Drug toxicity on cardiac pacemaking: A multi-scale modelling study

Drugs, such as cisapride, have to be withdrawn from clinical uses due to their side effects, i.e., cardiotoxicity. As an agonist, it can activate 5-Hydroxytryptamine 4 (5-HT4) receptors which are localized in sinoatrial node (SAN) and atrium. Our goal was to investigate the actions of cisapride alone and its combined effects with 5-HT4 receptors that impair cardiac pacemaking action potentials (APs) and their conduction using multi-scale models (the Zhang et al. models of APs of rabbit SAN cells and an anatomically detailed 2-D model of the intact SAN-atrium tissue models). At single cell level, the action of cisapride on IKr had positive chronotropic effect in the central SAN cell, but had virtually no effect on the peripheral cell. When its activation to 5-HT4 receptors was also considered, cisapride increased the pacing rate (PR) in centre SAN cell; but decreased it substantially in the periphery SAN cell. At the tissue level of the intact SAN-atrium, cisapride increased the PR and amplified the tachycardia effect of 5-HT4 receptor activation. It altered the activation sequence of cardiac excitation waves and reduced the maximum up-stroke velocity of the atrium. Moreover, early afterdepolarization was observed in the atrium. Our study shed light on the mechanisms of cisapride-induced arrhythmogenesis, suggesting that 5-HT4 receptors activation should be avoided in designing new anti-arrhythmic drugs.