Kågström Jens, Laumola Eva-Lena, Poijes Niklas, Johansson Maria, Ericson Ann-Christin
Safety Pharmacology, Safety Assessment, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.
J Pharmacol Toxicol Methods. 2012 Jan;65(1):1-7. doi: 10.1016/j.vascn.2011.11.004. Epub 2011 Dec 8.
Anaesthetised guinea pigs are commonly used within Safety Pharmacology to evaluate drug effects on cardiac electrophysiology. However, anesthesia compromises the ability to thermoregulate, which can be further challenged when more invasive surgery is required. As anaesthetised animals are often used when screening for cardiotoxicity, thereby influencing go/no-go decisions, we wanted to quantify the impact of small temperature changes on the recorded electrophysiological parameters.
Male guinea pigs were anaesthetised by pentobarbital, placed on a pre-heated table and a rectal thermistor inserted for monitoring of body temperature. After intubation animals were vagotomised and β-blocked, and lead II ECG needle electrodes attached. Following thoracotomy an atrial pacing electrode was attached and a suction MAP electrode positioned on the ventricular epicardium. In control animals temperature was kept constant (38.1±0.1°C) over the duration of the experiment. Animals in one group were slowly warmed to 41.9°C by a heating plate and a heating lamp, and in another group slowly cooled to 34.4°C by turning off all heating equipment. MAP duration at 90% repolarisation (MAPD90), AV conduction, ECG and body temperature were recorded during cardiac pacing every 5min up to 50min.
No time-dependent changes were seen in the control group. In contrast, a linear correlation was found between changes in body temperature and MAPD90, AV conduction, QTc and QRS intervals. For each degree temperature fell below 38°C MAPD90 was prolonged by 6.1ms, and for each degree above 38°C MAPD90 was shortened by 5.3ms. Corresponding changes were seen for QTc interval and AV conduction time, while effects on the QRS interval were smaller.
The data highlights the importance of carefully controlling body temperature when performing electrophysiological recordings in laboratory animals. A change by a single degree can affect electrophysiological parameters by 5-10%, thus increasing the risk for a false positive or negative interpretation of cardiotoxicity.
