Comparison of four rate-correction algorithms for the ventricular repolarization period in assessing net effects of IKr blockers in dogs.
The utility of corrected and uncorrected QT interval changes for assessing net repolarization delay by I(Kr) (a rapid component of delayed rectifier K(+) currents) blockers was assessed in halothane-anesthetized dogs using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of dl-sotalol (0.2 - 2 mg/kg) prolonged the MAP duration and RR interval, while terfenadine (3 mg/kg) increased the MAP duration but transiently shortened RR interval. The order of correlation coefficient between the MAP duration at a pacing cycle length of 400 ms and MAP duration itself or that with arithmetical correction was uncorrected > Van de Water = Matsunaga > Fridericia > Bazett. These results suggest that Matsunaga's and Van de Water's formulae would better predict the net repolarization delay in the in vivo canine model. Also, the risk of drug candidates that may prolong the QT interval should be judged by change in uncorrected QT interval as well as corrected QT interval.
Takahara
Akira
A
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Sugiyama
Atsushi
A
Satoh
Yoshioki
Y
Hashimoto
Keitaro
K
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D011237:Predictive Value of Tests; D018570:Risk Assessment; D013015:Sotalol / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects*
D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D016593:Terfenadine; D013015:Sotalol