alpha-MSH and zona glomerulosa function in the rat

The responses of rat adrenal zona glomerulosa cells to stimulation by alpha-MSH and ACTH and related peptides have been studied. The major findings were that: (1) alpha-MSH stimulated corticosterone production in glomerulosa cells from from normal animals at concentrations of about 10(-10) mol/l, but other steroids, including aldosterone, were not significantly stimulated until levels of 10(-7) mol/l were used. Peptide structure-function relationships showed that in the adrenal cortex, in contrast with other systems, ACTH 4-10 had no effect and did not block the response of glomerulosa cells to alpha-MSH, bisacetyl Ser 1-alpha-MSH, (nor-valine-12)-alpha-MSH, and ACTH 1-13 amide were equipotent with alpha-MSH, while alpha-MSH 1-10 had activity but was considerably less potent. alpha-MSH 6-13, 7-13, 8-13 and lys-11-acetyl-alpha-MSH were all inactive. N-formyl-N-epsilon-benzyloxycarbonyl alpha-MSH stimulated only at 10(-6) mol/l. (2) Normalised alpha-MSH dose-response curves for aldosterone production in glomerulosa cells from normal rats, and corticosterone in inner zone cells were coincident. In glomerulosa cells, prior sodium depletion shifts the dose-response curve for aldosterone to the left, indicating a more sensitive response, and for corticosterone to the right. Bromocriptine treatment (which depresses the level of alpha-MSH in circulating plasma) and metoclopramide (which enhances it) respectively increased and decreased the sensitivity of the response of corticosterone to alpha-MSH in subsequently incubated glomerulosa cells, but had no effect on aldosterone. (3) In contrast, normalised ACTH stimulated dose-response curves for glomerulosa corticosterone and aldosterone, and for fasciculata corticosterone production were all coincident, and were unaffected by sodium depletion, or by metoclopramide or bromocriptine pretreatment. (4) Cyclic-AMP production by glomerulosa cells was stimulated by alpha-MSH only at levels of in excess of 10(-5) mol/l, five orders of magnitude greater than required to produce significant corticosterone stimulation. Under cyclic-AMP stimulation, the normalised responses of glomerulosa corticosterone and aldosterone, and of inner zone corticosterone were all coincident. The data suggest that alpha-MSH at low concentrations (less than 10(-7) mol/l) interacts with a glomerulosa cell receptor which is distinct from the ACTH receptor but interacts with the ACTH receptor at concentrations greater than 10(-'5) mol/l. Corticosterone production is stimulated by alpha-MSH in cells from normal animals at concentrations within the normal range for circulating plasma (approximately 3 X 10(-10) mol/l), while aldosterone is stimulated by similar concentrations of alpha-MSH in cells from sodium depleted animals. The effects of sodium depletion are not modulated through changes in plasma alpha-MSH levels. At low concentrations alpha-MSH stimulation of glomerulosa cells is unlikely to be modulated by cyclic-AMP as second messenger.