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 .British Journal of Pharmacology (2005) 146 , 561–567. doi: 10.1038/sj.bjp.0706352