hypo- and hyperthermia prolonged or shortened the QTc interval, respectively, without ... in the anesthetized rabbit models of short QT and long QT syndromes.
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Abstracts
systolic, diastolic, mean arterial pressures, and pulse rate, respectively, with direct BP endpoints (N= 4 beagle dogs). Use of a cat cuff was also assessed, as recommended by the manufacturer since greater flexibility was expected to induce less tissue compression over time compared to the dog cuff. With the cat cuff there were 9%, 12%, 11%, and 7% differences observed when comparing systolic, diastolic, mean arterial pressures, and pulse rate, respectively, between the two methodologies (N= 4 beagle dogs). Data from the dog cuff were more variable than the cat cuff when compared to the direct method. HDO-BP data are more prone to sampling error and data drop compared to direct BP values. This study demonstrates that HDO-BP data are highly variable compared to direct BP values. The HDO method may not be reliable for BP measurement in a standard toxicology study. doi:10.1016/j.vascn.2013.01.016
004 Bimodel inotropic response of dl-sotalol: Cardiovascular evaluation via pressure–volume analysis in isoflurane-anesthetized beagle dogs Tomomichi Ishizakaa,b, Yukie Ueyamac, Adriana Pedraza-Toscanoc, Pam Kloepferc, Carlos del Rioc, Robert Hamlina,c a
Department of Veterinary Biosciences, the Ohio State University, Columbus, OH, USA b Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka, Japan c QTest Labs, Columbus, OH, USA Background: The pressure–volume relationship of the left ventricle obtained by inferior vena cava occlusion is well known as a useful parameter to investigate the load-independent mechanical properties of the heart. dl-Sotalol is a representative class III antiarrhythmic drug but few data describing its load-independent effects on inotropy are available. Methods: In this study, the preload recruitable stroke work (PRSW — the linear relationship between stroke work and end-diastolic volume) was assessed in beagle dogs (n=4) intravenously administered with dl-sotalol at doses of 0.1, 0.2, 0.7 and 2.0 mg/kg (0.1, 0.3, 1.0 and 3.0 mg/kg in total) using a combined micro-manometer/conductance catheter under isoflurane anesthesia. The body surface electrocardiogram, His-bundle electrogram, body blood pressure, and pulmonary artery pressure were simultaneously measured. Results: The slope of the PRSW appeared to change bi-modally during dl-sotalol administration: it tended to decrease at a low dose (−18%), but increased at a high dose (+45%). As expected, dl-sotalol decreased heart rate and prolonged the AH and QT intervals in a dose-dependent manner. Conclusion: Consistent with its β-blocking action(s), a predominantly negative inotropic response to dl-sotalol was observed at low doses. However, at higher dose-levels, it appeared to have a dominantly positive inotropic effect; this positive inotropy might be indirectly due to the electro-physiological properties of dl-sotalol (e.g., blockade). doi:10.1016/j.vascn.2013.01.017
005 IKr inhibition-induced QTc prolongation during hypo- and hyperthermia in anesthetized guinea pigs Vijay Urmaliya, Jan Verrelst, Hanne Daems, Brigitte Loenders, Ard Teisman, David J. Gallacher Safety Pharmacology Research, Translational Sciences, Janssen Research & Development, Janssen Pharmaceutica N.V., Beerse, Belgium
In vitro cardiovascular safety assessments (in particular patchclamping) have gone through an extensive debate on the effects of room versus physiological temperature. In vivo, body temperature has received much less attention. Earlier studies in house suggested that hypo- and hyperthermia prolonged or shortened the QTc interval, respectively, without any pro-arrhythmic effects. However, the effect of body temperature on IKr inhibition-induced QTc interval prolongation is unknown. The aim of this study was to characterize the cardiohemodynamic and electrophysiological effects of the IKr inhibitor (dofetilide) at low (34 °C), control (37 °C) and high (41 °C) temperatures in the anesthetized guinea-pig model. Anesthetized female guineapigs were placed on a heating plate to control their body temperature. The left carotid artery was cannulated to measure the mean arterial blood pressure (MBP), needle electrodes were attached for the recording of the surface ECG and a rectal temperature probe was used to measure the body temperature. After 30 min of stabilization, the effect of dofetilide (0.005, 0.02 and 0.08 mg/kg i.v.) on heart rate, MBP and ECG was analyzed for up to 45 min. Consistent with the findings already reported, QTc prolongation and shortening was observed at low (34 °C) and high temperatures (41 °C), respectively, during the baseline period. Compared to high temperature, low temperature dofetilide-induced (all doses) QTc prolongation was significantly higher (+23% at low temperature versus +14% at high temperature) without any arrhythmia. No effects on mean arterial pressure or QRS interval were observed. The data suggest that IKr inhibition-induced QTc prolongation was greater at low temperature. doi:10.1016/j.vascn.2013.01.018
006 Assessment of electromechanical window in the anesthetized rabbit models of short QT and long QT syndromes Vudhiporn Limprasutr, Nakkawee Saengklub, Pradtana Meedech, Anusak Kijtawornrat Chulalongkorn University, Bangkok, Thailand Torsade de pointes (TdP) and ventricular fibrillation (VF) remain a major concern for drug discovery and safety evaluation. Due to the experimental complexity of using TdP and VF as the end point, the duration of QT/QTc interval has been used as the surrogate markers for ventricular arrhythmias. It is well-known that the relationship between drug-induced TdP or VF arrhythmia and the duration of QT/QTc interval is very poor. Recently, an electromechanical window (EMW) has been proposed as a new biomarker for TdP liability in anesthetized dog and guinea pig models of acquired long QT syndrome (LQT1). However, information on EMW in LQT2 and short QT syndrome (SQTs) was exiguous. In the present study we have investigated the change of the EMW in anesthetized rabbit models of LQT2 and SQT syndromes. LQT2 was induced by intravenous infusion of dofetilide (n= 5) while SQTs was induced by infusion of pinacidil (n= 5) or nicorandil (n= 3). At baseline, QT was 179 ms, QTc(F) was 276 ms, and EMW was 7.64 ms. In response to dofetilide (10 μg/kg/min), QT and QTc(F) intervals were significantly lengthened while EMW was negative (−122 ms). Pinacidil (0.1, 0.3, 1.0 mg/kg/min) and nicorandil (0.3, 0.5, 1.0 mg/kg/min) significantly shortened QT and QTc(F) intervals and produced positive EMW in a dose-dependent manner (94 and 39 ms, respectively). Dofetilide administration induced TdP 40% while pinacidil induced VF 40%. No VF was observed with nicorandil infusion. In conclusion, EMW may be used to assess ventricular arrhythmias in addition to the current surrogate marker, QT/QTc intervals. doi:10.1016/j.vascn.2013.01.019
