Species plays an important role in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated Purkinje fibers.
BACKGROUND
Although isolated Purkinje fibers (PFs) often are used to evaluate the electrophysiologic effects of new drugs in terms of prolongation of action potential duration (APD) and induction of early afterdepolarizations (EADs), species differences in this respect remain elusive. We evaluated potential species-specific differences in drug-induced prolongation of APD and EADs in isolated PF from various species.


RESULTS
Using a microelectrode technique, PFs (n = 7 to 11 per species) were isolated from hearts of rabbits, guinea pigs, dogs, swine, goats, or sheep, superperfused in Tyrode's solution with dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M) for 25 minutes, and stimulated at 1 Hz for 20 minutes and at 0.2 Hz for another 5 minutes. Dofetilide increased APD at 90% repolarization (APD90) at 1 Hz by 83% (rabbit), 24% (guinea pig), 65% (dogs), 18% (swine), 61% (goat), and 30% (sheep), and prolonged APD90 at 0.2 Hz by 187% (rabbit), 31% (guinea pig), 154% (dog), 17% (swine), 61% (goat), and 8% (sheep). Similarly, quinidine changed APD90 by 93% (rabbit), 0% (guinea pig), 16% (dog), -3% (swine), 0% (goat), and -24% (sheep) at 1 Hz, and by 124% (rabbit), 15% (guinea pig), 53% (dog), 17% (swine), 11% (goat), and -39% (sheep) at 0.2 Hz in PF. During superfusion of dofetilide or quinidine, EADs occurred in most preparations in rabbit PFs at 0.2 Hz, but not in any of the PFs from other species at 0.2 Hz.


CONCLUSIONS
Our study demonstrates that species plays an important role in the response of PF to drug-induced prolongation of APD and EADs. Rabbit PFs constitute the most sensitive model for detecting drug-induced, potential long APD and proarrhythmogenic effects in vitro.
Lu
H R
HR
Department of Cardiovascular Safety Pharmacology, Janssen Research Foundation, Beerse, Belgium. hlu@janbe.jnj.com
Mariën
R
R
Saels
A
A
De Clerck
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004594:Electrophysiology; D066298:In Vitro Techniques; D008322:Mammals; D010627:Phenethylamines / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D011802:Quinidine; C063533:dofetilide