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

Bromopride, an analogue of metoclopramide, is approved in some countries to treat gastrointestinal diseases. These therapeutic effects of bromopride are explained by antagonism at D₂-dopamine receptors in the gut and the brain. We tested here the hypothesis that bromopride acts as an agonist or antagonist at the human cardiac 5-HT₄-serotonin receptors. To this end, the force of contraction (FOC) was measured in isolated human atrial preparations (HAP), in isolated left atrial preparations (LA), and in isolated spontaneously beating right atrial (RA) preparations from mice with cardiac specific overexpression of the human 5-HT₄-serotonin receptors (5-HT₄-TG). Bromopride concentration dependently increased FOC in LA from 5-HT₄-TG. The positive inotropic effect (PIE) of bromopride in LA from 5-HT₄-TG was abolished by GR125487, a 5-HT₄-serotonin receptor antagonist. Only in the presence of the phosphodiesterase III inhibitor cilostamide did bromopride raise FOC under isometric conditions in HAP. The PIE of 10 µM bromopride in HAP was extinguished by 1 µM GR125487. When serotonin had elevated FOC in HAP, additionally applied bromopride reduced FOC. These data suggest that bromopride is a partial agonist at human cardiac 5-HT₄-serotonin receptors.