Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization.
BACKGROUND
QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres.


RESULTS
Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at 0.5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25% in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater extent than APD(90).


CONCLUSIONS
Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.
Terrar
Derek A
DA
University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, United Kingdom. Derek.terrar@pharm.ox.ac.uk
Wilson
C M
CM
Graham
S G
SG
Bryant
S M
SM
Heath
B M
BM
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D020117:Cisapride / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010627:Phenethylamines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D016593:Terfenadine; D013015:Sotalol; D014700:Verapamil; D009543:Nifedipine; D006220:Haloperidol; C063533:dofetilide; D020117:Cisapride