Maurice Normand

Analysis through mathematical models of the dynamics of the adrenal cortical response to ACTH in the rat.

The distribution and metabolism of ACTH and the dynamics of the adrenal cortical response to this tropic hormone were characterized in the rat, through mathematical models involving data derived from experiments, where plasma corticosterone concentrations were measured following both single injections and infusions of ACTH. The models, which incorporate a previously established model of the dynamics of plasma corticosterone, were statistically validated. The simulated dynamics of the different processes linking ACTH secretion by the adenohypophysis to corticosterone secretion by the adrenal cortex include: (1) a variable MCR for plasma ACTH, modeled as the sum of a constant and a saturable degradation process; (2) the ability of the adrenal gland to secrete at a maximal rate aven after the plasma ACTH concentration has become negligible, modeled as the accumulation of an intermediary productZ directly controlled by the plasma ACTH concentration; (3) a saturable secretion with a small time constant and which, for single injections, always starts in the same fashion, modeled as a “synthesis process” whose input is a saturable function ofZ; (4) an immediate fall of the plasma corticosterone concentration at the end of the ACTH infusions, modeled as a “release process” also controlled byZ.

Studies on the dynamics of adrenocortical responses to ACTH in the rat

Abstract The transient dynamics of plasma ACTH, adrenal cyclic AMP, adrenal corticosterone and plasma corticosterone were evaluated in male Sprague-Dawley rats, whose endogenous release of ACTH had been blocked by dexamethasone: (1) 40 min after single injections of ACTH ranging from 2 to 300 ng ACTH/100 g B.W., i.V.; (2) at time intervals after single injections of 9, 37 and 300 ng ACTH/100 g B.W.; (3) during and after prolonged infusion of 4 ng ACTH/min/100 g B.W. Plasma corticosterone concentration was still at a nearly maximal level 40 min after the injection of ACTH at a dose level for which the adrenal cyclic AMP content had fallen back to a value that was scarcely above the control one; a narrow window, defined by a 2-fold increase in the dose of ACTH, represents the transition between a minimal and a maximal adrenal cyclic AMP content. The adrenal cyclic AMP transient response after injection of graded doses of ACTH increased rapidly to a peak whose amplitude was dose-dependent; the duration of the cyclic nucleotide response, however, appeared to be independent of the ACTH dose level. The adrenal corticosterone content rose rapidly, and the eventual fall was delayed by increasing doses of ACTH. The time course of the early plasma corticosterone concentrations exhibited a similar rate of increase after any dose of ACTH; in any case, a steady state whose duration was dose-dependent was eventually reached and the ensuing fall therefrom occurred at a time when the adrenal cyclic AMP had fallen to very low levels. The adrenal cyclic AMP content showed an overshoot at a time when ACTH and corticosterone had reached a constant steady state, during a prolonged infusion of ACTH; adrenal cyclic AMP stabilized during the later phase of the infusion. After removal of the infusion, plasma ACTH levels fell relatively slowly as compared with adrenal cyclic AMP, whereas corticosterone remained at a maximal level for at least 120 min. Our results, derived from experiments in vivo, support the recent proposal by Bristow et al. (1980), derived from studies in vitro, that ACTH can act via either of two types of receptor: binding to one receptor elicits steroidogenesis via cyclic AMP production whereas binding to the other receptor elicits steroidogenesis through some other mechanism.