Positive inotropic and chronotropic effects of amisulpride via stimulation of 5-HT4 serotonin receptors in the isolated atrium from mouse and humans

Based on the chemical structure of amisulpride as a benzamide (4-amino-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-5-(ethylsulfonyl)-2-methoxy-benzamide), we hypothesized that like many other benzamides, amisulpride might be an agonist or antagonist at the human cardiac 5-HT₄ serotonin receptor. To test this hypothesis, we utilized isolated atria from transgenic adult mice with cardiac overexpression of the human 5-HT₄ serotonin receptor (5-HT₄-TG). In the presence of rolipram (100 nM, a phosphodiesterase IV inhibitor), amisulpride (10 µM) raised the force of contraction in isolated left atrial preparations and the beating rate in isolated spontaneously beating right atrial preparations from 5-HT₄-TG but not from adult wild-type mice. The positive chronotropic effects of amisulpride in right atrial preparations from 5-HT₄-TG were smaller than those of 1 µM serotonin and were reversed by 1 µM GR125487, an antagonist at the 5-HT₄ serotonin receptor. Amisulpride (10 µM) raised the force of contraction in human right atrial preparations, obtained from patients undergoing cardiac surgery, only in the presence of 100 nM cilostamide, a phosphodiesterase III inhibitor. The positive inotropic effects of amisulpride in human right atrial preparations were reversed by 1 µM GR125487. These data indeed suggest that amisulpride acts as an agonist at the human cardiac serotonin receptor.