Differential effects of human ether-a-go-go-related gene (HERG) blocking agents on QT duration variability in conscious dogs.
The effects of drugs that inhibit human ether-a-go-go-related gene (HERG) related cardiac potassium channels on the variability of QT duration as a sign of repolarisation instability were evaluated in conscious telemetered dogs. QT duration variability was determined using a beat-to-beat analysis before and after the infusions of HERG channel blocking agents. Variability was evaluated as increased mean width (P(width)) and length (P(length)) of Poincaré plots of 100 consecutive beats. As HERG channel blockers which are associated with arrhythmias of the torsades de pointes (TdP) type, dofetilide and sotalol were infused. Verapamil was used as an HERG channel blocker that is not associated with TdP. Dofetilide (0.01 and 0.03 mg/kg) dose-dependently prolonged QT(c) duration (12% and 16%). Dofetilide also induced an increase of QT variability that reached statistical significance for P(length) at the higher dose (64%). A dose of 3 mg/kg sotalol neither prolonged QT(c) duration nor QT duration variability. In contrast, at 10 mg/kg sotalol prolonged QT(c) duration (15%) and increased P(length) (33%). Doses of 0.1 and 0.3 mg/kg verapamil did not increase QT(c) duration nor QT time variability. QT duration variability in conscious dogs may be a useful preclinical marker to discriminate pro-arrhythmogenic and non-arrhythmogenic activities of HERG blocking agents.
Schneider
Johannes
J
Grünenthal GmbH, Department of Safety Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany. Johannes.Schneider@grunenthal.de
Hauser
Renate
R
Andreas
Jens-Otto
JO
Linz
Klaus
K
Jahnel
Ulrich
U
D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008297:Male; D010627:Phenethylamines / Q000009:adverse effects / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D014700:Verapamil / Q000009:adverse effects / Q000494:pharmacology
D002121:Calcium Channel Blockers; D051638:Ether-A-Go-Go Potassium Channels; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; D013015:Sotalol; D014700:Verapamil; C063533:dofetilide