Distribution, functional role, and signaling mechanism of adrenomedullin receptors in the rat adrenal gland.
Adrenomedullin (ADM) is a hypotensive peptide, highly expressed in the mammalian adrenal medulla, which belongs to a peptide superfamily including calcitonin gene-related peptide (CGRP) and amylin. Quantitative autoradiography demonstrated the presence of abundant [125I]ADM binding sites in both zona glomerulosa (ZG) and adrenal medulla. ADM binding was selectively displaced by ADM(22-52), a putative ADM-receptor antagonist, and CGRP(8-37), a ligand that preferentially antagonizes the CGRP1-receptor subtype. ADM concentration-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 concentration-dependently raised basal catecholamine (epinephrine and norepinephrine) release by rat adrenomedullary fragments, and again the response was blocked by both ADM(22-52) and CGRP(8-37). ADM increased cyclic-AMP release by adrenal-medulla fragments, but not capsule-ZG preparations, and the catecholamine response to ADM was abolished by the PKA inhibitor H-89. Collectively, the present findings allow us to draw the following conclusions: (1) ADM modulates rat adrenal secretion, acting through ADM(22-52)-sensitive CGRP1 receptors, which are coupled with different signaling mechanisms in the cortex and medulla; (2) ADM selectively inhibits agonist-stimulated aldosterone 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.
Mazzocchi
G
G
Department of Human Anatomy and Physiology, University of Padua, Italy.
Albertin
G
G
Andreis
P G
PG
Neri
G
G
Malendowicz
L K
LK
Champion
H C
HC
Bahçelioglu
M
M
Kadowitz
P J
PJ
Nussdorfer
G G
GG
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000313:Adrenal Medulla / Q000378:metabolism; D053607:Adrenomedullin; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D015398:Signal Transduction; D014018:Tissue Distribution; D015384:Zona Glomerulosa / Q000378:metabolism
D002395:Catecholamines; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; C104782:adrenomedullin (22-52); C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D000450:Aldosterone; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium