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Drugs, such as cisapride, have to be withdrawn from clinical uses due to their side effects, i.e., cardiotoxicity.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 I_Kr 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.