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Vol. 299, Issue 3, 1007-1012, December 2001

Gastrointestinal Prokinetic Drugs have Different Affinity for the Human Cardiac Human Ether-à-gogo K+ Channel

Franck Potet, Thierry Bouyssou, Denis Escande and Isabelle Baró

Institut National de la Sante et de la Recherche Medicale U533 Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, Hôpital Hôtel-Dieu, Nantes, France (F.P., D.E., I.B.); and CHIESI SA, Center de Recherche, Trappes-Elancourt, France (T.B.)

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 Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects.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.

0022-3565/01/2993-1007$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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