Abstract
BACKGROUND AND PURPOSE
In drug research using the rat Langendorff heart preparation, it is possible to study left ventricular (LV) contractility using an
intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently
would halve animal requirements. We aimed to test the validity of this approach.
EXPERIMENTAL APPROACH
The electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents in a randomized
and blinded study.
KEY RESULTS
IVB-induced proarrhythmia was anticipated, but in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB
reduced ischaemia-induced ventricular fibrillation (VF) incidence as a trend. Repeating studies in hearts with large IZs revealed the
effect to be significant. There were no changes in QT interval or other variables that might explain the effect. Insertion of an IVB
that was minimally inflated had no effect on any variable compared with ‘no IVB’ controls. The antiarrhythmic effect of verapamil
(a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of
lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by
intracellular 31phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy.
CONCLUSIONS AND IMPLICATIONS
IVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely to be
due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach,
with implications for drug discovery and safety assessment.
In drug research using the rat Langendorff heart preparation, it is possible to study left ventricular (LV) contractility using an
intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently
would halve animal requirements. We aimed to test the validity of this approach.
EXPERIMENTAL APPROACH
The electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents in a randomized
and blinded study.
KEY RESULTS
IVB-induced proarrhythmia was anticipated, but in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB
reduced ischaemia-induced ventricular fibrillation (VF) incidence as a trend. Repeating studies in hearts with large IZs revealed the
effect to be significant. There were no changes in QT interval or other variables that might explain the effect. Insertion of an IVB
that was minimally inflated had no effect on any variable compared with ‘no IVB’ controls. The antiarrhythmic effect of verapamil
(a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of
lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by
intracellular 31phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy.
CONCLUSIONS AND IMPLICATIONS
IVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely to be
due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach,
with implications for drug discovery and safety assessment.
| Original language | English |
|---|---|
| Pages (from-to) | 39-52 |
| Number of pages | 14 |
| Journal | British Journal of Pharmacology |
| Volume | 173 |
| Issue number | 1 |
| Early online date | 17 Sept 2015 |
| DOIs | |
| Publication status | Published - 1 Jan 2016 |
