Influence of Cortisol Concentration on the Relationship Between Aldosterone Secretion Rate and Aldosterone Concentration: Modeling and Simulation Study

Presentation Number: SUN 520
Date of Presentation: April 2nd, 2017

Richard I Dorin*1, Frank K. Urban III2 and Clifford R. Qualls3
1University of New Mexico School of Medicine, Albuquerque, NM, 2Florida International University, Miami, FL, 3New Mexico Veterans Administrations Health Care System, Albuquerque, NM

Abstract

Background: Previous studies in healthy humans showed that steady-state plasma concentrations of isotopically labeled aldosterone were significantly decreased following administration of either ACTH or hydrocortisone. A putative mechanism involving cortisol-dependent increase in the metabolic clearance rate of aldosterone was proposed (1).

Hypothesis: We hypothesized that numerical modeling simultaneously accounting for secretion, elimination, and plasma protein binding for both aldosterone and cortisol would replicate cortisol-dependent variation in serum aldosterone concentration under conditions of constant aldosterone secretion.

Experimental Design: Aldosterone and cortisol secretion rates were modeled by simultaneous forward solution of 6 differential equations, reflecting secretion, free hormone elimination, and reversible binding to CBG and albumin for cortisol and aldosterone, respectively (2).

Major Results: In simulation studies, the decline in aldosterone concentration during transition from DEX suppression to maximal cortisol secretion replicated time course and magnitude of experimental findings of Zager et al.(1). The ratio of the steady state aldosterone concentration to aldosterone secretion rate was significantly decreased under conditions of (i) increased cortisol concentration, (ii) decreased CBG concentration, and (iii) higher affinity of cortisol binding to corticosteroid binding globulin (CBG). The principal variable affecting steady-state concentrations of aldosterone was related to CBG-cortisol binding.

Conclusions: (1) The correspondence between simulation and experimental data demonstrating cortisol-dependent variation in steady-state PAC provides preliminary validation for the model and selected parameters, (2) Our data support the proposed mechanism by which CBG-cortisol binding alters metabolic clearance of aldosterone, (3) The relationship between ASR and PAC was non-linear and significantly affected by cortisol concentration. (4) PAC was not a reliable surrogate for ASR. (5) In future studies, assessment of ASR by numerical modeling may provide a useful alternative to PAC, since it was less subject to bias in conditions, such as DEX suppression or ACTH stimulation, where serum concentrations of unbound CBG are highly variable.

 

Nothing to Disclose: RID, FKU III, CRQ