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

Figures

• 

  Fig. 1. Comparison of structural formulae of procainamide (A), bromopride (B), metoclopramide (C), and serotonin (D). Comparison of the structural formulae of the mother compound procainamide with its derivatives metoclopramide and bromopride compared to the physiological agonist at serotonin receptors namely serotonin

• 

  Fig. 2. Mechanism(s) of action of bromopride in cardiomyocytes. Bromopride is compared here to other compounds and putative mechanisms of action of bromopride are indicated. Serotonin (5-HT) is an agonist (red arrow) at 5-HT4 receptors. Procainamide is an antagonist at cardiac sodium channels, typical of class I antiarrhythmic agents. In part, bromopride acts like procainamide. Stimulation of 5-HT4 receptors increases (black arrow) in the cardiomyocyte finally cAMP levels (Dolce et al. 2021). This cAMP not only can have a PIE but also can lead to arrhythmias (Kaumann and Sanders 1994; Dolce et al. 2021). The cAMP is degraded in human hearts mainly by phosphodiesterase III (inhibited by cilostamide) to inactive 5´-AMP. Isoprenaline increases via β-adrenoceptors (not shown but indicated by two red arrows) cAMP in the heart. GR 125487 is an antagonist at 5-HT4 receptors. Bromopride is an antagonist at dopamine D2 receptors in the brain and this explains not only the antiemetic but also Parkinson-like untoward effects (EPM) of bromopride. Metoclopramide is an agonist but also an antagonist at 5-HT4 receptors in the heart and an antagonist at dopamine D2 receptors in the brain. Stimulation of…

• 

  Fig. 3. A Summarized data for the concentration-dependent effect of cumulatively applied bromopride on force of contraction in left atrial preparations from 5-HT4-TG (squares) and WT (circles) for comparison. Ordinates plot force of contraction in millinewton (A) and in percentage of pre-drug value (CTR, B) or beating rate (C). Abscissae indicate concentrations of bromopride in decadic logarithm of molar concentrations. Significant differences are indicated with an asterisk and a number sign. Numbers in brackets mean number of experiments

• 

  Fig. 4. A Summarized data for the effect of bromopride alone or in the presence of GR125487 on force of contraction in mN or % of pre-drug value (B) in left atrial preparations from 5-HT4-TG. Significant differences are indicated with an asterisk. Points in bars mean number of experiments

• 

  Fig. 5. A Summarized data for the effect of serotonin alone or in the presence of bromopride on force of contraction in mN or % of pre-drug value (B) in left atrial preparations from 5-HT4-TG. Significant differences are indicated with an asterisk. Points in bars mean number of experiments

• 

  Fig. 6. A Summarized data for the effect of bromopride (10 µM) alone, without the presence of cilostamide. In contrast, B and C show the effect of bromopride (10 µM) with 100 nM cilostamide or in the additional presence of GR125487 (1 µM) on the force of contraction, measured in mN (B) or in % of pre-drug value (C) in human right atrial preparations. Significant differences are indicated with an asterisk. The points in bars represent the number of experiments

• 

  Fig. 7. A Summarized data for the effect of serotonin (1 µM) alone or in the presence of bromopride (10 µM) on force of contraction in mN or % of pre-drug value (B) in human right atrial preparations. Significant differences are indicated with an asterisk. Points in bars mean number of experiments