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.