IN VITRO TEMPORAL cAMP AND CORTISOL RESPONSES TO ACTH BY THE NORMAL HUMAN ADRENAL GLAND

Abstract

The in vitro temporal cAMP and cortisol responses of normal human adrenocortical tissue to ACTH were evaluated. ACTH stimulated rapid increases in cAMP levels and cortisol output, however, significantly increased cAMP levels preceded steroid output only at the higher ACTH doses studied. Cortisol output plateaued with ACTH (10\p=n-\100 mIU/ml) while cAMP levels continued to increase. The findings indicate that the unitary role of cAMP as the second messenger of ACTH action in the human adrenal cannot be assumed from data derived from lower forms and that the mechanism of action of ACTH in the human may be modulated by additional factors. ACTH stimulated cAMP generation, first demonstrated in bovine adreno¬ cortical slices (Haynes 8c Berlhet 1957), precedes a rapid (3 min) increase in steroidogenesis (Grahame-Smith et al. 1967). However, modulation of this sequence has been demonstrated for at high ACTH levels increased cAMP accumulation continues even after steroidogenesis attains a maximal rate (Gra¬ hame-Smith et al. 1967; Beall 8c Sayers 1972). Further, low doses of ACTH stimulate steroidogenesis without detectable cAMP accumulation (Beall 8c Sayers 1972; Bowyer 8c Kitabchi 1974; Kitabchi et al. 1974; Sayers et al. 1974). Other factors may play a role for ACTH increases cGMP levels of mammalian (Kitabchi et al. 1974) and non-mammalian adrenals (Honn 8c Chavin 1975a).These considerations suggest that a number of factors may modulate the action of ACTH so that the unitary role of cAMP as the intracellular second mes¬ senger in the adrenal cortex may be questioned.

Calcium ion as "second messenger" in corticoidogenic action of ACTH.

“…in the presence of external Ca2+(1.2mM) (Yanagibashi et al, 1978), this is identical to the data reported by other workers (Beall and Sayers, 1972;Mackie et al, 1972;Bowyer and Kitabchi, 1974;Honn and Chavin, 1977). It has been proposed that calcium may act at the sites before and beyond cyclic AMP formation as well as a direct effect of calcium on cyclic AMP formation (Bowyer and Kitabchi, 1974).…”

“…It is generally recognized by many workers that there is a definite dissociation between ACTH effects on corticoidogenesis and cyclic AMP formation in adrenal cortex (Beall and Sayers, 1972;Mackie et al, 1972;Bowyer and Kitabchi, 1974;Sharma et al, 1976;Honn and Chavin, 1977).…”

Characterization of Adrenal Autonomy in Cushing's Syndrome: A Comparison betweenin Vivoandin VitroResponsiveness of the Adrenal Gland

“…The concentrations of ACTH used and the steroid responses measured were similar to those previously observed in normal adrenal glands and in diced adrenal tissue from breast cancer patients. Honn and Chavin (17) found that a maximally stimulatory concentration of 3 nmol/L ACTH stimulated cortisol output to levels 4-5 times higher than control values. Most previous studies with human adrenal glands obtained from patients with Cushing's syndrome showed that (partial) autonomy of the adrenal gland in vivo is generally also reflected by the functions of cells or tissues incubated in vitro, in that they become less responsive to ACTH than normal tissue (1)(2)(3)(4)(5).…”