Effect of metoclopramide, ondansetron and granisetron on aldosterone secretion in man

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.