Distribution, functional role, and signaling mechanism of adrenomedullin receptors in the rat adrenal gland

Adrenomedullin (ADM) is a hypotensive peptide, highly expressed in the mamm alian adrenal medulla, which belongs to a peptide superfamily including cal citonin gene-related peptide (CGRP) and amylin. Quantitative autoradiograph y demonstrated the presence of abundant [I-125]ADM binding sites in both zo na glomerulosa (ZG) and adrenal-medulla. ADM binding was selectively displa ced by ADM(22-52), a putative ADM-receptor antagonist, and CGRP(8-37), a li gand that preferentially antagonizes the CGRP1-receptor subtype. ADM concen tration-dependently inhibited K+-induced aldosterone secretion of dispersed rat ZG cells, without affecting basal hormone production. Both ADM(22-52) and CGRP(8-37) reversed the ADM effect in a concentration-dependent manner. ADM counteracted the aldosterone secretagogue action of the voltage-gated Ca2+-channel activator BAYK-8644, and blocked K+- and BAYK-8644-evoked rise in the intracellular Ca2+ concentration of dispersed ZG cells. ADM concent ration-dependently raised basal catecholamine (epinephrine and norepinephri ne) release by rat adrenomedullary fragments, and again the response was bl ocked by both ADM(22-52) and CGRP(8-37). ADM increased cyclic-AMP release b y adrenal-medulla fragments, but not capsule-ZG preparations, and the catec holamine response to ADM was abolished by the PKA inhibitor H-89. Collectiv ely, the present findings allow us to draw the following conclusions: (1) A DM modulates rat adrenal secretion, acting through ADM(22-52)-sensitive CGR P1 receptors, which are coupled with different signaling mechanisms in the cortex and medulla; (2) ADM selectively inhibits agonist-stimulated aldoste rone secretion, through a mechanism probably involving the blockade of the Ca2+ channel-mediated Ca2+ influx, (3) ADM raises catecholamine secretion, through the activation of the adenylate cyclase/PKA signaling pathway. (C) 1999 Elsevier Science Inc. All rights reserved.