Treatment functional GI disease: the complex pharmacology of serotonergic drugs.

Abstract

We have read the recent review [1] on the use of serotonergic drugs in functional gut disorders with great interest and would like to comment on two aspects that may confuse the readers involved in drug development in this difficult area. First, Dr Spiller states that prolongation of the QT interval by cisapride is due to an action on cardiac 5-HT4 receptors. However, there is now consensus that the occurrence of QT prolongation and ventricular tachyarrhythmias such as torsades de pointes by cisapride is due to blockade of human ether-a-go-go-related gene K+ channels [2–5]. Cisapride may indeed trigger tachycardia and supraventricular arrhythmia through stimulation of atrial 5-HT4 receptors [6]. However, the incidence of the atrial arrhythmia is very low [7], probably because cisapride behaves as a partial agonist on the human atrium and because the density of 5-HT4 receptors in the atrium is low [8]. The lack of involvement of 5-HT4 receptors in generating QT prolongation is also supported by the failure of the selective 5-HT4 receptor antagonist {type:entrez-nucleotide,attrs:{text:GR113808,term_id:238362519,term_text:GR113808}}GR113808 [9] to modify cisapride-induced action potential prolongation in guinea-pig isolated papillary muscles. Thus, we may conclude that QT prolongation is not a class effect necessarily shared by all 5-HT4 receptor agonists and that it is possible to develop selective 5-HT4 receptor agonists with no effect on the QT interval: tegaserod may be an example [10]. In addition, it should be noticed that all 5-HT4 receptor agonists so far developed (including cisapride, prucalopride and tegaserod) are partial agonists, but only tegaserod is presented as such in Table 1 of Dr Spiller's paper. Secondly, we would like to point out that buspirone and sumatriptan are both defined as 5-HT1P receptor agonists throughout the review, whereas buspirone is a 5-HT1A receptor agonist (and also a dopamine D2 receptor antagonist) [11] and sumatriptan is the prototype 5-HT1B/D receptor agonist [12]. Sumatriptan has been extensively investigated by Dr Tack's group [13, 14] and was found to have important effects on gastric tone and perception of gastric distension [14], but the receptors involved in mediating its effects are still a matter of debate. Therefore, the fact that 5-HT1P receptors are presented as potential therapeutic targets in functional gut disorders is misleading, all the more so because 5-HT1P receptors are not included in the official IUPHAR classification of serotonin receptors [12]. We are aware that the presence of 5-HT1P receptors is reported in enteric neurones [15], but the hypothesis that sumatriptan determines its gastric motor effects in vivo through these receptors still awaits confirmation by pharmacological studies with selective antagonists. It is noteworthy, however, that a preliminary report by our group [16] showed that the gastric motor effect of sumatriptan was blocked in vivo by {type:entrez-nucleotide,attrs:{text:GR127935,term_id:238377770,term_text:GR127935}}GR127935, a selective 5-HT1B/D receptor antagonist.