Transgenic mice overexpressing human KvLQT1 dominant-negative isoform PartII: 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 tran sgenic (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 block ade 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 f ormula 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 eit her in TG or in wild-type (WT) mice but dose-dependently lengthened the sin us period in TG mice but not in WT mice. Other I-Kr blockers including E 40 31, haloperidol, sultopride, astemizole, cisapride and terikalant behaved s imilarly to dofetilide. Tedisamil, a blocker of the transient outward curre nt, dose-dependently prolonged the QTrc in WT mice but not in TG mice and a lso reduced the sinus rhythm in both WT and TG mice. Lidocaine dose-depende ntly shortened the QTrc interval in TG mice and also lengthened the P wave duration. Nicardipine dose-dependently shortened QTrc and also produced sin us arrest in both WT and TG mice. Conclusions: We conclude that KvLQT1-inva lidated TG mice discriminates in vivo drugs that blocks I-Kr from drugs tha t block the transient outward current, the sodium current or the calcium cu rrent. (C) 2001 Elsevier Science B.V. All rights reserved.