Telemetric recordings
Twenty-four-hour telemetric ECG and arterial pressure recordings were collected in beagle dogs. All animal experiments were subjected to ethical review (ethics committee n° CEEA-111) according to European directive 2010/63/UE on animal welfare. Reporting of experiments follows the ARRIVE guidelines (Kilkenny et al ., 2010; McGrath and Lilley, 2015). This work complies with all of the requirements of the BJP’s Declaration on Experimental Design and Analysis. In accordance with the 3Rs encouraging the reduction in the number of animals used for experimental research, experiments already recorded in the internal ERBC database from 2008 were re-analyzed for this work. These reanalyses addressed the following compounds: cisapride, dofetilide (high dose), haloperidol, moxifloxacin (high dose), quinidine, risperidone, sotalol, terfenadine and thioridazine. Experiments specifically conducted for this study addressed the following compounds: astemizole, chlorpromazine, dofetilide (low dose), droperidol, ibutilide, milrinone, moxifloxacin (high dose), pimozide, prazosin and sertindole. All animal experiments were conducted in the following conditions described thereafter. Adult (3 males and 3 females per group for former studies or 6 males per group for recent studies due to logistic reasons linked to group housing) beagle dogs (10–15 kg, 8-24 months, CEDS, Mezilles, France) were fitted with radio telemetry transmitters (TL11M2D70PCT, L11 or M11 models, Data Sciences International, Saint Paul, USA). Dogs were premedicated with acetylpromazine (0.05 mg/kg, s.c.) and buprenorphine (0.01 mg/kg, s.c.). Anaesthesia was induced by thiopental (15–20 mg/kg, i.v.) and then maintained with isoflurane 0.5–1.5% in oxygen. After left thoracotomy, one electrode was sutured directly to the left ventricular epicardium near the apex while the second electrode was sutured to the pericardium above the right atrium to approximate a limb Lead II ECG. Arterial pressure sensor was introduced via the femoral artery up to the caudal portion of the abdominal aorta. Analgesic treatment with buprenorphine/meloxicam was continued for a minimum of 2 days to alleviate any post-operative pain. A minimum period of 3 weeks was allowed for recovery from the surgery. For experiments conducted for the present study, animals were housed in pens by groups of two to four animals at maximum with playing tools. Environmental parameters were recorded continuously and maintained within a fixed range, room temperature at 15–21°C at 45–65% relative humidity. The artificial day/night cycle was 12 h light and 12 h darkness with light on at 07:30 am. Drinking water was provided ad libitum. Solid diet (300 g/animal) was given daily in the morning. All dosing with drugs was performed between 2:00 and 3:30 pm. within less than 30 minutes in each study. Arterial pressure and ECGs were recorded continuously for a minimum of 2 h before dosing up to 24 h post dose. Animals serve as their own control according to a cross-over design with a washout period of 48 to 72 hours between dosing sessions. ECG and blood pressure (BP) signals were recorded at a sampling rate of 500 Hz using ARTTMacquisition software (release 4.33, Data Sciences International, St Paul, MN, USA) or PonemahTM (release 6.33, Data Sciences International, St Paul, MN, USA).