title: Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis: a study in healthy volunteers.
abstract: The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands. gjacobs@chdr.nl
authors.forename: G E
authors.initials: GE
authors.lastname: Jacobs
authors.forename: E G J
authors.initials: EG
authors.lastname: Hulskotte
authors.forename: M L
authors.initials: ML
authors.lastname: de Kam
authors.forename: G
authors.initials: G
authors.lastname: Zha
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.forename: P
authors.initials: P
authors.lastname: Hu
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: van Pelt
authors.forename: J G
authors.initials: JG
authors.lastname: Goekoop
authors.forename: F G
authors.initials: FG
authors.lastname: Zitman
authors.forename: J M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism*; D014667:Vasopressins / Q000097:blood*; D055815:Young Adult
chemical_list: D014667:Vasopressins; D008787:Metoclopramide; D006854:Hydrocortisone