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Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.
J Pharmacol Exp Ther. 2001 Dec; 299(3):1007-12.JP

Abstract

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 Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects.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 IC(50) of 2.4 10(-7) M. The IC(50) 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 (IC(50) = 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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11714889

Citation

Potet, F, et al. "Gastrointestinal Prokinetic Drugs Have Different Affinity for the Human Cardiac Human Ether-à-gogo K(+) Channel." The Journal of Pharmacology and Experimental Therapeutics, vol. 299, no. 3, 2001, pp. 1007-12.
Potet F, Bouyssou T, Escande D, et al. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel. J Pharmacol Exp Ther. 2001;299(3):1007-12.
Potet, F., Bouyssou, T., Escande, D., & Baró, I. (2001). Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel. The Journal of Pharmacology and Experimental Therapeutics, 299(3), 1007-12.
Potet F, et al. Gastrointestinal Prokinetic Drugs Have Different Affinity for the Human Cardiac Human Ether-à-gogo K(+) Channel. J Pharmacol Exp Ther. 2001;299(3):1007-12. PubMed PMID: 11714889.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel. AU - Potet,F, AU - Bouyssou,T, AU - Escande,D, AU - Baró,I, PY - 2001/11/21/pubmed PY - 2002/1/5/medline PY - 2001/11/21/entrez SP - 1007 EP - 12 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 299 IS - 3 N2 - 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 IC(50) of 2.4 10(-7) M. The IC(50) 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 (IC(50) = 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11714889/Gastrointestinal_prokinetic_drugs_have_different_affinity_for_the_human_cardiac_human_ether_à_gogo_K_+__channel_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11714889 DB - PRIME DP - Unbound Medicine ER -