Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile.
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.
Lande
G
G
INSERM 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.
Demolombe
S
S
Bammert
A
A
Moorman
A
A
Charpentier
F
F
Escande
D
D
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D003521:Cyclopropanes; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers; D013449:Sulfonamides; C059921:tedisamil; C063533:dofetilide