Clebopride stimulates 5-HT4-serotonin receptors in the human atrium

Clebopride resembles in its structural formula metoclopramide. Clebopride, an approved drug, is used to treat gastrointestinal diseases. Here, we tested the hypothesis that clebopride like metoclopramide acts as a partial agonist at human cardiac 5-HT₄-serotonin-receptors. Clebopride enhanced the force of contraction (FOC) in isolated, electrically stimulated (1 Hz) left atrial preparations (LA) from transgenic mice with cardiac specific overexpression of the human 5-HT₄-serotonin receptors (5-HT₄-TG). Subsequently applied GR125487 (1 µM), a specific 5-HT₄-serotonin-receptor antagonist, diminished this positive inotropic effect (PIE) of clebopride in LA from 5-HT₄-TG. Clebopride failed to heighten FOC in LA from littermate wild-type mouse hearts (WT). Clebopride augmented the beating rate in isolated right atrial preparations (RA) from 5-HT₄-TG but unable to do so in RA from WT. Clebopride alone (up to 10 µM) failed to augment FOC in isolated electrically stimulated (1Hz) human right atrial preparations (HAP) obtained during open heart surgery from adult patients with severe coronary heart disease. Interestingly, in the presence of the phosphodiesterase III inhibitor cilostamide, clebopride heightened FOC in HAP. GR125487 attenuated this PIE in HAP. Furthermore, when 1 µM serotonin had raised FOC in HAP, additionally applied 10 µM clebopride diminished FOC in HAP. We conclude that clebopride can act as an agonist and as an antagonist at 5-HT₄-serotonin receptors in the human atrium.