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Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile
G Lande1, S Demolombe, A Bammert
1INSERM 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.
Objective:
The acquired long QT syndrome results most often from the action of I(Kr) 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 I(Kr) 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 I(Kr) 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 I(Kr) 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 I(Kr) from drugs that block the transient outward current, the sodium current or the calcium current.
Insights
Transgenic mice overexpressing a dominant-negative KvLQT1 isoform effectively screen for drugs blocking the I(Kr) current. This model distinguishes I(Kr) blockers from those affecting other cardiac currents.
Area of Science:
- Cardiology
- Pharmacology
- Genetics
Background:
- Acquired long QT syndrome is frequently caused by drugs blocking the I(Kr) channel, impacting cardiac repolarization.
- A transgenic (TG) mouse model overexpressing a dominant-negative KvLQT1 isoform was developed to evaluate drug effects in vivo.
Purpose of the Study:
- To assess the utility of a TG mouse model for screening drugs that block the I(Kr) channel.
- To differentiate I(Kr) blockers from drugs affecting other ion channels involved in cardiac repolarization.
Main Methods:
- Transgenic (FVB) mice overexpressing a dominant-negative KvLQT1 isoform were used.
- Six-lead ECGs were recorded in TG and wild-type (WT) mice after autonomic blockade.
- Drug effects on corrected QT interval (QTrc) and sinus period were analyzed.
Main Results:
- Specific I(Kr) blockers (dofetilide, E 4031, etc.) lengthened the sinus period in TG mice but not WT mice.
- Tedisamil (transient outward current blocker) prolonged QTrc in WT mice but not TG mice.
- Lidocaine and nicardipine showed distinct effects on QTrc and heart rhythm in both genotypes.
Conclusions:
- KvLQT1-invalidated TG mice serve as a valuable in vivo model to distinguish I(Kr) blocking drugs.
- This model can differentiate I(Kr) blockers from drugs targeting transient outward, sodium, or calcium currents.