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Objective: Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at 5-HT4 receptors. The 5-HT3 antagonist tropisetron is thought to act as an antagonist at 5-HT4 receptors. In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the 5-HT4 receptor in aldosterone secretion., Methods: Following a single-blind, random design, ten normal male volunteers received one of the following regimens on three occasions, with at least 2-week intervals: metoclopramide 10 mg i.v.; tropisetron 5 mg by slow i.v.i., or; tropisetron by slow i.v.i., followed by 10 mg metoclopramide i.v., Results: In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149% of basal level and remained significantly elevated for the next 20 min. With tropisetron alone, there was a significant 37.8% drop at 60 min and the aldosterone levels remained low for the duration of the experiment. Metoclopramide reversed the decline mediated by tropisetron significantly at 30 and 90 min. Aldosterone levels after the latter regimen also did not differ significantly from baseline at any time period., Conclusion: These results would suggest the existence of a tonic stimulatory influence of 5-HT via 5-HT4 receptors on aldosterone secretion, which could be augmented by metoclopramide and blocked by tropisetron. However, the effect of tropisetron per se should be interpreted with caution given the lack of a saline group.

The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 (5-HT3&4) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i.v. in a randomised, cross-over sequence: ondansetron 8 mg, granisetron 3 mg, metoclopramide 20 mg, and saline 20 ml. Metoclopramide significantly increased the mean plasma aldosterone level to 196% of basal level at 5 min. It rose to 234% at 15 min and remained at more than 185% of basal level for the duration of the experiment. The response to ondansetron and granisetron did not differ significantly from placebo. If dopamine antagonism is discounted, the results suggest that metoclopramide-induced aldosterone secretion results from its agonist activity at 5-HT4 receptors, although slow neuronal depolarization via an unidentified receptor remains a possibility. Antagonism at the 5-HT3 receptor plays no role, as the selective antagonist, granisetron, did not elicit a significant response. It seems unlikely that the 5-HT4 receptor is the second, low affinity binding site of ondansetron, unless it had no agonist activity at this receptor.

1. The effects of the anticholinergic agent, propantheline, the opiate, codeine, and the prokinetic agent, metoclopramide, on oral-caecal transit time and on the absorption of theophylline from a sustained-release formulation were examined in six healthy male volunteers. 2. A cross-over randomised sequence design was followed, allowing at least 2 weeks interval between studies. On each occasion 500 mg theophylline in a sustained-release formulation was taken simultaneously with 2 g sulphasalazine at zero time. On three of the four occasions one of the following treatments was given concurrently at -0.5 h, +3.5 h, and +7.5 h: 30 mg codeine phosphate, 30 mg propantheline bromide, or 10 mg metoclopramide monohydrochloride. 3. The appearance of sulphapyridine in the plasma was used to assess oral-caecal transit time and the mean fraction absorbed-time profile of theophylline was calculated from serial serum theophylline concentration measurements using the Wagner-Nelson method. 4. Codeine increased the mean (s.d.) oral-caecal time (h) significantly (5.14 +/- 0.94) compared with the control value (3.78 +/- 0.34). Propantheline inhibited peristaltic contractions to such an extent that the oral-caecal transit time in five of the volunteers was between 9 and 25 h, while sulphapyridine appeared in the 9 h serum sample of the sixth. Metoclopramide did not significantly alter the oral-caecal transit time. 5. Despite the observed changes in oral-caecal transit time the rate and extent of theophylline absorption was similar with all regimens.