Background:

Metoclopramide (MCP) is a dopamine D₂-receptor antagonist, mainly used to treat post-operative or chemotherapy induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe cardiovascular especially arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels.

Methods and results:

13 hearts of New Zealand white rabbits were retrogradely perfused, while endo- and epicardial catheters were used to obtain action potential duration (APD₉₀) at seven different cycle-length between 900ms and 300ms and effective refractory period (ERP) at 500ms. After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10µM, MCP 50µM, MCP 100µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant and dose-dependent prolongation of APD₉₀ (baseline: 155.2 ± 29.1ms; MCP 10µM: 172.4 ± 22.5ms (p<0.05); MCP 50µM: 183.5  ±  23.2ms (p<0.05); MCP 100µM: 188.6 ± 19.3ms (p<0.05)) and QT-interval (baseline: 240.6 ± 39.4ms; MCP 10µM: 270.9 ± 40.5 (p<0.05); MCP 50µM: 299.0 ± 41.4ms (p<0.05); MCP 100µM: 318.9 ± 45.9ms (p<0.05)). Furthermore, the action potential configuration was changed from a rectangular configuration towards an action potential triangulation, as APD₉₀/APD₅₀-ratio was significantly augmented from 1.47±0.25 under baseline to 1.46±0.15 with MCP 10µM (p=ns.) to 1.56±0.18 under MCP 50µM (p<0.05) and 1.62±0.22 under MCP 100 µM (p<0.05). In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP (3 episodes under baseline, 7 episodes under 10µM MCP (p=0.157), 9 episodes under 50µM MCP (p=0.096), 13 episodes under 100µM MCP (p<0.05).

Conclusion:

This is the first experimental study that investigated the effect of increasing doses of metoclopramide in a sensitive whole-heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT-interval, meanwhile the number of ventricular tachycardias was significantly increased.