Characterization of the halothane-anesthetized guinea-pig heart as a model to detect the K+ channel blocker-induced QT-interval prolongation.
Our previous study using the urethane-anesthetized guinea-pig model has shown that an I(Ks) blocker chromanol 293B hardly affects the QT interval itself nor potentiates the I(Kr) blocker-induced QT-interval prolongation. The former is in good accordance with the previous results in the human isolated intact ventricular tissue, but the latter is in sharp contrast with them. In this study, we characterized the ventricular repolarization ability of a newly developed halothane-anesthetized guinea-pig model by using I(Kr) and I(Ks) blockers. Intravenous administration of a selective I(Kr) blocker d-sotalol (3 mg/kg) prolonged the QT interval by +27 ms. On the other hand, intravenous administration of chromanol 293B (1 mg/kg) prolonged the QT interval by +35 ms, and additional administration of the same dose of d-sotalol further prolonged the QT interval by +48 ms. These results suggest that the abundance of the repolarization reserve among the current and previous models may be in the order of the urethane-anesthetized guinea-pig heart>human intact ventricular tissue>halothane-anesthetized guinea-pig heart. Thus, the halothane-anesthetized guinea-pig model may be considered to be more sensitive than the previous models in predicting the QT-interval prolonging effects of new drugs in patients with high risks for the acquired long QT syndrome.
Takahara
Akira
A
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
Sugiyama
Atsushi
A
Hashimoto
Keitaro
K
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006221:Halothane; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D000889:Anti-Arrhythmia Agents; D002839:Chromans; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D013015:Sotalol; D006221:Halothane