title: Exendin-4, a GLP-1 receptor agonist, stimulates pituitary-adrenocortical axis in the rat: Investigations into the mechanism(s) underlying Ex4 effect.
abstract: Exendin-4 (Ex4) is a potent and long-lasting agonist of glucagon-like peptide-1 (GLP-1), which has been previously found to stimulate pituitary-adrenal axis in the rat. Aim of the present study was to gain insight into the mechanism(s) involved in the Ex4-induced rise in the rat plasma concentrations of ACTH, aldosterone and corticosterone. Preliminary time- and dose-response studies showed that the maximum stimulating effect of Ex4 occurred within 1 or 2 h and at dose ranging from 0.5 to 2.0 nmol/100 g body weight. The GLP-1 receptor (GLP-1R) antagonist Ex(9-39) did not significantly affect ACTH, aldosterone and cortico-sterone responses to Ex4. Neither the administration of CRH and arginine vasopressin (AVP)-receptor antagonists nor adrenal demedullation prevented pituitary-adrenal axis responses to Ex4. The prolonged (4 or 6 days) suppression of the pituitary ACTH release by dexamethasone impaired corticosterone, but not aldosterone response to Ex4. The following conclusions are drawn: i) Ex4 stimulates rat pituitary-adrenal axis through receptors other than the classic GLP-1R; ii) neither CRH and AVP nor medullary catecholamines are involved in the Ex4-induced stimulation of ACTH release; iii) ACTH stimulation accounts for the rise in corticosterone plasma concentration; and iv) the aldosterone secretagogue effect of Ex4 occurs via a mechanism independent of the stimulation of either ACTH or medullary catecholamines.
authors.affiliation: Department of Histology and Embryology, Karol Marcinkowski University of Medical Sciences, PL-60781 Poznan, Poland.
authors.forename: Ludwik K
authors.initials: LK
authors.lastname: Malendowicz
authors.forename: Gastone G
authors.initials: GG
authors.lastname: Nussdorfer
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Nowak
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ziolkowska
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tortorella
authors.forename: Marcin
authors.initials: M
authors.lastname: Trejter
mesh_terms: D000302:Adrenal Cortex / Q000601:surgery; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D006727:Hormone Antagonists / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists*; D013997:Time Factors; D014688:Venoms
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006727:Hormone Antagonists; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C069206:alpha helical corticotropin-releasing hormone; D001127:Arginine Vasopressin; D000450:Aldosterone; C025043:vasopressin, 1-(1-mercaptocyclohexaneacetic acid)-2-(O- methyl-L-tyrosine)-8-L-arginine-; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000077270:Exenatide; D003345:Corticosterone