© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part II: Pharmacological profile
aINSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires G&R Laennec, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France
bExperimental and Molecular Cardiology Group, and Facility for Genetically Modified Mice, Academic Medical Center, Amsterdam, The Netherlands
* Corresponding author. Tel.: +33-2-4041-2949; fax: +33-2-4041-2950 denis.escande{at}nantes.inserm.fr
Objective: The acquired long QT syndrome results most often from the action of IKr blocking-drugs on cardiac repolarization. We have evaluated a transgenic (TG) mouse (FVB) overexpressing a dominant-negative KvLQT1 isoform, as an in vivo screening model for IKr blocking drugs. Results: In TG mice, six-lead ECGs demonstrated sinus bradycardia, atrioventricular block, and QTc prolongation. Various drugs were injected intraperitoneally after blockade of the autonomic nervous system and serial ECGs were recorded. The end of the initial rapid phase of the T wave corrected for heart rate using a formula for mouse heart (QTrc), was used as a surrogate for the QT interval. Dofetilide, a specific IKr blocker, did not prolong the QTrc interval either in TG or in wild-type (WT) mice but dose-dependently lengthened the sinus period in TG mice but not in WT mice. Other IKr blockers including E 4031, haloperidol, sultopride, astemizole, cisapride and terikalant behaved similarly to dofetilide. Tedisamil, a blocker of the transient outward current, dose-dependently prolonged the QTrc in WT mice but not in TG mice and also reduced the sinus rhythm in both WT and TG mice. Lidocaine dose-dependently shortened the QTrc interval in TG mice and also lengthened the P wave duration. Nicardipine dose-dependently shortened QTrc and also produced sinus arrest in both WT and TG mice. Conclusions: We conclude that KvLQT1-invalidated TG mice discriminates in vivo drugs that blocks IKr from drugs that block the transient outward current, the sodium current or the calcium current.
KEYWORDS Antiarrhythmic agents; Congenital defects; ECG; K-channel; Long QT syndrome; Repolarization
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