Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K+ channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K+ currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC50 of 2.4 10-7 M. The IC50 value for prucalopride to block HERG (5.7 10-6 M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC50 = 1.8 10-6 M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Dec 12 2001|
ASJC Scopus subject areas
- Molecular Medicine