TRANSLATIONAL PHYSIOLOGY Dose-response downregulation within the span of single interpulse intervals

Keenan DM, Roelfsema F, Veldhuis JD. Dose-response downregulation within the span of single interpulse intervals. Am J Physiol Regul Integr Comp Physiol 299: R11–R18, 2010. First published April 21, 2010; doi:10.1152/ajpregu.00201.2010.—Pituitary ACTH drives adrenal glucocorticoid (cortisol) pulses via a time-delayed asymptotic dose-response process. To test the postulate that ACTH stimulates cortisol secretion dynamically (unequally during the initiation and termination of a cortisol secretory burst), a mathematical formalism was developed in which dose-response hysteretic shifts were allowed, but not required, within the time evolution of ACTHcortisol pulse pairs. A dual-waveform deconvolution model was used to quantify cortisol secretion rates and reconstruct ACTH concentration profiles in 28 healthy adults previously sampled every 10 min for 24 h in the unstressed state (8,120 measurements). ACTH concentration-cortisol secretion dose-response functions were then estimated in each subject 1) without hysteresis (base model) and with allowances for possible hysteresis in 2) ACTH potency, 3) adrenal sensitivity, and 4) ACTH efficacy. Model residual error was 40% lower in the potency and sensitivity models and 20% lower in the efficacy model than in the base model (P 0.001). Mean time shifts for inferable hysteretic inflection were model-independent, i.e., grand mean (95% confidence interval) 22 (12–39) min after the onset of a cortisol secretory burst. Half-maximally effective ACTH concentrations (EC50) differed before and after hysteretic inflection within individual pulses: 1) 9.4 and 54 ng/l in the potency model (P 0.001) and 2) 8.9 and 123 ng/l in the sensitivity model (P 0.001) compared with 16 ng/l in the no-hysteresis model (P 0.001). In the efficacy-shift model, estimated maximal ACTH drive varied by 17-fold within cortisol secretory bursts (from 22 to 1.3 nmol · l 1 ·min cortisol secretion , P 0.001). The collective results introduce the basis for modeling the dynamics of rapid, reversible physiological downregulation within the span of single interpulse intervals in vivo. This construct should have utility in parsing mechanisms of physiological regulation in other integrative systems.