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
May 31, 2011·Cardiovascular Research·Khai Le QuangStanley Nattel
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
Jun 9, 2005·Circulation·Antoine Ouvrard-PascaudFrederic Jaisser
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
Jan 26, 2008·The EMBO Journal·Dagmar HarzheimReinhard Seifert
Feb 24, 2015·Frontiers in Physiology·Pietro MesircaMatteo E Mangoni
Dec 16, 2016·Physiological Reviews·Christopher L-H Huang
Jul 24, 2004·American Journal of Physiology. Heart and Circulatory Physiology·Jingdong LiAnatoli N Lopatin
May 13, 2006·Circulation Research·Matteo E MangoniPhilippe Lory
Apr 6, 2005·Circulation·Anne RoyerFlavien Charpentier
May 14, 2005·Circulation Research·Marina CerroneSilvia G Priori
Apr 2, 2008·Circulation·Barnabas GellenJean-Jacques Mercadier
Oct 13, 2005·Physiological Genomics·Anne-Laure LeoniFlavien Charpentier
Jul 16, 2008·Physiological Reviews·Matteo E Mangoni, Joël Nargeot
May 15, 2015·The Journal of Toxicological Sciences·Junko KurokawaTetsushi Furukawa
Apr 8, 2014·American Journal of Physiology. Heart and Circulatory Physiology·Yanmin ZhangJames A Fraser