Zacopride stimulates 5-HT₄ serotonin receptors in the human atrium

Zacopride (4-amino-5-chloro-2-methoxy-N-(quinuclidin-3-yl)-benzamide) is a potent agonist in human 5-HT₄ serotonin receptors in vitro and in the gastrointestinal tract. Zacopride was studied as an antiemetic drug and was intended to treat gastric diseases. Zacopride has been speculated to be useful as an antiarrhythmic agent in the human ventricle by inhibiting cardiac potassium channels. It is unknown whether zacopride is an agonist in human cardiac 5-HT₄ serotonin receptors. We tested the hypothesis that zacopride stimulates human cardiac atrial 5-HT₄ serotonin receptors. Zacopride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac-specific overexpression of human 5-HT₄ serotonin receptors (5-HT₄-TG). However, it was inactive in wild-type mouse hearts (WT). Zacopride was as effective as serotonin in raising the force of contraction and beating rate in atrial preparations of 5-HT₄-TG. Zacopride raised the force of contraction in human right atrial preparations (HAP) in the absence and presence of the phosphodiesterase III inhibitor cilostamide (1 µM). The positive inotropic effect of zacopride in HAP was attenuated by either 10 µM tropisetron or 1 µM GR125487, both of which are antagonists at 5-HT₄ serotonin receptors. These data suggest that zacopride is also an agonist at 5-HT₄ serotonin receptors in the human atrium.