Isolated adrenal cortex cells: ACTH agonists, partial agonists, antagonists; cyclic AMP and corticosterone production

Abstract

Isolated adrenal cortex cells respond to the addition of ACTH 1–39 or analogs with increased production of cyclic AMP and corticosterone. It is estimated that cyclic AMP production need proceed at less than 20% of maximum to induce maximum corticosterone production. ACTH 1–24, [Lys 17, Lys 18]ACTH 1–8 amide, and ACTH 1–16 amide induce a maximum rate of cyclic AMP and of corticosterone production equal to those of ACTH 1–39. The relative potencies as determined by cyclic AMP and by corticosterone production are in excellent agreement. The analog, ACTH 5–24, induces maximum cyclic AMP production equal to 45% of that of the natural hormone, but as predicted, induces maximum corticosterone production equal to that of ACTH 1–39. The derivative, [Trp(Nps) 9]ACTH 1–39 induces 77% of maximum corticosterone production and less than 1% of maximum cyclic AMP production. The fragment ACTH 11–24 is a competitive antagonist of ACTH 1–39 for both cyclic AMP and corticosterone production. The observations on agonists, a partial agonist and a competitive antagonist are in harmony with the “second messenger” role assigned to cyclic AMP. A provisional model, based on the fit of the experimental observations to a set of equations, provides expressions of “intrinsic activity,” “receptor reserve”, “sensitivity”, and “amplification” in terms of maximum cyclic AMP production, concentration of ACTH which induces 1 2 maximum cyclic AMP production and concentration of cyclic AMP which induces 1 2 maximum corticosterone production.