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

Hypertension (Dallas, Tex. : 1979) (2013-11-06)
Jenifer M Brown, Jonathan S Williams, James M Luther, Rajesh Garg, Amanda E Garza, Luminita H Pojoga, Daniel T Ruan, Gordon H Williams, Gail K Adler, Anand Vaidya
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.

MATERIALS
Product Number
Brand
Product Description

Spironolactone, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Angiotensin II human, ≥93% (HPLC), powder
Sigma-Aldrich
Spironolactone, 97.0-103.0%
Sigma-Aldrich
Captopril, meets USP testing specifications
Sigma-Aldrich
Captopril, ≥98% (HPLC), powder
Sigma-Aldrich
Aldosterone, ≥95% (HPLC)
Supelco
Captopril, Pharmaceutical Secondary Standard; Certified Reference Material