Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.
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 Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects.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.
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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.
Bouyssou
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Escande
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Baró
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001549:Benzamides / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D027682:Cation Transport Proteins; D020117:Cisapride / Q000494:pharmacology; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006025:Glycosaminoglycans; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D001549:Benzamides; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; C105070:COS 8 preparation; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; D006025:Glycosaminoglycans; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D009025:Morpholines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C406662:prucalopride; C053006:renzapride; C062720:mosapride; D020117:Cisapride