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).