Role of adrenomedullin and related peptides in the regulation of the hypothalamo-pituitary-adrenal axis.

Adrenomedullin (ADM) is a hypotensive peptide, originally isolated from human pheochromocytomas, and then found to be widely distributed in the various body systems. ADM derives from preproadrenomedullin, a 185-amino acid residue prohormone, containing at its N-terminal a 20-amino acid sequence, named proadrenomedullin N-terminal 20 peptide (PAMP). ADM and PAMP immunoreactivities have been detected in the hypothalamo-pituitary-adrenal (HPA) axis of humans, rats, and pigs. Adrenal glands possess binding sites for both ADM and PAMP, the former being mainly of the subtype 1 of calcitonin gene-related peptide (CGRP) receptors. ADM exerts a direct inhibitory action on angiotensin II- or potassium-stimulated aldosterone secretion of zona glomerulosa cells. This effect is mediated by the CGRP1 receptor and its mechanism probably involves the blockade of Ca2+ influx. In contrast, ADM enhances aldosterone production by in situ perfused rat adrenals and human adrenal slices (containing medullary chromaffin cells), again through the activation of CGRP1 receptors. This aldosterone secretagogue effect of ADM is blocked by the beta-adrenoceptor antagonist l-alprenolol, thereby suggesting that it is indirectly mediated by the release of catecholamines by chromaffin cells. The effects of ADM on adrenal glucocorticoid release are doubtful and probably mediated by the increase in adrenal blood flow rate and the inhibition of ACTH release by pituitary corticotropes. The concentrations reached by ADM and PAMP in the blood rule out the possibility that they act on the HPA axis as circulating hormones. Conversely, their content in both adrenal and hypothalamo-pituitary complex is consistent with a paracrine mechanism of action, which may play a potentially important role in the regulation of fluid and electrolyte homeostasis.