Cushing's disease and hypertension: role of the renin-angiotensin-aldosterone system and effects of medical combination therapy, in vivo and in vitro studies

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 723-757-Renin-Angiotensin-Aldosterone System/Endocrine Hypertension
Bench to Bedside
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-745
Rob Van der Pas*1, Joep van Esch2, Christiaan de Bruin3, Alexander H Danser4, Alberto M. Pereira5, Pierre M J Zelissen6, Romana Netea-Maier7, Diana Sprij2, Ingrid Van den Berg-Garrelds2, Ron van Schaik2, Steven W Lamberts1, Ton van den Meiracker2, Leo J Hofland1 and Richard Abraham Feelders1
1Erasmus MC, Rotterdam, Netherlands, 2Erasmus MC, 3Erasmus Medical Center, Leiden, Netherlands, 4Erasmuc MC, Rotterdam, Netherlands, 5Leiden University Medical Center, The Netherlands, 6Univ Hosp Utrecht, Utrecht, Netherlands, 7University Medical Center St. Radboud
Context

Cushing’s disease (CD) is often accompanied by hypertension. Transsphenoidal surgery is the primary treatment of CD.

Objective

To evaluate plasma concentrations of parameters of the renin-angiotensin-aldosterone system (RAAS), endothelin-1 and NT-proBNP in patients with CD before and after medical combination therapy. Furthermore, to investigate the effects of the somatostatin analog pasireotide and the dopamine agonist cabergoline on in vitro arterial vasoconstriction.

Design

During 80 days, stepwise medical treatment was applied with pasireotide, cabergoline and ketoconazole, which suppresses adrenocortical steroidogenesis. After 80 days, patients underwent surgery or continued drug therapy. The effects on rat arterial constriction were studied using Mulvany myographs.

Setting

Four University Medical Centers in The Netherlands.

Patients

Seventeen patients with CD were included.

Main outcome measures

Blood pressure, plasma concentrations of RAAS parameters, endothelin-1, NT-proBNP and in vitro degree of vasoconstriction.

Results

At baseline, plasma concentrations of angiotensinogen were elevated, while levels of renin and aldosterone were suppressed even in patients treated with RAAS blockers. Endothelin-1 and NT-proBNP concentrations were low-normal. Systolic and diastolic blood pressure had decreased significantly after 80 days (p<0.01) and 15/17 patients reached normal cortisol concentrations, but plasma concentrations of RAAS parameters did not change. Endothelin-1 (p<0.05) and NT-proBNP (p<0.01) concentrations increased, but remained within the normal range. Angiotensinogen, renin and aldosterone were unaffected even after 4 years of remission in 9 patients.

In the presence of dexamethasone, pasireotide and octreotide inhibited the angiotensin II-mediated vasoconstriction of the iliac artery of the spontaneous hypertensive rat (p<0.05).

Conclusions

Hypertension in CD is characterized by suppressed plasma concentrations of renin, even in the presence of RAAS-blockers, and aldosterone. Despite normalization of both cortisol levels and blood pressure after short-term medical combination therapy, no changes occurred in renin and aldosterone levels. Similarly, angiotensinogen concentrations remained elevated. Finally, pasireotide may have direct blood pressure-lowering effects.

Disclosure: RAF: Clinical Researcher, Novartis Pharmaceuticals, Speaker, Novartis Pharmaceuticals. Nothing to Disclose: RV, JV, CD, AHD, AMP, PMJZ, RN, DS, IV, RV, SWL, TV, LJH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm