Proadrenomedullin-derived peptides in the paracrine control of the hypothalamo-pituitary-adrenal axis.

Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are widely distributed in various body tissues and organs, including the hypothalamo-pituitary-adrenal (HPA) axis. ADM and PAMP inhibit in vitro release of ACTH from pituitary corticotropes, and findings suggest that this effect may become relevant when an exceedingly high ACTH secretion must be counteracted. ADM directly supresses angiotensin-II- and K+-stimulated aldosterone secretion from ZG cells, acting through calcitonin gene-related peptide (CGRP) type 1 ADM(22-52)-sensitive receptors, the activation of which is likely to impair Ca2+ influx. In contrast, ADM stimulates medullary chromaffin cells to release catecholamines, which in turn enhance aldosterone secretion acting in a paracrine manner. Also this effect of ADM occurs via CGRP1 receptors, which are coupled with the adenylate cyclase-dependent cascade. There is indication that in vivo these two opposite effects of ADM on ZG may interact with each other when normal aldosterone secretion has to be restored. ADM exerts a mitogenic effect on rat ZG, acting via CGRP1 receptors that activate the tyrosine kinase-dependent mitogen-activated protein kinase cascade. These findings, along with the demonstration of a high level of ADM gene expression in adrenocortical adenomas and carcinomas, may suggest a role for ADM as adrenocortical growth stimulator and tumor promoter. PAMP, like ADM, suppresses aldosterone response of ZG cells to Ca2+-dependent agonists, but, in contrast with ADM, it inhibits catecholamine release by adrenal medulla. Both effects of PAMP are mediated by PAMP(12-20)-sensitive receptors, whose signaling mechanism is likely to involve the blockade of voltage-gated Ca2+ channels. The concentrations attained by ADM and PAMP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their content in the hypothalamo-pituitary complex and adrenal gland is consistent with a paracrine mechanism of action, which may play an important role in pathophysiological conditions where the function of the HPA axis has to be reset.