Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro.

We have previously shown that serotonin (5-hydroxytryptamine, 5-HT) stimulate corticosterone and aldosterone secretion from perifused frog adrenal gland in vitro through activation of 5-HT4 receptors. In the present study, we have used this model to investigate the effect of newly discovered 5-HT4 receptor agonists and antagonists on corticosteroid secretion. Serotonin, the benzamide derivatives (R,S)-zacopride ((R,S)-4-amino-N-(1- azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, HCI) and its enantiomers, the azabicycloalkyl benzimidazole derivatives BIMU 1 (endo-N- (8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo- 1H-benzimidazole-1-carboxamide, HCl) and BIMU 8 (endo-N-(8-methyl-8- azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H- benzimidazole-1-carboxamide, HCl) were all capable of enhancing corticosterone and aldosterone secretion in a dose-dependent manner. Serotonin was the most potent stimulator of steroidogenesis (EC50 = 1.5 x 10(-7) M) while the potency of the benzamide and the benzimidazolone derivatives was approximately 10 times lower. The rank order of efficacy of the different 5-HT4 receptor agonists was: (S)-zacopride > BIMU 8 = (R,S)-zacopride > BIMU 1 = (R)-zacopride = 5-HT. The stimulatory effects of 5-HT and the benzimidazolone derivatives on corticosteroid secretion were not additive, suggesting that they activated the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)