoxamine and the class III agent almokalant (at a rate of 5 or 25 nmol.kg-1.min-1, respectively) and the effects on incidence of torsade de pointes and QT dispersion were examined. Effects of almokalant on action potentials recorded from Purkinje fibres and ventricular cells of rabbits and cats were also studied.


RESULTS
"High rate" infusion of almokalant prolonged the QTc interval [from 162(SEM 6.2) ms to 211 (5.3) ms, p < 0.001] and initiated torsade de pointes in 9/10 rabbits after a dose of 391(116.3) nmol.kg-1. During "low rate" infusion, 1/8 rabbits developed torsade de pointes (p = 0.0029) despite infusion of 900 nmol.kg-1 almokalant and QTc prolongation from 162(3.6) ms to 230(12.6) ms (p < 0.01). In eight separate rabbits given the high rate infusion of almokalant, seven developed torsade de pointes and the QTc dispersion increased from 15(1.7) ms to 32(5.6) ms (p < 0.05). In six rabbits given the low rate infusion, none developed torsade de pointes (p = 0.0023), and the QTc dispersion was unaltered. In six cats, high rate infusion induced a QT interval lengthening from 241(6.0) ms to 349(8.0) ms (p < 0.001), but in only one cat was torsade de pointes initiated and preceded by a marked increase in QT dispersion (from 22 ms to 78 ms). In vitro, almokalant caused a marked lengthening of the action potential duration and early afterdepolarisations in Purkinje fibres but not in ventricular muscle cells of the rabbit. In the cat, however, almokalant induced a homogeneous prolongation of the action potential duration in both cell types, and early afterdepolarisations were never observed.


CONCLUSIONS
The rate of infusion of repolarisation delaying agents may influence the dispersion of repolarisation and play a decisive role in the initiation of torsade de pointes.
Carlsson
L
L
Astra Häsle AB, Mölndal, Sweden.
Abrahamsson
C
C
Andersson
B
B
Duker
G
G
Schiller-Linhardt
G
G
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D002415:Cats; D004334:Drug Administration Schedule; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000150:complications* / Q000503:physiopathology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D008729:Methoxamine; C074334:almokalant