Reduction of repolarization reserve by halothane anaesthesia sensitizes the guinea-pig heart for drug-induced QT interval prolongation.
The utility of halothane-anaesthetized guinea-pigs as an in vivo model for predicting the clinical potential of a drug to induce QT interval prolongation was assessed using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of D-sotalol (0.3 mg kg(-1)) and terfenadine (0.3 mg kg(-1)), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 32+/-7 and 23+/-6 ms, respectively, whereas chromanol 293B (1 mg kg(-1)), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 33+/-8 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. The MAP duration at the control was shortened by decreasing the pacing cycle length from 400 to 200 ms, but the MAP duration at each cycle length was prolonged by D-sotalol. The formulas of Van de Water, Matsunaga, Fridericia and Bazett showed good correlation of the repolarization period when compared with the MAP duration at a pacing cycle length of 400 ms. The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect drug-induced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.
Takahara
Akira
A
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi 409-3898, Japan.
Sugiyama
Atsushi
A
Hashimoto
Keitaro
K
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D000465:Algorithms; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015203:Reproducibility of Results; D013015:Sotalol / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016593:Terfenadine / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D018685:Anesthetics, Inhalation; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D006634:Histamine H1 Antagonists; D004364:Pharmaceutical Preparations; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D016593:Terfenadine; D013015:Sotalol; D006221:Halothane