Reduction of repolarization reserve by halothane anaesthesia sensitizes the guinea‐pig heart for drug‐induced QT interval prolongation

Abstract

1 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. 2 Intravenous administration of D-sotalol (0.3 mg kg À1 ) and terfenadine (0.3 mg kg À1 ), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 3277 and 2376 ms, respectively, whereas chromanol 293B (1 mg kg À1 ), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 3378 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. 3 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. 4 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. 5 The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect druginduced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.

Comparison of Four Rate-Correction Algorisms for the Ventricular Repolarization Period in Assessing Net Effects of IKr Blockers in Dogs

“…We administered dl-sotalol and terfenadine to the halothane-anesthetized canine model, which would provide a sub-therapeutic to supratherapeutic plasma drug level (7,24). The cardiovascular effects of dl-sotalol and terfenadine have been extensively examined (7,14,18,24,25), and the present results were essentially in accordance with those previous reports. As shown in the results, the extent of changes in the MAP 90 by these drugs was greater at a slower pacing rate, indicating reverse use-dependent prolongation of the ventricular repolarization process, which would reflect the presence of I Kr blockade (9,26).…”

“…Corrected QT intervals were calculated using the formulae of Bazett , Van de Water's formula: QTc = QT − 0.087 × (RR − 1000), and Matsunaga's formula: QTc = log600 × QT / logRR, where a unit of the RR interval is given in ms. In order to assess the reliability of the corrected and uncorrected QT interval, we compared the MAP 90 values themselves or those corrected by these rate-correction formulae for the QT interval with those at a pacing cycle length of 400 ms and calculated the correlation coefficients using a linear regression analysis, as previously reported (18). We selected a pacing cycle length of 400 ms (150 beats/ min), which is relatively and constantly shorter than the sinus cycle length in the pre-drug condition (100 -140 beats / min) in this model, and enough to detect the drug-induced QT interval prolongation with high sensitivity and specificity because of the presence of reduced repolarization reserve (7 -11).…”

“…We administered two types of drugs to the model; namely, the class III antiarrhythmic dl-sotalol as a QT-prolonging and bradycardiac drug (12) and the histamine H 1 -receptor antagonist terfenadine as a QT-prolonging and transient tachycardiac drug (13,14). In order to assess the reliability of corrected and uncorrected QT interval, we compared correlations between the duration of ventricular repolarization at a fixed ventricular rate and that obtained by arithmetical correction formulae of Bazett, Fridericia, Van de Water, and Matsunaga (5, 15 -17) in addition to that without arithmetical correction according to our previous report (18). Since the morphology of the T wave may change during the ventricular pacing, we estimated the ventricular repolarization period using the monophasic action potential duration, which is reported to correlate well with the QT interval (19).…”

Effects of the Antitussive Drug Cloperastine on Ventricular Repolarization in Halothane-Anesthetized Guinea Pigs

“…However, information is limited regarding the cardiovascular effects of cloperastine. To analyze the proarrhythmic potential of cloperastine, in this study, we precisely assessed electrophysiological effects of cloperastine on the hERG K + channels expressed in HEK293 cells and the halothane-anesthetized guinea-pig heart under the monitoring of monophasic action potential (MAP) (7,10). As shown in Fig.…”

Effects of the Fluoroquinolone Antibacterial Drug Ciprofloxacin on Ventricular Repolarization in the Halothane-Anesthetized Guinea Pig

“…Halothane anesthesia has been recognized to reduce the repolarization reserve of the ventricle via inhibition of cardiac ion channels, such as I Kr or a slow component of delayed rectifier K + channels (I Ks ), allowing sufficient sensitivity for detection of drugs suspected to prolong the QT interval (15,23). In this study, moxifloxacin at 3 mg/kg slightly prolonged the QT interval by 12 ms with a C max value of 3.5 mg/ml.…”