Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone

Abstract

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

Trial registration: ClinicalTrials.gov NCT00732160 NCT01406015 NCT01426529.

Keywords: aldosterone; calcium; parathyroid hormone; renin-angiotensin system; spironolactone; vitamin D.

Conflict of interest statement

CONFLICT OF INTEREST/DISCLOSURES: None.

Figures

Figure 1. Acute modulation of PTH with RAAS manipulation

Changes in PTH are displayed graphically as the percent change in PTH from baseline in response to either AngII infusion or ACE inhibition. Absolute values of PTH and related parameters are presented in the table below each graph. A)Study 1 (vitamin D deficient phase): The acute PTH-response to a 1 ng/kg/min infusion of AngII before and after a single dose of Captopril 25mg prior to vitamin D3 intervention. B)Study 1 (vitamin D sufficient phase): The acute PTH-response to a 1 ng/kg/min infusion of AngII before and after a single dose of Captopril 25mg after vitamin D3 intervention. C)Study 2: The acute PTH-response to a 3 ng/kg/min AngII infusion. Data are presented as means ± SEM. All comparisons are made with the visit baseline values. *p