Utility of an anaesthetised guinea-pig model for QT risk assessment with glucose-lowering agents

Karen Philp, Elizabeth Fantham, Nick Moore, Jean-Pierre Valentin, Chris Pollard. Safety Assessment UK, AstraZeneca R&D, Cheshire, United Kingdom.

Glucose lowering in an in vivo model can indirectly prolong ventricular repolarisation (the QT interval of the ECG); possibly a consequence of either sympathoadrenal stimulation or changes in blood potassium levels. This makes it difficult to establish whether a test compound with a primary pharmacology that leads to glucose lowering has any direct effects on ventricular repolarisation. In a guinea-pig model already shown to detect direct effects (Kågström J et al., J Pharm Tox Meth 2007, 56:186-93), we therefore tested the following hypothesis: that ventricular repolarisation in this model, in which autonomic influences had been eliminated, would be unaffected by insulin, a glucose-lowering agent unlikely to have any direct effects on ventricular repolarisation. Male guinea-pigs were anaesthetised with sodium pentobarbital (60 mg/kg i.p.) and mechanically ventilated. Animals were ß-blocked (propranolol (0.5 mg/kg)), bilaterally vagotomised and surgically prepared for the measurement of ventricular monophasic action potentials (MAP). MAP duration at 90% of repolarisation (MAPD90) was measured during left atrial pacing at 30 bpm above baseline heart rate. Animals were given a continuous, 60-minute i.v. infusion of vehicle (0.9% saline) or insulin (0.4 U/kg/min). Data are mean ± s.e.m (n = 6) and were compared with an unpaired, two-tailed t-test. Glucose levels were unchanged by vehicle (baseline 8.3 ± 1.2; end of infusion 8.4 ± 1.2 mmol/L) but significantly decreased by insulin (baseline 8.1 ± 1.0 mmol/L; end of infusion 5.0 ± 1.2 mmol/L). Neither vehicle nor insulin had a statistically significant effect on blood potassium (vehicle 4.9 ± 0.3 / 5 ± 0.5 mmol/L; insulin 4.6 ± 0.1 / 4.5 ± 0.2 mmol/L at baseline / end of infusion, respectively). Neither vehicle nor insulin had a statistically significant effect on MAPD90 (vehicle 115 ± 3 / 121 ± 4 ms; insulin 111 ± 3 / 117 ± 4 ms at baseline / end of infusion, respectively). Thus a significant insulin-induced lowering of blood glucose did not change ventricular repolarisation. This model may therefore be appropriate to assess direct effects of glucose-lowering drugs on ventricular repolarisation.