Inhibitory effect of adrenomedullin (ADM) on the aldosterone response of human adrenocortical cells to angiotensin-II: role of ADM(22-52)-sensitive receptors.
Human adrenomedullin (ADM) is a 52-amino acid hypotensive peptide, which possesses a disulfide bridge-formed six-membered ring in 16-21 position. The ring structure, and both the N- and C-terminal amino-acid sequences seem to play a key role in the vascular effects of ADM(1-52), and we have investigated whether the same is true for the inhibitory effect of this peptide on the aldosterone response of zona glomerulosa (ZG) cells to angiotensin-II (ANG-II). Autoradiography showed the presence of abundant [125I]ADM(1-52) binding sites in the ZG of human adrenals, which were displaced not only by cold ADM(1-52), but also by both ADM(13-52) and ADM(22-52); ADM fragments 1-12, 15-22 and 16-31 were ineffective. ADM(1-52) and ADM(13-52), but not other fragments, concentration-dependently inhibited ANG-II-stimulated aldosterone secretion of dispersed human adrenocortical cells. The aldosterone antisecretagogue actions of ADM(1-52) and ADM(13-52) were counteracted by ADM(22-52) in a concentration-dependent manner, while other ADM fragments were ineffective. In light of these findings the following conclusions could be drawn: (i) human ZG cells are provided with ADM(22-52)-sensitive receptors; (ii) the six-membered ring structure and the C-terminal, but not N-terminal, amino-acid sequence are both essential for ADM(1-52) to exert its antimineralocorticoid action; and probably (iii) the C-terminal sequence is needed for ADM(1-52) to bind its ZG receptors, while the ring structure is required for the receptor activation.
Belloni
A S
AS
Department of Human Anatomy, University of Padua, Padova, Italy.
Andreis
P G
PG
Rossi
G P
GP
Mingrino
A
A
Champion
H C
HC
Kadowitz
P J
PJ
Murphy
W A
WA
Coy
D H
DH
Nussdorfer
G G
GG
D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D053607:Adrenomedullin; D000328:Adult; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; C104782:adrenomedullin (22-52); D000804:Angiotensin II; D053607:Adrenomedullin; D000450:Aldosterone