Effects of 5-HT4-Receptor Agonists, Cisapride, Mosapride Citrate, and Zacopride, on Cardiac Action Potentials in Guinea Pig Isolated Papillary Muscles :

With regard to currently available class III agents, although their class III effect may reduce the likelihood of tachycardia initiation, their reverse use-dependent prolongation of action potential duration reduces their effectiveness during tachycardias and may even render them proarrhythmic, especially after long diastolic intervals. In contrast, agents that exhibit normal use-dependent prolongation of refractoriness hold great promise: While having relatively less effects on the normal heart beat, they could induce self-termination of a tachycardia. Prolongation of refractoriness can be achieved by lengthening of action potential duration and delaying recovery of excitability. Combination of these drug actions may yield important clinical applications.

We have previusly shown that a non-classical 5-hydroxytryptamine (5-HT4) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological characteristics of this receptor exclude the possibility that it belongs to the known 5-HT1, 5-HT2 or 5-HT3 receptor types. Here we report that this 5-HT receptor can be stimulated by 4-amino-5-chloro-2-methoxy substituted benzamide derivatives. All these compounds have been reported to be potent stimulants of gastrointestinal motility and some of them are 5-HT3 receptor antagonists. The rank order of potency of these substituted benzamide derivatives in stimulating cAMP formation was: cisapride greater than BRL 24924 greater than 5-HT greater than zacopride greater than BRL 20627 greater than metoclopramide. The non-additivity of benzamide and 5-HT activities suggests that 5-HT and the substituted benzamide derivatives act on the same receptor. Only ICS 205930, a recognized 5-HT3 receptor antagonist, competitively antagonized the stimulatory effect of cisapride, zacopride and BRL 24924. However, its pKi (6-6.3) for this new receptor was very different from its pKi for 5-HT3 receptors (pKi = 8-10). Other selective 5-HT3 receptor antagonists with an indole group (BRL 43694 and GR 38032F), with a benzoate group (cocaïne, MDL 72222) or with a piperazine group (quipazine) were ineffective in reversing the stimulatory effect of benzamide derivatives. Exposure of neuronal cells to potent agonists at this receptor such as BRL 24924 rapidly reduces its capacity to stimulate cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Since their first description five years ago, knowledge about human atrial 5-HT4 receptors has increased considerably. Progress has been facilitated by the advent of selective antagonists with high affinity for human atrial 5-HT4 receptors. The receptors have been detected in both right and left atrium where they mediate increases in contractile force. Human sinoatrial 5-HT4 receptors may mediate the tachycardia caused by 5-HT and cisapride, and 5-HT elicits arrhythmias via 5-HT4 receptors in human atrium. In this article, Alberto Kaumann suggests that 5-HT may be involved in the genesis of atrial fibrillation and associated thromboembolic stroke and that both the arrhythmia and stroke could be prevented by inhibiting 5-HT4 receptors.