PMID: 11334836May 4, 2001Paper

Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile

Cardiovascular Research
G LandeDenis Escande

Abstract

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. 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...Continue Reading

Citations

Nov 23, 2010·Molecular Neurobiology·David Henry VandaelEmilio Carbone
Jun 28, 2005·Progress in Biophysics and Molecular Biology·Matteo E MangoniJoël Nargeot
Mar 18, 2003·Life Sciences·Alysia A ChavesCynthia A Carnes
Oct 1, 2010·Journal of Cardiovascular Pharmacology·Zhenjiang Yang, Katherine T Murray
May 6, 2008·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Junji MorokumaMichael Levin
Apr 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Matteo E MangoniJoël Nargeot
Apr 22, 2015·International Journal of Cardiology·Wen-Chin TsaiYi-Jen Chen
Jul 27, 2011·Journal of Molecular and Cellular Cardiology·Olivier BignolaisSophie Demolombe
Feb 22, 2005·The Journal of Pharmacy and Pharmacology·Vincenzo CalderoneMaria Cristina Breschi
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Jul 24, 2004·American Journal of Physiology. Heart and Circulatory Physiology·Jingdong LiAnatoli N Lopatin
Jul 16, 2008·Physiological Reviews·Matteo E Mangoni, Joël Nargeot
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Apr 8, 2014·American Journal of Physiology. Heart and Circulatory Physiology·Yanmin ZhangJames A Fraser

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