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We compared dl-sotalol-induced electrocardiographic responses in intact dogs using a repeated-measures design among 1% halothane anesthesia, 1.5% isoflurane anesthesia with nitrous oxide (N2O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N2O or in conscious state, reflecting sympathetic nerve suppression for the atrioventricular node by halothane. Both anesthetics exhibited longer basal QRS width than conscious state, suggesting their ventricular INainhibition. Also, both anesthetics showed longer basal QT interval, QTcF and Tpeak-Tendthan conscious state, indicating their ventricular IKrinhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N2O and in conscious state, which was less great in halothane, suggesting further sympathetic nerve suppression for the atrioventricular node might be limited in halothane. dl-Sotalol prolonged QT interval and QTcF >3 times greater in either of the anesthetics than in conscious state; moreover, dl-sotalol prolonged Tpeak-Tendsimilarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N2O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward IKrsuppression. Thus, isoflurane with nitrous oxide could be useful for in vivo IKrassay like halothane.

We analyzed the effects of intravenously as well as orally administered moxifloxacin on the pharmacokinetic and electrocardiographic variables along with its torsadogenic action using the chronic atrioventricular block cynomolgus monkeys with a cross-over design. Initially, moxifloxacin was intravenously administered in doses of 60 mg/kg/2 h, 60 mg/kg/1 h and 105 mg/kg/1.75 h with an interval of >1 week (n = 3), which provided Cmaxof 19.7, 25.4 and 37.8 μg/mL, and induced torsade de pointes in 1, 0 and 3 out of 3 animals, respectively. Next, moxifloxacin was orally administered in doses of 10, 30 and 100 mg/kg with an interval of >1 week (n = 6), which provided Cmaxof 1.8, 4.2 and 8.9 μg/mL, and induced torsade de pointes in 0, 0 and 2 out of 6 animals, respectively. A close analysis of pharmacokinetic and electrocardiographic variables indicates that torsade de pointes was induced in animals that had experienced larger systemic exposure of moxifloxacin and/or greater peak QTcF, although Cmaxby itself did not necessarily reflect the incidence of torsade de pointes when its administration route was different. These findings may provide a basic guide how to use moxifloxacin in safe for patients with labile repolarization process.

Since microminipigis becoming attractive model for various cardiac electropharmacological applications, which may meet consideration of 3Rs. We characterized microminipigsby analyzing how multi-ionic channel inhibitor bepridil may affect their in situ hearts in comparison with dogs. Bepridil in doses of 0.3 and 3.0 mg/kg were intravenously administered over 10 min under halothane anesthesia (n = 4). Microminipigsmay be less sensitive for ICaTinhibition of bepridil, whereas they are more responsive to INa, IKrand IKssuppression than dogs. This information would help predict cardiovascular effects of a drug in patients with the remodeled hearts having similar electrophysiological profile to microminipigs.

It has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. We assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). Terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not induce it at all. Thus, the chronic atrioventricular block cynomolgus monkeys can be used for studying drug interaction-associated torsade de pointes, providing a non-clinical strategy to circumvent untoward drug interactions in patients specially under polypharmacy.

Information is still limited whether β-blockade may augment or attenuate the onset of torsade de pointes in patients with IKrinhibitor-induced labile repolarization process. We compared the proarrhythmic effects of d-sotalol with those of dl-sotalol using the chronic atrioventricular block dogs, since d- and l-isomers share a similar blocking action on IKrbut β-blocking activity resides only in l-isomer. dl-Sotalol (3 mg/kg, p.o.) induced torsade de pointes in 3 out of 4 animals, whereas d-sotalol (3 mg/kg, p.o.) induced it in only 1 out of 4 animals. Thus, β-blockade can augment torsadogenic action of IKrinhibitor.

We assessed torsadogenic action of risperidone, which can potently inhibit IKras well as α1-adrenoceptor. A toxic dose of 3 mg/kg of risperidone was intravenously administered over 10 min to chronic atrioventricular block dogs without anesthesia with monitoring Holter electrocardiogram (n = 4). Risperidone increased atrial/ventricular rate for 1–12 h/1–6 h and prolonged QTcF at 6 h after its administration, whereas it did not increase short-term variability of repolarization or induced torsade de pointes. These results suggest that α1-adrenoceptor blockade-dependent, hypotension-induced, reflex-mediated increase of sympathetic tone by risperidone might play a role in protecting the heart from IKrinhibition-associated torsade de pointes.

We studied the impact of mechanically regulated, expiratory negative airway pressure (ENAP) ventilation on pulmonary and systemic circulation including its mechanisms and potential applications. Microminipigsweighing about 10 kg were anesthetized (n= 5). First, hemodynamic variables were evaluated without and with ENAP to approximately −16 cmH2O. ENAP significantly increased heart rate and cardiac output, but decreased right atrial, pulmonary arterial and pulmonary capillary wedge pressures. Second, the evaluation was repeated following pharmacological adrenergic blockade, modestly blunting ENAP effects. Third, fluvoxamine (10 mg/kg) was intravenously administered to intentionally induce cardiovascular collapse in the presence of adrenergic blockade. ENAP was started when systolic pressure was < 40 mmHg in the animals assigned to ENAP treatment-group. Fluvoxamine induced cardiovascular collapse within 4 out of 5 animals. ENAP increased systolic pressure to > 50 mmHg (n= 2): both animals fully recovered without neurological deficit, whereas without ENAP both animals died of cardiac arrest (n= 2). ENAP may become an innovative treatment for drug-induced cardiovascular collapse.

We assessed concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables using a cross-over design in intact beagle dogs (n = 4). Elevation of inhaled halothane from 1.0% to 2.0% or isoflurane from 1.5% to 2.5% decreased the mean blood pressure and prolonged the QRS width without significantly altering the heart rate, PR interval or QT interval. However, the observed changes disappeared after regressions of both anesthetic conditions to their initial settings. These results indicate that hypotension-induced, reflex-mediated increase of sympathetic tone may have counterbalanced the direct negative chronotropic, dromotropic and repolarization slowing effects of the anesthetics.