title: A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications.
abstract: BACKGROUND
  Desmopressin is a synthetic agonist of vasopressin receptors (AVPRs). The desmopressin stimulation test is used in the diagnosis and postsurgery prognosis of Cushing disease (CD). However, the cellular and molecular mechanisms underlying the desmopressin-induced ACTH increase in patients with CD are poorly understood.
  
  
  OBJECTIVE
  The objectives of this study were to determine, for the first time, whether desmopressin acts directly and exclusively on pituitary corticotropinoma cells to stimulate ACTH expression/release and to elucidate the cellular and molecular mechanisms involved in desmopressin-induced ACTH increase in CD.
  
  
  METHODS
  A total of 8 normal pituitaries (NPs), 23 corticotropinomas, 14 nonfunctioning pituitary adenomas, 17 somatotropinomas, and 3 prolactinomas were analyzed for AVPR expression by quantitative real-time RT-PCR. Primary cultures derived from corticotropinomas, nonfunctioning pituitary adenomas, somatotropinomas, prolactinomas, and NPs were treated with desmopressin, and ACTH secretion/expression, [Ca(2+)]i kinetics, and AVPR expression and/or proliferative response were evaluated. The relationship between AVPR expression and plasma adrenocorticotropin/cortisol levels obtained from desmopressin tests was assessed.
  
  
  RESULTS
  Desmopressin affects all functional parameters evaluated in corticotropinoma cells but not in NPs or other pituitary adenomas cells. These effects might be due to the dramatic elevation of AVPR1b expression levels found in corticotropinomas. In line with this notion, the use of an AVPR1b antagonist completely blocked desmopressin stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma adrenocorticotropin levels in corticotropinomas.
  
  
  CONCLUSIONS
  The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Campus Universitario de Rabanales, Edificio Severo Ochoa (C6), Planta 3, University of Córdoba, E-14014 Córdoba, Spain. raul.luque@uco.es.
authors.forename: R M
authors.initials: RM
authors.lastname: Luque
authors.forename: A
authors.initials: A
authors.lastname: Ibáñez-Costa
authors.forename: L M
authors.initials: LM
authors.lastname: López-Sánchez
authors.forename: L
authors.initials: L
authors.lastname: Jiménez-Reina
authors.forename: E
authors.initials: E
authors.lastname: Venegas-Moreno
authors.forename: M A
authors.initials: MA
authors.lastname: Gálvez
authors.forename: A
authors.initials: A
authors.lastname: Villa-Osaba
authors.forename: A M
authors.initials: AM
authors.lastname: Madrazo-Atutxa
authors.forename: M A
authors.initials: MA
authors.lastname: Japón
authors.forename: A
authors.initials: A
authors.lastname: de la Riva
authors.forename: D A
authors.initials: DA
authors.lastname: Cano
authors.forename: P
authors.initials: P
authors.lastname: Benito-López
authors.forename: A
authors.initials: A
authors.lastname: Soto-Moreno
authors.forename: M D
authors.initials: MD
authors.lastname: Gahete
authors.forename: A
authors.initials: A
authors.lastname: Leal-Cerro
authors.forename: J P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D000236:Adenoma / Q000097:blood / Q000175:diagnosis / Q000601:surgery; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000368:Aged; D003894:Deamino Arginine Vasopressin; D006801:Humans; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000175:diagnosis* / Q000378:metabolism* / Q000601:surgery; D010901:Pituitary Function Tests; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000097:blood / Q000175:diagnosis / Q000601:surgery; D011379:Prognosis; D017483:Receptors, Vasopressin / Q000378:metabolism*
chemical_list: D017483:Receptors, Vasopressin; D000324:Adrenocorticotropic Hormone; D003894:Deamino Arginine Vasopressin