Phosphodiesterase III inhibitors (VIVUS)

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.

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.