Benzamide derivatives provide evidence for the involvement of a 5-HT4 receptor type in the mechanism of action of serotonin in frog adrenocortical cells.
We have previously shown that serotonin (5-HT) is a potent stimulator of corticosterone and aldosterone secretion by frog adrenocortical cells and we have demonstrated that the action of 5-HT is not mediated by the classical 5-HT receptor subtypes i.e. 5-HT1, 5-HT2 and 5-HT3. Recently, a non-classical 5-HT receptor (termed 5-HT4) has been characterized using 4-amino-5-chloro-2-methoxy-benzamide derivatives as serotonergic agonists. In the present report, we have investigated the possible involvement of the 5-HT4 receptor subtype in the mechanism of action of 5-HT on steroid secretion. Increasing concentrations of benzamide derivatives (zacopride, cisapride and BRL 24924) gave rise to a dose-related stimulation of corticosteroid production, zacopride being the most potent compound of this series to enhance steroidogenesis. Prolonged administration (230 min) of zacopride induced a rapid increase in corticosterone and aldosterone output followed by a gradual decline of corticosteroid secretion. During prolonged exposure of adrenal tissue to zacopride (10(-5) M), the corticotropic activity of 5-HT (10(-6) M) was totally abolished. The stimulatory effects of 5-HT and zacopride were abolished by the non-selective 5-HT3 antagonist ICS 205 930. In contrast methysergide, a 5-HT1 receptor antagonist, and MDL 72222, a selective 5-HT3 antagonist did not block zacopride-induced corticosteroid secretion. Both 5-HT and zacopride induced a dose-related increase in cAMP production by frog adrenal slices. Taken together, these results indicate that the stimulatory effect of 5-HT on frog adrenocortical tissue is mediated by activation of a 5-HT4 receptor subtype positively coupled to adenylate cyclase.
Idres
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S
CNRS URA 650, Unité Affiliée à l'INSERM, Université de Rouen, Mont-Saint-Aignan, France.
Delarue
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C
Lefebvre
H
H
Vaudry
H
H
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000302:Adrenal Cortex / Q000187:drug effects / Q000502:physiology*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000450:Aldosterone / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020117:Cisapride; D003345:Corticosterone / Q000096:biosynthesis / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008784:Methysergide / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011895:Rana ridibunda; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D000450:Aldosterone; C045918:2-methyl-5-HT; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C053006:renzapride; C055971:zacopride; D020117:Cisapride; D003345:Corticosterone; D008784:Methysergide