title: Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy.
abstract: OBJECTIVE
  Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone.
  
  
  RESULTS
  Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction.
  
  
  CONCLUSIONS
  The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.
authors.affiliation: Division of Endocrinology.
authors.forename: R
authors.initials: R
authors.lastname: van der Pas
authors.forename: J H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: C
authors.initials: C
authors.lastname: de Bruin
authors.forename: A H J
authors.initials: AH
authors.lastname: Danser
authors.forename: A M
authors.initials: AM
authors.lastname: Pereira
authors.forename: P M
authors.initials: PM
authors.lastname: Zelissen
authors.forename: R
authors.initials: R
authors.lastname: Netea-Maier
authors.forename: D M
authors.initials: DM
authors.lastname: Sprij-Mooij
authors.forename: I M
authors.initials: IM
authors.lastname: van den Berg-Garrelds
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: S W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: A H
authors.initials: AH
authors.lastname: van den Meiracker
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: R A
authors.initials: RA
authors.lastname: Feelders
mesh_terms: D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood; D000808:Angiotensinogen / Q000097:blood / Q000494:pharmacology; D000818:Animals; D000077465:Cabergoline; D004873:Ergolines / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D007083:Iliac Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004873:Ergolines; D000808:Angiotensinogen; D000450:Aldosterone; D013004:Somatostatin; C517782:pasireotide; D012083:Renin; D000077465:Cabergoline